raclopride and Schizophrenia

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D2 occupancy in rats using a method similar in principle to the [11C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Haloperidol; Male; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Schizophrenia

PET scan studies of regional brain energy metabolism in schizophrenia have hitherto not been consistent in demonstrating any specific perturbation in heterogenous groups of patients. In some studies there was a tendency to reduced metabolic values in several regions in chronic patients. The variance of metabolic rates also tended to be greater in the group of schizophrenic subjects, but rates for most patients overlapped with those of the controls. Studies of regional brain energy metabolism also failed to disclose consistent effects of clinical antipsychotic drug treatment in schizophrenic patients. PET measurements of dopamine receptor functions in the major basal ganglia using different radioligands for D2 dopamine receptors also gave inconsistent results. One group reporting elevated densities of D2 dopamine receptors in the major basal ganglia of drug-naive schizophrenic patients could not be confirmed. PET measurements of dopamine receptor binding demonstrated profound and selective effects of clinical antipsychotic drug treatment on D2 and D1 dopamine receptor occupancy in schizophrenic patients. All chemically different categories of antipsychotic drugs induced a substantial occupancy of D2 dopamine receptors in relation to clinical treatment. This effect has been shown to be dose dependent and fully reversible. It appears much earlier than the antipsychotic effect and it is also present in neuroleptic-resistant patients. Accordingly, neuroleptic resistance is not related to individual pharmacodynamic or pharmacokinetic factors. Drug resistance is in all probability related to heterogeneity of biologic factors causing schizophrenia. Some, but not all, of the antipsychotic drugs also induce a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 and D2 dopamine receptor blockade when given in conventional clinical doses. Further refinements of the resolution of PET scan instruments in the years to come and the development and application of new tracers will supply powerful tools for the further search for fundamental alterations of brain function in schizophrenia.

Topics: Brain; Carbon Radioisotopes; Deoxyglucose; Dopamine Antagonists; Energy Metabolism; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glucose; Humans; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Recently, two research groups published numbers for D2 receptor sites in the neostriatum of drug-naive schizophrenic patients, obtained in vivo by positron emission tomography (PET). One study appeared to confirm the increase of D2 receptor numbers, while the other study did not. A workshop was convened in Montreal to examine the reasons for the discrepancy between the results obtained by the two groups. The workshop considered patient populations, PET instrumentation and scanning methods, pharmacology, and modeling. The workshop identified differences between the approaches of the two groups that could contribute to the divergent results, including age and chronicity of the patient samples, brain region selected for study, metabolism of the different radioligands in blood and brain, reversibility of binding, PET instrumentation, and complexity of data analysis. The workshop concluded that these initial efforts had made considerable progress in establishing the role of PET in the understanding of the biochemical processes underlying mental illness. In particular, the unique ability to quantify regional neuroreceptor density at different stages in the evolution of the disease has been implemented. At the same time, the work so far and this conference served to identify the main sources contributing to the different findings from the two centers. This information will be important in designing the next phase of the research which will build upon and reconcile these apparent discrepancies.

Topics: Adult; Corpus Striatum; Haloperidol; Humans; National Institute of Mental Health (U.S.); Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology; Spiperone; Tomography, Emission-Computed; United States

Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application.. This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness.. Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns.. Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia.. JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

Topics: Adult; Antipsychotic Agents; Corpus Striatum; Female; Humans; Japan; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia; Transdermal Patch; Young Adult

Dopamine D

Topics: Adult; Antipsychotic Agents; Butyrophenones; Carbon Radioisotopes; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Middle Aged; Neostriatum; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia

Although hyperprolactinemia carries a long-term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean ± SD age = 60.2 ± 6.7 years) taking olanzapine or risperidone. Subjects underwent [¹¹C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels.. The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests.. Prolactin levels decreased following dose reduction (mean ± SD = 24.1 ± 30.2 ng/mL to 17.2 ± 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (β = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers.. Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects.. ClinicalTrials.gov identifier: NCT00716755.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Corpus Striatum; Dopamine Antagonists; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Prolactin; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D(2/3) receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D(2/3) relative receptor occupancy (RRO) on clinical outcomes in this population.. Open-label intervention.. Centre for Addiction and Mental Health, Toronto.. Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for D(2/3) RRO in dorsal putamen was assessed, using the region of interest analysis of [¹¹C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale.. Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D(2/3) RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D(2/3) RRO.. EPS diminished less than 70% D(2/3) RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

Topics: Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Functional Neuroimaging; Humans; Male; Middle Aged; Pilot Projects; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

Ziprasidone is an atypical antipsychotic recommended to be administered twice daily.. The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design.. Positron emission tomography (PET) scans with [(11)C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [(11)C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum.. Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans.. The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %).. 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298 , NCT00818298.

Topics: Adult; Antipsychotic Agents; Brain; Case-Control Studies; Dopamine Antagonists; Female; Half-Life; Humans; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Prolactin; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiazoles; Time Factors; Young Adult

Positron emission tomography (PET) is an imaging technique that provides direct measurements of receptor binding in neurons. The present study was performed to find reasons for the common observation of rapid metabolism of receptor radioligands during time of a brain PET scan. To this aim, the 1-h phase during which imaging-data are acquired was evaluated by using a pharmacokinetic approach. The values of half-lives, volumes of distribution, and dilution calculated for a set of metabolite corrected plasma curves of D2-receptor radioligand [(11)C]raclopride (PETc) during 50 min after radioligand injection in tracer dose were compared with the reference values obtained from a set of plasma curves (REFc) during 30 h after i.v. infusion of unlabelled raclopride in pharmacological doses. We found that the half-life of PETc correspond to the distribution half-life of REFc. Accordingly, the distribution volume during the terminal phase of PETc (13.6 ± 10.8 L) was significantly lower than that during the terminal phase (82.2 ± 30.5 L) and at steady state (59.4 ± 20 L) for REFc, and the dilution of raclopride in body for PETc at 50 min was 38 L, whereas it was 1015 L for REFc at 30 h. The [(11)C]raclopride in plasma at 50 min was higher (10% of dose) than the value for unlabelled raclopride at 30 h (4%). We concluded that the kinetic behavior of the radiolabelled drug [(11)C]raclopride during the 1 h time of a PET corresponds to the distribution phase. The high percentage of [(11)C]raclopride in plasma during this phase is a likely reason for the observed rapid radioligand metabolism.

Topics: Adult; Aged; Antipsychotic Agents; Brain; Case-Control Studies; Dopamine Antagonists; Female; Half-Life; Humans; Ligands; Male; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Schizophrenia; Young Adult

The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.

Topics: Adult; Apomorphine; Brain; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Ligands; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Risperidone; Schizophrenia; Young Adult

A genetic alteration in sensitivity to stress, mediated by mesolimbic hyperdopaminergia, is thought to play a role in the onset, exacerbation and relapse of schizophrenia. Dopamine sensitivity to stress was tested in individuals at higher than average genetic risk for schizophrenia (siblings of patients). Using a PET paradigm of [(11)C]raclopride in a bolus plus constant infusion tracer injection, the central DA response to acute metabolic stress (bolus of 2-Deoxy-d-Glucose, 40mg/kg) in unaffected siblings of patients with schizophrenia (n=8) and healthy controls (n=10) was measured by BP(ND) of [(11)C]raclopride before and after the 2DG challenge. After metabolic stress, controls but not siblings displayed a significant decrease in BP(ND) of [(11)C]raclopride in the striatum; no such differences were apparent in the ventral striatum. Siblings but not controls displayed significant asymmetry (L>R) in the stress-induced DA release, especially in ventral striatum, which correlated strongly with psychometric measures of psychosis liability. The results suggest that asymmetry in the mesolimbic DA response to stress is associated with genetic risk for schizophrenia, possibly reflecting the functional consequences of structural disconnectivity underlying psychotic symptoms.

Topics: Adult; Carbon Isotopes; Case-Control Studies; Corpus Striatum; Deoxyglucose; Dopamine; Dopamine Antagonists; Female; Functional Laterality; Humans; Male; Nucleus Accumbens; Positron-Emission Tomography; Psychometrics; Raclopride; Schizophrenia; Siblings; Stress, Physiological; Synaptic Transmission

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes.. To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions.. Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients.. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Twenty-three patients with schizophrenia and 23 healthy controls.. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride.. The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole.. Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzodiazepines; Benzothiazoles; Binding, Competitive; Carbon Radioisotopes; Caudate Nucleus; Clozapine; Dopamine Agonists; Dopamine Antagonists; Double-Blind Method; Female; Globus Pallidus; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Oxazines; Positron-Emission Tomography; Pramipexole; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [C]raclopride-PET study, striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions (temporal cortex: 39 ng/mL; putamen: 64 ng/mL), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzamides; Binding, Competitive; Carbon Radioisotopes; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiazoles; Time Factors; Young Adult

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Benztropine; Dopamine Antagonists; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Muscarinic Antagonists; Neostriatum; Positron-Emission Tomography; Prolactin; Prospective Studies; Psychiatric Status Rating Scales; Psychomotor Agitation; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology

Antipsychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D(2) receptors, which is thought to mediate their efficacy, has also been implicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D(2) receptor binding potential and occupancy values and adverse subjective experience.. Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D(2) receptors (determined with [(11)C]raclopride and [(11)C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment.. Higher dopamine D(2) receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relationship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values).. Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Corpus Striatum; Female; Humans; Male; Middle Aged; Olanzapine; Raclopride; Radionuclide Imaging; Receptors, Dopamine D2; Risperidone; Schizophrenia; Schizophrenic Psychology

Aripiprazole has a unique pharmacological profile that includes partial agonism at D(2) receptors, antagonism at 5-HT(2) receptors, and partial agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder.. Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635.. Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%.. Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Basal Ganglia; Basal Ganglia Diseases; Carbon Radioisotopes; Caudate Nucleus; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Psychotic Disorders; Putamen; Pyridines; Pyrimidinones; Quinolones; Raclopride; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome

Response to typical antipsychotic medication has been associated with achieving a level of striatal dopamine D2 receptor occupancy in the range of 65% to 70%. We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D2 receptor occupancy.. Eighteen patients who presented with a first episode of psychosis were randomized to receive olanzapine 5 mg daily or haloperidol 2 mg daily in a double-blind design. We acquired positron emission tomography (PET) scans using the D2 ligand [11C]raclopride within the first 15 days of treatment to determine the percentage of D2 receptors occupied by the medication. According to response, dosage was then adjusted to a maximum dosage of 20 mg daily of either drug. PET scans were repeated after 10 to 12 weeks of treatment.. At the first PET scan, the 8 olanzapine-treated patients had significantly lower D2 receptor occupancies (mean 63.4%, SD 7.3) than those observed in the 10 patients treated with haloperidol (mean 73.0%, SD 6.1). When patients were rescanned following dosage adjustment, mean D2 receptor occupancies were greater than 70% in both groups. D2 receptor occupancies did not differ significantly between the olanzapine-treated group (mean 72.0%, SD 5.7) and the haloperidol-treated group (mean 78.7%, SD 7.6).. These results suggest that, in patients being treated for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D2 receptor occupancy as are achieved with low dosages of haloperidol.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Corpus Striatum; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.. The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.. The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy.. These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.

Topics: Adult; Antipsychotic Agents; Brain; Corpus Striatum; Drug Administration Schedule; Female; Humans; Male; Piperazines; Psychotic Disorders; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Thiazoles; Tomography, Emission-Computed

11C-Raclopride is a widely used positron emission tomography (PET) tracer for measurement of striatal D2 dopamine receptor binding characteristics. Recently, 11C-raclopride has also been used for quantification of thalamic D2 receptor binding. We studied reproducibility and validity issues on the thalamic D2 binding measurements using healthy volunteer test-retest data and simulated data. Eight healthy male volunteers received 11C-raclopride as a bolus injection in a standard test-retest design using 3-dimensional PET. The displacement of thalamic 11C-raclopride binding by the D2 receptor antagonist haloperidol was studied in two female schizophrenic patients. With regards to reproducibility and reliability, thalamic 11C-raclopride binding could be described with a simplified reference tissue model resulting in binding potentials (BPs) between 0.38 and 0.66. In comparison, the model failed to describe 11C-raclopride binding consistently in temporal cortex due to low specific signal. Measurement of thalamic 11C-raclopride BP was reproducible with a test-retest variability of 7.6+/-6.2% and reliable with an intraclass correlation coefficient (ICC) of 0.87. Comparable ICCs were observed in caudate and putamen (0.84-0.96). With regard to validity, subchronic low dose haloperidol treatment reduced specific 11C-raclopride binding equally in putamen and thalamus but a higher dose induced clearly higher D2 receptor occupancy in putamen than in thalamus. Noise simulations indicated that this can partly be explained by an over-estimation of thalamic D2 receptor BP in noisy conditions (low signal, high occupancy). The D2 receptor BP in putamen was clearly more resistant to noise. We conclude that the reproducibility and reliability of thalamic 11C-raclopride BP is good and equal to, or only slightly less than, those observed in caudate or putamen. However, the signal-to-noise ratio for quantification may become too low especially in receptor occupancy-type studies, leading to an artefactual underestimation of measured D2 receptor occupancy.

Topics: Adult; Corpus Striatum; Female; Humans; Imaging, Three-Dimensional; Male; Metabolic Clearance Rate; Protein Binding; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Reproducibility of Results; Schizophrenia; Sensitivity and Specificity; Thalamus; Tissue Distribution; Tomography, Emission-Computed

Extrapyramidal side-effects (EPSE) of antipsychotic medication are related to the occupancy of dopamine D2 receptors and there appears to be a threshold of D2 occupancy below which clinically EPSE are unlikely to occur. It is unclear whether there are motor changes produced by 'subthreshold' levels of D2 occupancy that are not detectable by clinical examination. This study was designed to investigate whether a number of electromechanical instrumental techniques could detect 'subthreshold' motor changes and whether these changes correlate with dopamine D2 occupancy as measured by [11C]-raclopride PET scan. Twenty medication naïve patients were studied before and during treatment with low dose haloperidol. Instrumental techniques detected an asymmetrical worsening in motor function with drug treatment despite the failure of the group to experience significant EPSE. These changes did not correlate with D2 occupancy and measurements of rigidity, tremor, and bradykinesia did not closely inter-correlate.

Topics: Adult; Carbon Radioisotopes; Cerebellum; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Humans; Hypokinesia; Male; Motor Activity; Muscle Rigidity; Raclopride; Receptors, Dopamine D2; Schizophrenia; Schizophrenia, Paranoid; Tomography, Emission-Computed; Tremor

Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia.. In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients.. The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively.. The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Carbon Radioisotopes; Corpus Striatum; Dopamine D2 Receptor Antagonists; Double-Blind Method; Female; Haloperidol; Humans; Hyperprolactinemia; Male; Middle Aged; Raclopride; Receptors, Dopamine D2; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile.. Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose.. Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours.. Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine's low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Brain; Carbon Radioisotopes; Dibenzothiazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Tomography, Emission-Computed; Treatment Outcome

Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy.. Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy.. Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time.. Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Brain; Carbon Radioisotopes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Psychiatric Status Rating Scales; Raclopride; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Salicylamides; Schizophrenia; Schizophrenic Psychology; Spiperone; Tomography, Emission-Computed; Treatment Outcome

Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5 5 h. In the present study, we used PET to compare the time course of blockade of dopamine D2 and serotonin 5HT2 receptors of quetiapine using C11-raclopride and C11-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D2 receptors in striatum and 2 h (t[max]) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT2 receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D2 receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT2 receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D2/5HT2 occupancy. This could suggest that the combination of D2/5HT2 receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily.

Topics: Adult; Animals; Antipsychotic Agents; Area Under Curve; Brain; Carbon Radioisotopes; Dibenzothiazepines; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Half-Life; Humans; Male; Metabolic Clearance Rate; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses.. Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained.. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%.. Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Olanzapine; Pirenzepine; Prolactin; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51% +/- 10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P < 0.01), no such trend was apparent for N-[11C]methylspiperone (P > 0.09, maximal occupancy values were 2% +/- 3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.

Topics: Adult; Antipsychotic Agents; Caudate Nucleus; Cerebellum; Dibenzothiazepines; Dopamine; Dose-Response Relationship, Drug; Humans; Male; Putamen; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed

The purpose of this study was to determine the dopamine D2 receptor occupancy induced by low-dose haloperidol treatment in a prospective trial.. Seven patients with schizophrenia were treated with 2 mg/day of haloperidol for 2 weeks, and D2 receptor occupancy was measured by [11C]raclopride and positron emission tomography.. The patients showed high levels of D2 occupancy (53%-74%); five of them showed substantial clinical improvement, and none showed important side effects.. The findings demonstrate that low doses of haloperidol induce D2 receptor occupancies that are in the putative therapeutic range. In combination with recent empirical trials, these findings should encourage clinicians to initiate treatment of psychotic episodes with low (2-4 mg haloperidol equivalent) doses of typical neuroleptics, particularly for first-episode patients.

Topics: Adult; Brain; Carbon Radioisotopes; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; Male; Prospective Studies; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed

Thirty-two acutely psychotic, male schizophrenic patients received raclopride, at 2, 6, or 12 mg/day, or haloperidol, 15 mg/day for 4 weeks after randomized, double-blind assignment. Twenty-six patients, including 19 who had been assigned one of the three doses of raclopride, completed the study. Raclopride, particularly at 12 mg/day, increased CSF homovanillic acid (HVA) at 4 weeks, and plasma HVA at 2 days, of treatment. The clinical response to raclopride was significantly correlated with plasma raclopride concentrations and baseline plasma HVA concentrations. Although raclopride is a substituted benzamide with atypical properties in animals, these results suggest that the doses of raclopride required for clinical efficacy and elevation of clinical indices of brain dopamine turnover are similar.

Topics: Adult; Dopamine Antagonists; Double-Blind Method; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Psychiatric Status Rating Scales; Raclopride; Salicylamides; Schizophrenia; Schizophrenic Psychology

The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.

Topics: Acute Disease; Adult; Antipsychotic Agents; Biogenic Monoamines; Hemodynamics; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine D2; Ritanserin; Salicylamides; Schizophrenia; Schizophrenic Psychology; Serotonin; Tomography, Emission-Computed

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

Topics: Adult; Antipsychotic Agents; Arousal; Cerebral Cortex; Dopamine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electroencephalography; Evoked Potentials, Auditory; Evoked Potentials, Visual; Haloperidol; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Raclopride; Salicylamides; Schizophrenia; Schizophrenic Psychology

The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D2 and 5-HT2 receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [11C]N-methylspiperone were used to determine cortical 5-HT2 receptor occupancy in three psychotic patients treated with 125 mg, 175mg and 200mg clozapine daily. The uptake of [11C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT2 receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT2 receptor occupancy in psychotic patients at a low dose level.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine Agonists; Female; Humans; Male; Middle Aged; Prefrontal Cortex; Psychotic Disorders; Raclopride; Receptors, Serotonin; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed

Following a 4-7 day drug-free washout period, eight male inpatients took an extended-release (ER) formulation of raclopride. After the initial 8 mg dose on day 1 of the study, repeated plasma samples were collected over the ensuing 36 h. Subsequently, patients received raclopride 8 mg b.i.d. through day 7, 12 mg b.i.d. through day 14, and, if tolerated, 16 mg b.i.d. through day 21. On days 7, 14, and 21, repeated plasma samples were drawn over the 12 h following the morning dose. Relative to the previously studied immediate release form of raclopride, the ER formulation delayed and extended the absorption of raclopride, and produced lower maximum raclopride concentrations. Linear kinetics were preserved across the dose range studied. Two patients could not tolerate the highest raclopride dose because of extrapyramidal side effects.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Blood Pressure; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Humans; Male; Middle Aged; Prolactin; Psychiatric Status Rating Scales; Pulse; Raclopride; Salicylamides; Schizophrenia

The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy (p < 0.05). Patients with extrapyramidal side effects had significantly higher D2-receptor occupancy than those without (p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.

Topics: Adult; Antipsychotic Agents; Brain; Dopamine D2 Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed

This is the first comparative double-blind study of raclopride. Ninety-one patients with acute schizophrenia received either raclopride 2-8 mg twice daily or haloperidol 5-20 mg twice daily for 4 weeks. Both neuroleptics produced clinical improvements. There were no significant between-drug differences in overall efficacy measurements as assessed by the schizophrenia change sub-scale of the Comprehensive Psychopathological Rating Scale and the Krawiecka (Manchester) Rating Scale. Assessment by the Clinical Global Impression scale found haloperidol to be more effective. There were significantly fewer extrapyramidal symptoms with raclopride and a significantly lower incidence of acute dystonia. The results suggest that raclopride has an antipsychotic effect with a low incidence of extrapyramidal side effects.

Topics: Adolescent; Adult; Aged; Dopamine D2 Receptor Antagonists; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Prolactin; Raclopride; Salicylamides; Schizophrenia; Severity of Illness Index

Fifteen acutely ill patients (8 male, 7 female) aged 19 to 63 who met DSM-III criteria for schizophrenic disorder or schizophreniform disorder participated in a 4-week open trial of raclopride. The starting dose of raclopride was 2 mg increasing to 4 mg twice daily in the first week, further increments to 6 mg twice daily at day 14, and 8 mg twice daily at day 21 depending on response. Weekly assessments were made using the BPRS, Montgomery Schizophrenia Scale, Krawiecka-Goldberg Scale and Clinical Global Impression Scale. Extra-pyramidal symptoms and other side-effects were recorded weekly. Four patients failed to complete. Two were withdrawn because of clinical deterioration, and 2 others left hospital against advice after 2 weeks having shown initial improvement. Of the 11 completers, 4 were very much improved and 6 much improved; one was minimally worse. Extra-pyramidal symptoms were infrequent: 3 patients expressed occasional mild akathisia. Six patients complained of mild drowsiness. No major deviations were found in biochemical and physiological safety parameters. Plasma concentrations of raclopride were stable throughout treatment or proportional to dose changes. There was approximately a 6-fold inter-individual difference in steady-state drug concentrations. Plasma levels of prolactin increased transiently after raclopride intake to a maximum of up to 80 and 130 ng/ml in male and female patients respectively.

Topics: Acute Disease; Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Cognition; Decision Trees; Humans; Patient Acuity; Positron-Emission Tomography; Raclopride; Schizophrenia

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [

Topics: Adult; Amphetamine; Carbon Radioisotopes; Case-Control Studies; Central Nervous System Stimulants; Dextroamphetamine; Dopamine; Dopamine Agonists; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Radionuclide Imaging; Receptors, Dopamine D2; Schizophrenia

Topics: Adult; Aripiprazole; Cognition; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Memory, Short-Term; Positron-Emission Tomography; Prospective Studies; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Schizophrenic Psychology

Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo.. Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined.. Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate.. The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Apomorphine; Brain Mapping; Corpus Striatum; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Radioligand Assay; Radiopharmaceuticals; Receptors, Dopamine D2; Schizophrenia; Statistics as Topic; Young Adult

To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D. Open-label prospective PET [. A tertiary care center outpatient setting.. Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months.. Gradual reduction in their olanzapine or risperidone daily dose of up to 40%.. Clinical and cognitive assessments, and [. Reducing the antipsychotic dose resulted in an increase in D. Our findings suggest that optimizing D

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Cognitive Dysfunction; Corpus Striatum; Female; Humans; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia

Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested.. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value.. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone).. D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Brain; Carbon Radioisotopes; Chromatography, Liquid; Female; Humans; Male; Middle Aged; Olanzapine; Paliperidone Palmitate; Positron-Emission Tomography; Prospective Studies; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia; Tandem Mass Spectrometry

Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial.. The objective of this study was to examine the relationship between antipsychotic-related dopamine D. Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [. No significant relationship was found between antipsychotic-related dopamine D. Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

Topics: Adult; Antipsychotic Agents; Brain; Carbon Radioisotopes; Cross-Sectional Studies; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Schizophrenic Psychology

No study has examined dopamine D₂/₃ receptor (D₂/₃R) availability in antipsychotic-free older patients with schizophrenia.. We included patients with schizophrenia 50 years or older who were antipsychotic-free for at least 3 months. We compared non-displaceable binding potential (BPND) of [(11)C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls.. Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52).. The preliminary results suggest no differences in D₂/₃R availability between antipsychotic-free older patients with schizophrenia and controls.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Carbon Isotopes; Corpus Striatum; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia

Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS.. To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS.. An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015.. Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction.. Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels).. Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with baseline EPSs and 76.9% (10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancies were lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58% [15%] vs 72% [10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased.. Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Topics: Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Brain; Carbon Radioisotopes; Female; Humans; Male; Middle Aged; Neostriatum; Olanzapine; Positron-Emission Tomography; Prolactin; Prospective Studies; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia; Treatment Outcome

AKT1 (also known as protein kinase B, α), a serine/threonine kinase of AKT family, has been implicated in both schizophrenia and methamphetamine (Meth) use disorders. AKT1 or its protein also has epistatic effects on the regulation of dopamine-dependent behaviors or drug effects, especially in the striatum. The aim of this study is to investigate the sex-specific role of Akt1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using Akt1(-/-) mice and wild-type littermates as a model. A series of 4 Experiments were conducted. Meth-induced hyperlocomotion and Meth-related alterations of brain activity were measured. The neural properties of striatal medium spiny neurons (MSNs) were also characterized. Further, 17β-estradiol was applied to examine its protective effect in Meth-sensitized male mice. Our findings indicate that (1) Akt1(-/-) males were less sensitive to Meth-induced hyperlocomotion during Meth challenge compared with wild-type controls and Akt1(-/-) females, (2) further sex differences were revealed by coinjection of Meth with raclopride but not SCH23390 in Meth-sensitized Akt1(-/-) males, (3) Meth-induced alterations of striatal activity were confirmed in Akt1(-/-) males using microPET scan with (18)F-flurodeoxyglucose, (4) Akt1 deficiency had a significant impact on the electrophysiological and neuromorphological properties of striatal MSNs in male mice, and (5) subchronic injections of 17β-estradiol prevented the reduction of Meth-induced hyperactivity in Meth-sensitized Akt1(-/-) male mice. This study highlights a sex- and region-specific effect of Akt1 in the regulation of dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth sensitivity and schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzazepines; Disease Models, Animal; Estradiol; Estrogens; Female; Hyperkinesis; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Neostriatum; Neurons; Proto-Oncogene Proteins c-akt; Psychoses, Substance-Induced; Raclopride; Schizophrenia; Sex Factors

Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

Topics: Adult; Antipsychotic Agents; Blood-Brain Barrier; Brain; Case-Control Studies; Corpus Striatum; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tissue Distribution; Young Adult

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate.. To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration-occupancy relationship in terms of EC(50) between patients and healthy volunteers.. Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [(11)C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D(2) receptor occupancy using E (max) model and calculated EC(50).. The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC(50) was 7.6 ng/ml (95% confidence interval (CI) 6.2-9.0) in healthy volunteers and 8.6 (95% CI 7.4-9.9) in patients.. The antipsychotic concentration-occupancy relationship in patients can be estimated from the EC(50) data of healthy volunteers.

Topics: Adult; Alkaloids; Antipsychotic Agents; Binding, Competitive; Carbon Radioisotopes; Clinical Trials as Topic; Data Interpretation, Statistical; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Middle Aged; Models, Biological; Patient Selection; Positron-Emission Tomography; Protein Binding; Raclopride; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Young Adult

Topics: Adult; Antipsychotic Agents; Corpus Striatum; Dopamine; Humans; Male; Positron-Emission Tomography; Prefrontal Cortex; Raclopride; Schizophrenia; Transcranial Magnetic Stimulation

A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists.. To localize dopaminergic hyperactivity within the striatum in schizophrenia.. Case-control study.. Inpatient research unit.. Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight.. Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion.. In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum.. These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

Topics: Adult; alpha-Methyltyrosine; Brain Mapping; Carbon Radioisotopes; Case-Control Studies; Caudate Nucleus; Corpus Striatum; Dopamine; Female; Humans; Image Processing, Computer-Assisted; Male; Positron-Emission Tomography; Prefrontal Cortex; Putamen; Raclopride; Receptors, Dopamine D2; Schizophrenia; Synapses; Synaptic Transmission

Perospirone is a novel second-generation antipsychotic drug with high affinity to dopamine D(2) receptor and short half-life of plasma concentration. There has been no investigation of dopamine D(2) receptor occupancy in patients with schizophrenia and the time course of occupancy by antipsychotics with perospirone-like properties.. We investigated dopamine D(2) receptor occupancy by perospirone in patients with schizophrenia and the time course of occupancy in healthy subjects.. Six patients with schizophrenia taking 16-48 mg/day of perospirone participated. Positron emission tomography (PET) scans using [(11)C]FLB457 were performed on each subject, and dopamine D(2) receptor occupancies were calculated. Moreover, baseline and three serial PET using [(11)C]raclopride were performed at 1.5, 8, and 25.5 h after administration of a single dose of 16 mg of perospirone on four healthy male subjects, and occupancy was calculated for each scan.. Dopamine D(2) receptor occupancy in the temporal cortex of patients ranged from 39.6% to 83.8%. Especially, occupancy in two patients who took 16 mg of perospirone 2.5 h before PET was over 70%. Mean occupancy in the striatum of healthy subjects was 74.8% at 1.5 h, 60.1% at 8 h, and 31.9% at 25.5 h after administration.. Sixteen milligrams of perospirone caused over 70% dopamine D(2) receptor occupancy near its peak level, and then occupancy dropped to about half after 22 h. The time courses of receptor occupancy and plasma concentration were quite different. This single dosage may be sufficient for the treatment of schizophrenia and might be useful as a new dosing schedule choice.

Topics: Adult; Antipsychotic Agents; Binding, Competitive; Brain; Case-Control Studies; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Humans; Isoindoles; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia; Thiazoles; Time Factors

While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D(2) receptor density over 6-24 months, no study has examined the long-term stability of D(2) receptor measures in medicated patients.. Four schizophrenia patients receiving a stable dose of risperidone underwent [(11)C]raclopride positron emission tomography scans on two occasions 5-14 months apart.. Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D(2) binding potential and D(2) occupancy were good.. The finding supports the validity of quantification of D(2) receptor binding in longitudinal PET studies of medicated patients with schizophrenia.

Topics: Aged; Antipsychotic Agents; Brain; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia

It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect.. Cross-sectional.. Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Thirteen subjects aged 50 (mean +/- standard deviation age: 62 +/- 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone.. Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis.. The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%.. The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Basal Ganglia Diseases; Case-Control Studies; Cross-Sectional Studies; Dopamine Antagonists; Female; Humans; Isoxazoles; Male; Middle Aged; Ontario; Paliperidone Palmitate; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Pyrimidines; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia; Treatment Outcome

Increased responsiveness to stress plays an important role in the manifestation of schizophrenia symptoms. Evidence indicates that the prefrontal cortex (PFC), and dopamine neurotransmission in the PFC in particular, is involved in the modulation of stress responsiveness. Decreased dopaminergic activity and loss of dopamine fibres have been reported in PFC in schizophrenia patients. Consequently, it was hypothesized that depletion of dopamine in PFC may facilitate increased stress responsiveness. Adult Sprague-Dawley rats received injections of 6-hydroxydopamine or saline bilaterally into the medial PFC (mPFC) following desipramine pretreatment to selectively deplete dopaminergic fibres. Following a 3-wk recovery period, the lesioned and control rats received injections of a D1 or D2 dopamine receptor agonist or vehicle into the mPFC and were immediately subjected to forced swimming as a stressor. Results showed that frequency of locomotion and rearing, behavioural measures indicative of increased dopaminergic activity in the nucleus accumbens (NAc), were significantly increased following stress in prefrontal cortical dopamine-depleted rats. This effect was significantly ameliorated by infusions of a D1 dopamine receptor agonist directly into the mPFC in a dose-dependent manner but not by infusion of a D2 dopamine receptor agonist. In addition, stress-induced behavioural changes in prefrontal cortical dopamine-depleted rats were significantly reduced following selective discrete infusions of a D2 dopamine receptor antagonist into the NAc shell. The results suggest that dopaminergic transmission via D1 receptors in the mPFC modulates D2 dopamine receptor-mediated stress responsiveness in the NAc, a feature that may be disrupted in schizophrenia patients.

Topics: Animals; Behavior, Animal; Benzazepines; Desipramine; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Infusions, Parenteral; Injections, Intraperitoneal; Locomotion; Male; Nucleus Accumbens; Oxidopamine; Prefrontal Cortex; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Stress, Psychological; Swimming

The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018). To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029), and two of them (rs12673091, rs3735440) were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012) also displayed a significant association. The SNP7 (rs12673091) was therefore significantly associated in all three samples, and shared the same susceptibility allele (A) across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these psychiatric disorders.

Topics: Adolescent; Adult; Animals; Antimanic Agents; Asian People; Bipolar Disorder; Carbamazepine; Case-Control Studies; Dopamine Antagonists; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Hippocampus; Humans; Linkage Disequilibrium; Male; Mice; Mice, Mutant Strains; Middle Aged; Polymorphism, Single Nucleotide; Raclopride; Schizophrenia; Sensory Gating; Sp4 Transcription Factor; White People; Young Adult

Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.. In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.. Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated.. The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex.. The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.

Topics: Adult; Antipsychotic Agents; Brain Chemistry; Data Interpretation, Statistical; Delayed-Action Preparations; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Isoxazoles; Male; Neostriatum; Paliperidone Palmitate; Positron-Emission Tomography; Psychiatric Status Rating Scales; Pyrimidines; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Salicylamides; Schizophrenia

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Calcium Signaling; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunoblotting; Lisuride; MAP Kinase Signaling System; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1; Phosphorylation; Piperazines; Piperidines; Quinolones; Raclopride; Receptors, Dopamine D2; Schizophrenia; Time Factors; Transfection

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine- (0.5 mg/kg intravenously (i.v.)) induced decrease in [11C]raclopride equilibrium-specific binding (V3'') was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [11C]raclopride V3'' by 28+/-7% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [11C]raclopride V3'' was significantly enhanced (35+/-7%, p=0.002). The enhancement of the amphetamine-induced reduction in [11C]raclopride V3'' by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [11C]raclopride V3''. In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission.

Topics: Amphetamine; Animals; Brain; Bridged Bicyclo Compounds; Dopamine; Dopamine Agents; Dopamine Antagonists; Excitatory Amino Acid Agonists; Female; Male; Papio anubis; Positron-Emission Tomography; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks.. After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone.. Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy.. All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Brain; Carbon Radioisotopes; Corpus Striatum; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections; Isoxazoles; Male; Middle Aged; Paliperidone Palmitate; Positron-Emission Tomography; Prolactin; Psychotic Disorders; Pyrimidines; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D(2)-like dopamine binding using the radioligand [(11)C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D(2) binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D(2) BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D(2) BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D(2) BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D(2) BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [(11)C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Caudate Nucleus; Corpus Striatum; Dominance, Cerebral; Dopamine Antagonists; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Reference Values; Schizophrenia; Schizophrenia, Paranoid; Thalamus

Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis.. To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain.. Population-based twin cohort study.. Finland.. Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders.. Striatal dopamine D(2) receptor availability estimated with positron emission tomographic imaging and carbon 11 ((11)C)-labeled raclopride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability.. Unaffected monozygotic co-twins had increased caudate D(2) density compared with unaffected dizygotic co-twins and healthy control twins. Higher D(2) receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample.. The caudate dopamine D(2) receptor up-regulation is related to genetic risk for schizophrenia. Higher dopamine D(2) receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D(2) receptor blocking drugs.

Topics: Carbon Radioisotopes; Caudate Nucleus; Cognition Disorders; Cohort Studies; Diseases in Twins; Dopamine; Female; Finland; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia; Twins, Dizygotic; Twins, Monozygotic

Topics: Adult; Basal Ganglia; Benperidol; Carbon Radioisotopes; Clozapine; Dihydroxyphenylalanine; Dyskinesia, Drug-Induced; Fluorine Radioisotopes; Humans; Male; Raclopride; Receptors, Dopamine D2; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome; Ultrasonography

Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics.. Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone.. Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).. Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzazepines; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Many psychomotor behaviors depend on an interaction between dopamine D(1) and D(2) receptors. This study tested the hypothesis that agonist stimulation of dopamine D(1) receptors leads to the conversion of D(2) receptors from a state of high affinity for dopamine into a state of low affinity for dopamine. To test this hypothesis, dopamine was competed against [(3)H]raclopride for binding to rat and human striatal homogenates. Although the detection of high-affinity states of the dopamine D(2) receptor in rat or postmortem human striatum is normally difficult because the proportions of such sites are very low in the presence of physiological concentrations of sodium ions, the present work found that in the presence of 100 nM SCH 23390 to block D(1) receptors, a significant proportion of D(2) high-affinity sites were unmasked and readily revealed to be 10-35% of the D(2) population, illustrating the presence of a strong D(1)-D(2) link in both rat and human striata.

Topics: Adult; Aged; Animals; Benzazepines; Binding, Competitive; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Raclopride; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia

The aim of these studies was to examine whether amphetamine-induced sensitization in rats could be used as an animal model to study the basis of certain abnormalities seen in schizophrenia. Specifically, these experiments examined whether rats subjected to a sensitizing regimen of amphetamine would show the sensorimotor gating and greater amphetamine-induced displacement of radio-raclopride binding deficit that is observed in schizophrenia. In the first experiment, animals were divided into two groups with each rat receiving an intraperitoneal injection of amphetamine (AMPH) or saline (SAL) (1 ml/kg) three times per week for 3 weeks for a total of nine injections. AMPH dose was increased weekly from 1 mg/kg in the first week to 3 mg/kg in the third. Twenty-two days after the last injection, prepulse inhibition (PPI) of the acoustic startle response was tested. In addition, rats were tested for the effects of a challenge dose of 0.5 mg/kg AMPH on locomotor activity and [3H]raclopride (RAC) binding potential (BP) in the striatum. The tests for PPI confirmed that sensorimotor gating was disrupted in the AMPH-induced sensitized-state rats at baseline. The AMPH-sensitized rats also exhibited higher locomotor response to AMPH and a lower binding of striatal [3H]raclopride when challenged with the drug. The results were replicated and even more pronounced in rats that were treated with AMPH for 5 weeks, with doses ranging from 1mg/kg in the first week to 5 mg/kg in the fifth. These sensorimotor gating deficits and neurochemical (greater AMPH-induced displacement of radio-raclopride binding) abnormalities show similarities with the pathophysiology of schizophrenia and suggest that the AMPH-sensitized-state rats could be used to model certain aspects of schizophrenia.

Topics: Acoustic Stimulation; Amphetamine; Animals; Corpus Striatum; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Motor Activity; Neural Inhibition; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reflex, Startle; Schizophrenia; Sensory Thresholds

It has been suggested that transiently high dopamine-2 (D(2)) receptor occupancy by antipsychotic medication may be sufficient for inducing an antipsychotic response. We treated patients experiencing their first episode of schizophrenia with a single daily dose of quetiapine to achieve a transient daily peak of D(2) receptor blockade, to determine if this would lead to an antipsychotic response.. Fourteen patients with a DSM-IV diagnosis of schizophrenia or schizophreniform or schizoaffective disorder were treated with quetiapine titrated to a single daily dose (mean +/- SD dose at the time of the positron emission tomography [PET] scan = 427 +/- 69 mg) for 12 weeks. Peak D(2) occupancy approximately 2 hours postdose and trough D(2) occupancy approximately 20 hours postdose were determined using PET and [(11)C]raclopride. Clinical symptoms and side effects were measured at baseline and every 2 weeks during the treatment phase.. Quetiapine administration led to a mean peak D(2) occupancy of 62% +/- 10% 2 hours postdose, which declined to 14% +/- 8% approximately 20 hours postdose. Ten (71%) of 14 patients responded to treatment with quetiapine, scoring "much improved" or greater on the Clinical Global Impressions-Improvement scale. Plasma drug levels and peak D(2) occupancy were highly correlated (r = 0.84; p =.003), as were prolactin and plasma drug levels when measured 2.5 hours after drug administration (r = 0.60; p <.05). Mean weight gain for the 10 subjects who completed the 12-week study was 4.2 +/- 4.6 kg (9.3 +/- 10.2 lb). No clinically relevant motor side effects occurred during the trial.. Patients with a first episode of schizophrenia responded to treatment with a single daily dose of quetiapine despite only transiently high D(2) receptor occupancy. Our findings raise the question of whether continuously high D(2) blockade is necessary for obtaining an antipsychotic response. Future studies aimed at evaluating the relative merits of "transiently high" versus "continuously high" D(2) occupancy are warranted.

Topics: Adult; Antipsychotic Agents; Brain; Carbon Radioisotopes; Dibenzothiazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed; Treatment Outcome

Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Aripiprazole; Binding, Competitive; Brain; Cerebellum; Corpus Striatum; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Neurons; Piperazines; Quinolones; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Tomography, Emission-Computed

The prefrontal cortex plays a fundamental role in the working memory functions of the cerebral cortex and is also the site of dysfunction in several neurological and psychiatric disorders, including schizophrenia. Prefrontal neurons are distinguished by their capacity for sustained activity during the time a stimulus is held in memory, and this mnemonic response is considered a substrate for a variety of cognitive functions. The neuronal basis for sustained activity in prefrontal neurons is unknown but is thought to involve recurrent excitation among pyramidal neurons. Recent studies in awake behaving monkeys have demonstrated that the persistent activity in prefrontal neurons is modulated by dopamine. To examine the mechanisms by which dopamine might modulate transmission in local excitatory circuits, we have performed dual whole-cell recordings in connected pyramidal cell pairs with and without dopamine application. We find that dopamine reduces the efficacy of unitary excitatory neurotransmission in layer V pyramidal cells by decreasing its reliability. These effects, which are reproduced by a selective D1 agonist and blocked by a D1 antagonist, are independent of voltage changes and are not attenuated by blockade of sodium and potassium channels in the postsynaptic neurons. We conclude that attenuation of local horizontal excitatory synaptic transmission in layer V pyramidal neurons by dopamine is through D1 actions at a presynaptic site.

Topics: Animals; Benzazepines; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Postsynaptic Potentials; Ferrets; In Vitro Techniques; Patch-Clamp Techniques; Potassium Channels; Prefrontal Cortex; Presynaptic Terminals; Pyramidal Cells; Raclopride; Receptors, Dopamine D1; Schizophrenia; Sodium Channels; Synaptic Transmission; Wakefulness

The authors added haloperidol, a potent D(2) blocker, to ongoing treatment with clozapine in patients with schizophrenia to determine the effects of this combination on dopamine D(2) receptor blockade, prolactin level, and extrapyramidal side effects.. At baseline and 4-8 weeks after the addition of haloperidol (4 mg/day) to ongoing clozapine treatment, five patients were examined for prolactin elevation, extrapyramidal side effects, drug plasma levels, and D(2) receptor occupancy measured with [(11)C]raclopride and positron emission tomography imaging.. Adding haloperidol significantly increased D(2) receptor occupancy, from a mean of 55% to 79%, and significantly increased the prolactin level. One patient developed akathisia, and another manifested mild extrapyramidal side effects.. Adding a modest dose of haloperidol to clozapine results in the high D(2) receptor occupancy and sustained prolactin elevation usually associated with typical antipsychotics. These findings suggest that the lack of prolactin elevation associated with clozapine derives mainly from low D(2) receptor occupancy and not from the medication's effects on other receptors.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Corpus Striatum; Drug Therapy, Combination; Haloperidol; Humans; Male; Prolactin; Raclopride; Receptors, Dopamine D2; Schizophrenia; Tomography, Emission-Computed

The authors' goal was to test the hypothesis of extrastriatal D(2) receptor selectivity as the mechanism of action of clozapine.. Positron emission tomography (PET) was used to examine extrastriatal as well as striatal dopamine D(2) receptor occupancy in four patients treated with clozapine and three patients treated with haloperidol. The reference radioligand [(11)C]raclopride was used for determination of D(2) receptor occupancy in the striatum. The radioligand [(11)C]FLB 457 was chosen for determination of D(2) receptor occupancy in the thalamus, the temporal cortex, and the frontal cortex.. In patients treated with haloperidol the D(2) receptor occupancy was high in all examined brain regions. In clozapine-treated patients the D(2) receptor occupancy was relatively low in both the striatum and the extrastriatal regions.. The results from the present study give no support for the hypothesis of regional selectivity as the mechanism of action for clozapine.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Corpus Striatum; Female; Haloperidol; Humans; Male; Middle Aged; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenia, Paranoid; Tomography, Emission-Computed

Several studies have shown antagonism by anticholinergics of antipsychotic-induced suppression of conditioned avoidance behavior, as well as of catalepsy, in rats. These observations provide pharmacological evidence for these behaviors mediated via nigro-striatal dopaminergic projections, as well as known dopaminergic-cholinergic interactions in the neostriatum. The objective of the present study was to examine the quality of behavioral change produced by scopolamine (0.25-1.00 mgkg(-1) s.c.) on conditioned avoidance behavior, by itself, and in combination with raclopride (0.1 mgkg(-1) s.c.) in the rat. Adult male Wistar rats were trained to perform a conditioned avoidance response requiring a brightness discrimination. A two-way avoidance shuttle-box was used with the modification that there were two passages in the partition separating the two compartments of the shuttle-box. In order to make a correct avoidance in the response to white noise conditioned stimulus, the rat had to take background light into consideration. Correct passage under dim background conditions was to the left and, with increased background lights, to the right. A weak, intermittent, electric shock (approximately 0.2 mA) was used as unconditioned stimulus. Scopolamine by itself (0.25-1.00 mgkg(-1) s.c.) disrupted the visual discrimination without affecting avoidance performance. As expected, raclopride (0.1 mgkg(-1) s.c.) produced a suppression of conditioned avoidance behavior. A dose of 1.00 mgkg(-1) of scopolamine was needed to restore raclopride-induced suppression of conditioned avoidance behavior. Thus, restoration of the avoidance behavior by scopolamine treatment was not possible at doses that allow normal performance of the visual discrimination. It is concluded that anticholinergics do not restore normal behavior after neuroleptic-induced suppression of conditioned avoidance behavior.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Conditioning, Psychological; Discrimination Learning; Drug Interactions; Male; Muscarinic Antagonists; Neostriatum; Parkinson Disease; Photic Stimulation; Raclopride; Rats; Rats, Sprague-Dawley; Schizophrenia; Scopolamine

Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = -0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.

Topics: Adult; Amphetamine; Aspartic Acid; Carbon Radioisotopes; Corpus Striatum; Dopamine; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Spectroscopy; Male; Neurons; Prefrontal Cortex; Raclopride; Reference Values; Schizophrenia; Tomography, Emission-Computed

In a recent study, we demonstrated that cytochrome-c oxidase (COX), an indicator of neuronal activity, is increased in several brain regions from chronic, medicated schizophrenics. In the present study, to address the functional significance of those findings, we have measured COX activity in a group of schizophrenics in whom antemortem geriatric measures of motor, intellectual, and emotional impairment had been assessed. COX activity in the putamen was strongly negatively correlated with emotional (r = -.76; p < .005) and intellectual impairment (r = -0.76; p < .005), but not with motor impairment (r = 0.01). No significant correlations could be found in the frontal cortex, thalamus, caudate nucleus, globus pallidus, mesencephalon, or nucleus accumbens. Dopamine D2 receptor density in the putamen, measured with [3H]raclopride, was elevated in schizophrenics as compared to controls, as were Kd values. In contrast to COX activity, D2 receptor binding was moderately, but significantly positively correlated with intellectual impairment (r = 0.64; p < .05) but not with motor impairment. Results expose a unique anomaly in the effects of neuroleptics in terms of increasing neuronal signaling in the putamen, which may underlie a reversal of cognitive deficits in schizophrenics, while at the same time, elevating D2 receptor density that seems to be detrimental.

Topics: Aged; Aged, 80 and over; Electron Transport Complex IV; Emotions; Energy Metabolism; Female; Humans; Intelligence; Male; Middle Aged; Mitochondria; Putamen; Raclopride; Receptors, Dopamine D2; Reference Values; Regression Analysis; Schizophrenia; Schizophrenic Psychology

PET studies with [11C]raclopride provide an indirect measure of changes in synaptic dopamine. Previously, we used the bolus-plus-infusion (B/I) method to assess dopamine response from the percentage change in binding potential (deltaBP) before and after administration of amphetamine. The goal of this work is to optimize the measurement of changes in neurotransmitter with the B/I method by choosing the optimal timing for pre- and poststimulus scanning.. Two sources of variability in deltaBP were considered: within-subject and between-subject noise. A noise model based on a phantom study and human data was used to evaluate the within-subject noise. For between-subject noise, simulated time--activity curves were generated from measured [11C]raclopride input functions. Optimal timing to measure deltaBP was determined and applied to human data.. According to the simulation study, the optimal scan times for pre-and poststimulus scans were 39-50 and 58-100 min, respectively. The optimal timing resulted in a 28% noise reduction compared with the original timing. By applying the optimal timing to human studies, the statistical significance of the difference in deltaBP between patients with schizophrenia and healthy volunteers increased from P = 0.038 to 0.012.. Careful assessment of the sources of noise in receptor imaging studies can increase the sensitivity of the B/I method for the detection of biologic signals.

Topics: Adult; Brain; Dopamine; Dopamine Antagonists; Humans; Image Processing, Computer-Assisted; Infusions, Intravenous; Phantoms, Imaging; Raclopride; Schizophrenia; Sensitivity and Specificity; Signal Processing, Computer-Assisted; Time Factors; Tomography, Emission-Computed

Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens.. Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging.. Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine.. Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Salicylamides; Schizophrenia; Tomography, Emission-Computed

There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine A1 and dopamine D1 and between adenosine A2A and dopamine D2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine D1 receptor antagonist [125I]SCH-23982, the dopamine D2-3 receptor antagonist [3H]raclopride, the adenosine A1 receptor antagonist [3H]DPCPX and the adenosine A2A receptor antagonist [3H]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine D2-3 and adenosine A2A receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A1 receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and VH-lesioned rats.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Benzazepines; Corpus Striatum; Disease Models, Animal; Dopamine Antagonists; Female; Hippocampus; Male; Pregnancy; Purinergic P1 Receptor Antagonists; Pyrimidines; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Salicylamides; Schizophrenia; Triazoles; Xanthines

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured

Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs. Here the alpha2 adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance responding were analyzed. Idazoxan selectively potentiated the cortical output of dopamine and augmented the suppression of conditioned avoidance responding induced by raclopride. These results challenge basic assumptions underlying the dopamine hypothesis of schizophrenia and provide insight into clozapine's mode of action.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Antipsychotic Agents; Avoidance Learning; Catalepsy; Conditioning, Psychological; Corpus Striatum; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Idazoxan; Nucleus Accumbens; Prefrontal Cortex; Raclopride; Rats; Receptors, Adrenergic, alpha-2; Salicylamides; Schizophrenia

Topics: Antipsychotic Agents; Carbon Radioisotopes; Dopamine Antagonists; Humans; Raclopride; Receptors, Dopamine D2; Risperidone; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dopamine Antagonists; Female; Humans; Male; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychiatric Status Rating Scales; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Previous studies of the relationship between plasma prolactin and clinical effects in patients treated with antipsychotic drugs have yielded inconsistent results. A possible explanation may be that most studies have not included subtherapeutic or low doses of antipsychotics. In this exploratory, double-blind study, the relationship between plasma prolactin concentration and central D2 receptor occupancy was examined in 13 schizophrenic patients treated with the experimental antipsychotic drug raclopride (2, 6, or 12 mg daily). D2 receptor occupancy was determined by positron emission tomography and was related to antipsychotic effect as measured by the Brief Psychiatric Rating Scale. Plasma prolactin concentration was increased in eight of nine patients with a D2 receptor occupancy greater than 50%, whereas it was normal among patients with a D2 receptor occupancy less than 50% (p < 0.01). Plasma prolactin concentration measured 4 hours after the morning dose of raclopride correlated significantly with plasma raclopride concentration (r = 0.92, p < 0.01), the degree of D2 receptor occupancy (r = 0.81,p < 0.01), and the antipsychotic effect (r = 0.79, p < 0.01). Further controlled studies that include low doses of antipsychotic drugs may warrant a reconciliation of plasma prolactin as a useful tool in clinical monitoring of antipsychotic drug treatment.

Topics: Adult; Antipsychotic Agents; Biological Availability; Brain; Dopamine Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outflow. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D2/D3 positron-emission tomography radioligand [11C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n = 4), doubling the amphetamine dose produced a doubling in [11C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg/kg) was 44:1, demonstrating that relatively small binding changes reflect large changes in dopamine outflow. In the clinical study, patients with schizophrenia (n = 11) compared with healthy volunteers (n = 12) had significantly greater amphetamine-related reductions in [11C]raclopride specific binding (mean +/- SEM): -22.3% (+/-2.7) vs. -15.5% (+/-1.8),P = 0.04, respectively. Inferences from the preclinical study suggest that the patients' elevation in synaptic dopamine concentrations was substantially greater than controls. These data provide direct evidence for the hypothesis of elevated amphetamine-induced synaptic dopamine concentrations in schizophrenia.

Topics: Amphetamine; Animals; Carbon Radioisotopes; Corpus Striatum; Dopamine; Humans; Macaca mulatta; Microdialysis; Raclopride; Reference Values; Regression Analysis; Salicylamides; Schizophrenia; Synapses; Tomography, Emission-Computed

The binding of [3H]raclopride to particulate membrane and frozen sections (with quantitative autoradiography) from the caudate-putamen, obtained at autopsy from schizophrenic and non-schizophrenic subjects, was measured. The affinity of [3H]raclopride to particulate membrane was significantly decreased in the schizophrenic compared to non-schizophrenic subjects. The density of [3H]raclopride binding to tissue from subjects with schizophrenia was increased, unchanged or decreased depending on the methodology used. Finally, there was an age-dependent decrease in [3H]raclopride binding in the frozen sections from the caudate-putamen of the non-schizophrenic subjects. This age-dependent decrease was not apparent using particulate membrane from schizophrenic or non-schizophrenic subjects or tissue sections from the schizophrenic subjects. We conclude that the binding of [3H]raclopride is dependent on methodology and therefore data from in vitro and in vivo studies using this drug should be interpreted with caution.

Topics: Adult; Aged; Autoradiography; Brain; Caudate Nucleus; Cell Membrane; Dopamine Antagonists; Female; Humans; In Vitro Techniques; Male; Middle Aged; Protein Binding; Putamen; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia

The difference between the binding of [3H]nemonapride and [3H]raclopride has been used to quantify dopamine D4 receptors in postmortem schizophrenic brain studies. Recent work, however, has suggested that at least part of the differential between [3H]nemonapride and [3H]raclopride binding may represent sigma rather than D4 receptor sites. We applied the nemonapride-raclopride subtraction method to postmortem, non-schizophrenic human striatum to examine the variation in dopaminergic receptor binding labeled by these ligands. Variation in sigma receptor binding labeled by [3H]nemonapride was studied in frontal cortex, striatum and cerebellum. Specific binding was defined by sulpiride (dopamine receptor ligand), PPAP (sigma receptor ligand) and haloperidol (mixed dopaminergic/sigma agent), respectively. Haloperidol defined a combination of sites, which were approximately the sum of the dopaminergic and sigma components defined by sulpiride and PPAP, respectively. Significant inter-individual variation in the amount of specific binding for dopaminergic and sigma receptor sites was observed. However, no significant nor consistent observation of striatal dopamine D4 receptors or D4-like binding sites was observed in the striatum even though two independent sets of tissues, with different dissections were used. The inconsistencies in some previous postmortem studies appear to be at least partially explained by the inclusion of both sigma and dopaminergic components in [3H]nemonapride binding and the inherent high inter-individual variability of the different components.

Topics: Adult; Aged; Benzamides; Brain Chemistry; Dopamine Antagonists; Humans; In Vitro Techniques; Kinetics; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, sigma; Salicylamides; Schizophrenia

We performed a postmortem autoradiographic study to compare the density of dopamine D4-like sites in caudate putamen section from age-matched schizophrenia (n = 15) and control (n = 15) populations. The densities of the D4-like sites were estimated by subtracting the density of [3H]raclopride (binding D2 and D3 receptors) from the density of [3H]nemonapride (binding D2, D3, and D4 receptors). The findings revealed that in the schizophrenia population there was a significant increase in the binding of both [3H]nemonapride (2.3-fold) and [3H]raclopride (1.9-fold). In addition, in the schizophrenia population the density of D4-like sites was increased 2.6-fold.

Topics: Adult; Aged; Antipsychotic Agents; Autoradiography; Benzamides; Caudate Nucleus; Cerebral Cortex; Female; Humans; Male; Middle Aged; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Reference Values; Salicylamides; Schizophrenia

Antipsychotic drugs in depot formulations may prevent psychotic relapses, even after complete withdrawal. To examine the duration of drug remaining in the brain, central D2 dopamine receptor occupancy was measured with positron emission tomography for a year after discontinuation of depot neuroleptic treatment.. Four schizophrenic patients were withdrawn from low-dose treatment with haloperidol decanoate (30-50 mg every 4 weeks). They were examined repeatedly with positron emission tomography and the radioligand carbon 11-labeled raclopride during the following year. At end point, a Scatchard analysis was performed to determine the density and affinity of D2 dopamine receptors.. Occupancy of D2 dopamine receptors was highest 1 week after depot injection (66%, 77%, 82%, and 78% in 4 patients) and then decreased slowly. Six months after discontinuation of treatment, D2 dopamine receptor occupancy was 24%, 32%, and 34% in 3 patients. After 1 year, D2 dopamine receptor density and affinity in 2 patients were within the ranges of control subjects, suggesting no remaining haloperidol.. Our preliminary finding of persistence of D2 dopamine receptor occupancy indicates that commonly used doses of haloperidol decanoate (200 mg every 4 weeks) maintain antipsychotic levels of receptor occupancy even 16 weeks after discontinuation of treatment. This may explain the lower relapse rates in patients withdrawn from depot neuroleptic treatment compared with those withdrawn from oral treatment. In addition, the remaining occupancy may confound the clinical evaluation of subsequent treatments. For controlled clinical trials of new antipsychotic drugs, we suggest a minimum washout of 6 months after the last depot injection.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Brain; Delayed-Action Preparations; Dopamine Antagonists; Female; Haloperidol; Humans; Male; Mathematics; Middle Aged; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses.. Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively.. The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors.. Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

Topics: Adult; Cerebellum; Corpus Striatum; Dopamine Antagonists; Female; Fluorine Radioisotopes; Humans; Loxapine; Male; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed

The density of the presumed dopamine D4 receptor ([3H]YM-09151-2 minus [3H]raclopride), as well as the densities of the two ligands themselves were compared in various areas of cerebral tissue from normal versus schizophrenic subjects off or on antipsychotic drugs at the time of death. Using autoradiographic techniques, and analyzing various brain areas, no differences were found in the density of the D4 receptor, nor were differences found between the groups, in any brain region, in the amount of bound [3H]YM-09151-2 or [3H]raclopride. There were, therefore, no differences in the density of the D3-type receptors, including the D4 receptor, in normal and schizophrenic subjects off or on antipsychotic drugs at the time of death.

Topics: Adult; Binding, Competitive; Brain; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia

Central D2 dopamine receptor occupancy may be a useful measure to establish clinical guidelines for optimal antipsychotic drug treatment. The use of positron emission tomography (PET) to explore quantitative relationships among D2 receptor occupancy and clinical effects depends on the reliability of such measurements. The calculation of D2 receptor occupancy using [11C]raclopride is routinely based on a ratio-equilibrium analysis, in which the ratio of radioactivity concentration in the striatum to that in the cerebellum is determined. To examine the reliability of such ratios, a test-retest analysis was performed in four schizophrenic patients treated with haloperidol decanoate. PET experiments with [11C]raclopride were repeated in each subject during the same day. The putamen to cerebellum ratio (P/C ratio) ranged from 1.44 to 1.07 among the four patients, corresponding to a D2 receptor occupancy of 62 to 71%. In each subject, the P/C ratios remained highly similar, with quotients 0.98, 1.01, 1.04 and 1.06 between the two experiments. The high test-retest reproducibility of the P/C ratios indicates that measurements of D2 receptor occupancy with the present methods are highly reliable, and support the further use of PET to optimize the drug treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Binding Sites; Cerebellum; Corpus Striatum; Haloperidol; Humans; Middle Aged; Putamen; Raclopride; Receptors, Dopamine D2; Reproducibility of Results; Salicylamides; Schizophrenia; Tomography, Emission-Computed

The densities of dopamine-D4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D4 receptor binding was defined as the difference between binding sites labeled by [3H]YM-09151-2 (D2 + D3 + D4 receptors) and those by [3H]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D2 + D3 receptors). D4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 microM Gpp(NH)p to the assay significantly increased the amount of specific binding of [3H]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D2 receptor. [3H]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [3H]raclopride binding in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Caudate Nucleus; Depressive Disorder; Dopamine Antagonists; Female; GTP-Binding Proteins; Guanine Nucleotides; Guanylyl Imidodiphosphate; Humans; In Vitro Techniques; Kinetics; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Schizophrenia

Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations.. Seventeen patients treated with clozapine (125-600 mg/day) were examined with positron emission tomography (PET) and one to three of the following selective radioligands: [11C]SCH23390 (N = 11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5). Clozapine concentration in serum was determined by gas chromatography/mass spectrometry.. D2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high (84%-94%), even at low clozapine doses. Despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of PET examination, D2 receptor occupancy was low in all patients and was not described by the curvilinear relationship between serum drug concentration and receptor occupancy that has been demonstrated for classical antipsychotics.. The results confirm in an extended series of patients that clozapine is atypical with regard to degree of D2 receptor occupancy, a finding that may explain the lack of extrapyramidal side effects. The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy values is unique to clozapine. Clozapine serum concentrations have not been unequivocally shown to predict clinical effects. In this study, concentration did not predict degree of occupancy in brain. Thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients.

Topics: Adult; Benzazepines; Brain; Clozapine; Female; Humans; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Serotonin; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed; Treatment Outcome

Topics: Benzamides; Binding, Competitive; Dopamine Antagonists; Humans; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Schizophrenia

The tolerability and pharmacokinetics of raclopride extended release (ER) capsules have been evaluated after a single oral dose and at steady state, with 3 different daily doses in 4 male patients requiring neuroleptic treatment. In this 3-week open study, the drug was administered to patients in increasing bid doses of 8 mg, 12 mg and 16 mg, respectively, for each 1-week treatment period, following a 1-week placebo washout. With this limited number of patients, assessments of clinical chemistry, hematology, cardiovascular variables and adverse symptoms suggest that raclopride is safe and well-tolerated in the group studied. The administration of repeated doses of raclopride showed linear pharmacokinetics based on parameter values which are either constant (effective elimination half-life, total plasma clearance, and dose-normalized area under the plasma concentration-time curve) or varying proportionally (trough plasma concentration, peak plasma concentration, average plasma concentration and the area under the plasma concentration-time curve for a dosage interval at steady state) with the doses. The linear 1-compartment open model with zero-order absorption was the most appropriate pharmacokinetic model describing the raclopride plasma concentration profile after a single 8 mg dose of raclopride ER capsules. The ER formulation reduced the fluctuation between peak and trough plasma drug concentrations which has been reported before with instant release dosage forms. In this study, the increase of plasma prolactin concentrations above the normal limit was transient and returned to normal levels. Although the plasma prolactin concentration tended to increase with the drug dose, no direct relationship between raclopride dose and prolactin plasma concentrations was found. The correlation of plasma prolactin response with the plasma raclopride concentration showed a low level of hysteresis.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Half-Life; Humans; Male; Metabolic Clearance Rate; Prolactin; Raclopride; Salicylamides; Schizophrenia; Schizophrenic Psychology

Three independent studies have found that the density of dopamine D4-like receptors is elevated in postmortem brain striata in schizophrenia. This elevation has been questioned by a fourth study that used a different method and failed to detect a biphasic component when raclopride was used to complete against the binding of 1 nM [3H]nemonapride to schizophrenia tissue. To test whether this competition method could distinguish between dopamine D2 and D4 receptors, the present study used mixtures of only these two cloned receptors, free of all other receptors. Using combinations of cloned dopamine D2 and D4 receptors, this competition method could not resolve these components up to a level of 48% D4 receptors. Thus, the objections raised by the findings of the fourth study, mentioned above, do not appear valid. Furthermore, the present results indicate that the data using such a competition method actually mask a manyfold marked elevation in the density of dopamine D4-like receptors in schizophrenia.

Topics: Animals; Benzamides; Binding, Competitive; Dopamine Antagonists; Humans; In Vitro Techniques; Raclopride; Rats; Receptors, Dopamine; Receptors, Dopamine D2; Recombinant Proteins; Salicylamides; Schizophrenia

The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively "motor" striatum.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzamides; Corpus Striatum; Female; Humans; Male; Mental Disorders; Middle Aged; Nucleus Accumbens; Raclopride; Radioligand Assay; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Schizophrenia; Suicide; Up-Regulation

Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6-hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.

Topics: Animals; Antipsychotic Agents; Benzazepines; Cerebral Cortex; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Gene Expression Regulation; Haloperidol; Humans; Limbic System; Male; Mesencephalon; Mianserin; Models, Neurological; Oxidopamine; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Salicylamides; Schizophrenia; Serotonin; Substantia Nigra

Topics: Animals; Dopamine Antagonists; Haloperidol; Raclopride; Receptors, Dopamine D1; Salicylamides; Schizophrenia

The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.

Topics: Animals; Benzazepines; Dizocilpine Maleate; Hyperkinesis; Male; Mice; Raclopride; Receptors, Adrenergic, alpha-2; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Salicylamides; Schizophrenia; Yohimbine

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.

Topics: Autoradiography; Benzazepines; Binding Sites; Cell Count; Corpus Striatum; Culture Techniques; Humans; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Schizophrenia

Recent studies have shown the existence of a specific antagonistic interaction between adenosine A2a receptors and dopamine D2 receptors in the brain. This A2a-D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A2a-D2 interaction in the ventral striopallidal system. In the presence of the A2a agonist (2-p-carboxyethyl)phenylamino-5'-N carboxamidoadenosine, dopamine exhibited a lower efficacy in displacing the radiolabelled D2 receptor antagonist [125I]iodosulpiride from the rat ventral striatum, specially in the nucleus accumbens. A tonic dopaminergic modulation of the striopallidal neurons from the ventral striopallidal system was demonstrated by a dual-probe approach, by infusing selective dopamine agonists and antagonists in the nucleus and by measuring dopamine extracellular levels in the nucleus accumbens and GABA extracellular levels in the nucleus accumbens and in the ipsilateral ventral pallidum. The infusion of (2-p-carboxyethyl)phenylamino-5'-N-carboxamidoadenosine in the nucleus accumbens induced the same postsynaptic changes as the D2 antagonist raclopride, i.e. an increase in pallidal GABA extracellular levels, without changing those levels in the nucleus accumbens. Furthermore, the coinfusion in the nucleus accumbens of low concentrations of (2-p-carboxyethyl) phenylamino-5'-N-carboxamido-adenosine and raclopride, which were ineffective when administered alone, induced a significant increase in pallidal gamma-aminobutyric acids extracellular levels. These results suggest that A2a agonists, alone or in combination with D2 antagonists, could be advantageous antischizophrenic drugs, as blockage of D2 receptors in the ventral striopallidal system appears to be associated with the antipsychotic activity of neuroleptics but not with their extrapyramidal motor-side effects.

Topics: Adenosine; Animals; Antihypertensive Agents; Antipsychotic Agents; Autoradiography; Binding, Competitive; Dopamine D2 Receptor Antagonists; gamma-Aminobutyric Acid; Globus Pallidus; Microdialysis; Neostriatum; Nucleus Accumbens; Phenethylamines; Purinergic P1 Receptor Antagonists; Raclopride; Rats; Rats, Sprague-Dawley; Salicylamides; Schizophrenia; Sulpiride

According to the D2 dopamine receptor hypothesis of schizophrenia, there is an increased number of D2 receptors in the brains of schizophrenic patients than in those of healthy controls. We tested this hypothesis in 13 newly admitted neuroleptic-naive schizophrenic patients and 10 healthy volunteers using positron emission tomography.. The quantification of striatal D2 dopamine receptor density (Bmax) and affinity (Kd) was done using an equilibrium model described for raclopride labeled with carbon 11.. No statistically significant alterations were found in D2 receptor densities or affinities between the patient and control groups. However, a subgroup of four patients with a relatively high striatal D2 dopamine density was identified. Two patients, especially, had D2 dopamine densities almost twice as high as the mean control Bmax value. The Kd values also tended to be higher in this subset of patients than in the controls. No consistent striatal D2 dopamine receptor laterality was observed in schizophrenic patients or controls. However, an association of high D2 dopamine density in the left striatum and the mass of raclopride injected in the scan with low-specific radioactivity was observed in patients but not in controls.. There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.

Topics: Adult; Age Factors; Antipsychotic Agents; Carbon Radioisotopes; Cerebellum; Corpus Striatum; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Up-Regulation

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. However, an elevated number of D2 dopamine receptors in the left putamen of non-treated schizophrenics has been reported which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Ergolines; Functional Laterality; Hippocampus; Humans; Male; Nucleus Accumbens; Quinpirole; Raclopride; Rats; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Synaptic Transmission; Temporal Lobe; Time Factors

The density of dopamine D2-like receptors was determined using [3H]emonapride binding in putamen tissue taken postmortem from schizophrenic subjects and matched controls. A 72% increase in number of these receptors was identified in the schizophrenics, although three patients not receiving antipsychotic drug treatment before death exhibited receptor densities in the control range. Displacement of 1 nM [3H]emonapride binding by raclopride was used to define the contribution of the D4 subtype of dopamine receptors to total [3H]emonapride binding. No evidence was obtained for the presence of D4 receptors in putamen tissue from either control or schizophrenic subjects, indicating that the increase in D2-like receptor density in schizophrenia is due not to an increase in number of D4 sites in the disease, but to an up-regulation of D2 or D3 receptors probably induced by chronic treatment with antipsychotic drugs.

Topics: Aged; Animals; Antipsychotic Agents; Benzamides; Binding, Competitive; Corpus Striatum; Dopamine D2 Receptor Antagonists; Humans; Kinetics; Pyrrolidines; Raclopride; Receptors, Dopamine; Receptors, Dopamine D4; Reference Values; Salicylamides; Schizophrenia

The purpose of this study was to determine whether dopamine D4 receptors could be detected in the human brain striatum by means of an indirect ligand-binding method, because no dopamine D4 receptor-selective ligand presently exists. The antipsychotic clozapine is more selective for the dopamine D4 receptor than for other dopamine receptors. Although most antipsychotic drugs act in the striatum to elicit Parkinson-like side-effects, clozapine is atypical in that it does not produce Parkinsonism. To understand this atypical action of clozapine, it would be helpful to know whether the presumed target for clozapine, the dopamine D4 receptor, is or is not present in the human striatum. We measured dopamine D4 receptors indirectly, using [3H]emonapride and [3H]raclopride. Emonapride has a high affinity (K = 90 pM) for the dopamine D4 receptor, while raclopride has a very low affinity for this receptor (K = 240 nM); thus, any difference in the densities of these two [3H]ligands (in the absence of dopamine) could be attributed to the presence of dopamine D4 receptors. Since the binding of [3H]raclopride is sensitive to endogenous dopamine, we used Parkinson-diseased tissue which has little dopamine. We found that the densities of the two ligands were identical in Parkinson striata, indicating a low density (< 1 pmol/g) for dopamine D4 receptors in the human striatum. This low or undetectable density of dopamine D4 receptors in the striatum is consistent with other data indicating that clozapine does not have its major action in the human striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Corpus Striatum; Dopamine D2 Receptor Antagonists; Humans; In Vitro Techniques; Kinetics; Parkinson Disease; Pituitary Gland, Anterior; Pyrrolidines; Raclopride; Rats; Receptors, Dopamine; Receptors, Dopamine D4; Salicylamides; Schizophrenia; Spiperone; Swine; Tomography, Emission-Computed

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.

Topics: Amphetamine; Animals; Apomorphine; Benzazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Electric Stimulation; Electroencephalography; Habituation, Psychophysiologic; Haloperidol; Limbic System; Male; Models, Neurological; Motor Activity; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Salicylamides; Schizophrenia; Seizures; Stereotyped Behavior; Tegmentum Mesencephali; Time Factors

Although the biological basis of schizophrenia is not known, possible causes include genetic defects, viruses, amines, brain structure and metabolism, neuroreceptors, and G proteins. The hypothesis of dopamine overactivity in schizophrenia is based on the fact that neuroleptics block dopamine D2 receptors in direct relation to their clinical antipsychotic potencies. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue. This elevation, however, is only found in vivo using [11C]methylspiperone but not [11C]raclopride. The dopamine D4 receptor gene has not yet been excluded in schizophrenia because the 21 gene variants of D4 have not yet been tested. Because the link between D1 and D2 receptors is reduced in schizophrenia tissue, we tested whether one component of this link was sensitive to guanine nucleotide. We report here that the binding of [3H]raclopride to D2 receptors in schizophrenia was not sensitive to guanine nucleotide. This finding permitted analysis of data on the binding of [3H]emonapride to the D2, D3 and D4 receptors. We conclude that the combined density of D2 and D3 receptors (labelled by [3H]raclopride) is increased by only 10% in schizophrenia brain, as found by Farde et al., but that it is the density of dopamine D4 receptors which is sixfold elevated in schizophrenia. These findings resolve the apparent discrepancy, mentioned above, wherein the density of [11C]methylspiperone-labelled sites (D2, D3 and D4), but not that of [11C]raclopride-labelled sites (D2 and D3), was found elevated in the schizophrenia striatum.

Topics: Aged; Aged, 80 and over; Corpus Striatum; Dopamine; Female; Guanine Nucleotides; Humans; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Schizophrenia

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia; Basal Ganglia Diseases; Benzazepines; Clozapine; Dopamine Antagonists; Female; Humans; Iodine Radioisotopes; Male; Putamen; Raclopride; Receptors, Dopamine; Salicylamides; Schizophrenia; Tomography, Emission-Computed

The specific binding of the D2-dopamine receptor antagonist radioligand [3H] raclopride was quantitated in the postmortem caudate and frontal cortex from schizophrenic suicide victims and control subjects. In schizophrenic suicides the density of binding sites (Bmax) was higher (40%, P < 0.05) in the caudate, whereas it did not change in the cortex as compared to those in controls. The apparent dissociation constants (KD) were also found increased both in caudate (24%) and cortex (75%) from schizophrenics, but these apparent decreases in receptor affinity did not reach statistical significance. The mean Bmax value in drug-free schizophrenic suicides (n = 3) did not differ from the Bmax value in neuroleptic drug-treated schizophrenics (n = 7) but it was found increased in respect to control subjects (n = 9). No differences in [3H] raclopride binding were observed between non-schizophrenic suicide victims (n = 4) and matched controls (n = 4), suggesting that the modifications of D2-dopamine receptors in schizophrenia are not related to suicide.

Topics: Adult; Antipsychotic Agents; Brain Chemistry; Caudate Nucleus; Dopamine Antagonists; Female; Humans; Male; Membranes; Middle Aged; Postmortem Changes; Prefrontal Cortex; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Suicide

Topics: Brain; Carbon Radioisotopes; Cerebellum; Dopamine; Dopamine Antagonists; Humans; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Brain; Carbon Radioisotopes; Dopamine Antagonists; Humans; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed; Tritium

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D1-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310-810 micrograms. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [11C]SCH 23390 binding in the basal ganglia was at a high level with a central D1-dopamine receptor occupancy of 45-59%. The D2-dopamine receptor antagonist [11C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [11C]raclopride binding in the basal ganglia. The findings for [11C]raclopride and [11C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.

Topics: Adolescent; Adult; Akathisia, Drug-Induced; Benzazepines; Carbon Radioisotopes; Cerebellum; Dopamine Antagonists; Female; Humans; Male; Psychomotor Agitation; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Time Factors; Tomography, Emission-Computed

Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.

Topics: Analysis of Variance; Animals; Apomorphine; Benzazepines; Clozapine; Male; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Reflex, Startle; Salicylamides; Schizophrenia; Spiperone

Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Carbon Radioisotopes; Caudate Nucleus; Dopamine; Female; Humans; Male; Putamen; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Up-Regulation

Remoxipride is a new antipsychotic drug that binds selectively to the D2-dopamine receptor subtype as demonstrated in animal studies in vitro and in vivo. It is generally assumed that the antipsychotic effect of neuroleptic drugs is mediated by blockade of dopamine receptors. The aim of the present study was to use positron emission tomography (PET) and the ligand [11C] raclopride to examine the central D2-dopamine receptor occupancy in man during oral administration of remoxipride. After oral administration of remoxipride 100 mg three times daily to a healthy male subject there was a 73% central D2-dopamine receptor occupancy. In a schizophrenic patient treated with remoxipride 200 mg twice daily there was a 71% occupancy. These occupancy values are similar to the values of 65-85% previously found in a series of patients treated with neuroleptics representative of all currently used chemical classes. In a separate experiment, remoxipride was labelled with 11C and injected intravenously and the distribution of radioactivity to the brain examined. Radioactivity appeared in the brain during the first minutes after injection and 4.5 min after injection it accounted for 0.8% of the total radioactivity injected, thus indicating that [11C]remoxipride had rapidly passed through the blood-brain barrier.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzamides; Brain; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Intravenous; Male; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Remoxipride; Salicylamides; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed

1. It has been unequivocally shown that antipsychotic compounds reduce dopaminergic transmission. A relationship in vitro between the potency for the antipsychotic effect and the blockade of D2-dopamine receptors has been shown. No such relationships have been demonstrated for any other central receptor population. 2. Positron emission tomography (PET) has made it possible to investigate interactions of psychotropic drugs with central receptors in the living human brain. Using the selective D2 receptor antagonist raclopride labelled with positron emitting isotope 11C, it has been shown that chemically distinct classical neuroleptics in conventional doses occupy a high degree (65-89%) of the D2-receptors in the human brain. The results substantiate the opinion that the antipsychotic effects is mediated by a blockade of D2-dopamine receptors. 3. The degree of binding to D1-receptors using the 11C-labelled D1-antagonist from Schering (SCH 23390) as the ligand was also determined. The D1-receptor occupancy seemed to be dependent on the type of the antipsychotic compound studied. 4. The atypical neuroleptic compound clozapine demonstrated a different binding profile than the classical neuroleptics. Thus, clozapine in conventional doses occupied D2-receptors to a smaller extent (40%, 40%, 65%) than classical neuroleptics. The occupation of D1-receptors was higher (40%, 42%) than that of classical compounds (0-36%). 5. The unique clinical profile of clozapine may be related to its potency on both D1- and D2-receptors. The distribution of D1-receptors varies from that of D2-receptors in the human brain which may be one reason for the importance of blocking both D1- and D2-receptors for a full antipsychotic response.

Topics: Adult; Antipsychotic Agents; Benzazepines; Brain; Carbon Radioisotopes; Humans; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Animals; Brain; Carbon Radioisotopes; Caudate Nucleus; Cerebellum; Corpus Striatum; Dopamine; Dopamine Antagonists; Humans; Putamen; Raclopride; Receptors, Dopamine; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed; Tritium

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Topics: Adult; Antipsychotic Agents; Butyrophenones; Female; Humans; Male; Prolactin; Psychotic Disorders; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Antipsychotic Agents; Blood Proteins; Brain Chemistry; Humans; Protein Binding; Raclopride; Receptors, Dopamine; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Dopamine receptor types D1 and D2 can oppose or enhance each other's actions for electrical, biochemical, and psychomotor effects. We report a D1-D2 interaction in homogenized tissue as revealed by ligand binding. D2 agonists lowered the binding of [3H]raclopride to D2 receptors in striatal and anterior pituitary tissues. Pretreating the tissue with the D1-selective antagonist SCH 23390 prevented the agonist-induced decrease in [3H]raclopride binding to D2 sites in the striatum but not in the anterior pituitary, which has no D1 receptors. Conversely, a dopamine-induced reduction in the binding of [3H]SCH 23390 to D1 receptors could be prevented by the D2-selective antagonist eticlopride. Receptor photolabeling experiments confirmed both these D1-D2 interactions. The blocking effect by SCH 23390 was similar to that produced by a nonhydrolyzable guanine nucleotide analogue, and SCH 23390 reduced the number of agonist-labeled D2 receptors in the high-affinity state. Thus, the D1-D2 link may be mediated by guanine nucleotide-binding protein components. The link may underlie D1-D2 interactions influencing behavior, since the link was missing in over half the postmortem striata from patients with schizophrenia and Huntington disease (both diseases that show some hyperdopamine signs) but was present in human control, Alzheimer, and Parkinson striata.

Topics: Affinity Labels; Animals; Antipsychotic Agents; Benzazepines; Binding, Competitive; Corpus Striatum; Dogs; Dopamine Antagonists; GTP-Binding Proteins; Humans; Huntington Disease; Kinetics; Models, Biological; Pituitary Gland, Anterior; Raclopride; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Reference Values; Salicylamides; Schizophrenia; Swine

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were "very much" or "much" improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Topics: Acute Disease; Adolescent; Adult; Female; Hemodynamics; Homovanillic Acid; Humans; Male; Middle Aged; Prolactin; Raclopride; Receptors, Dopamine; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Brain; Brain Chemistry; Carbon Radioisotopes; Cerebellum; Corpus Striatum; Dopamine; Humans; Raclopride; Receptors, Dopamine; Research Design; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Topics: Adult; Carbon Radioisotopes; Female; Functional Laterality; Humans; Male; Putamen; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Tracer doses of 11C-SCH 23390 and 11C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not 11C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. 11C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.

Topics: Adult; Benzazepines; Brain; Carbon Radioisotopes; Flupenthixol; Humans; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Sulpiride

D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.

Topics: Adult; Animals; Antipsychotic Agents; Benzamides; Brain; Cerebellum; Humans; Male; Middle Aged; Putamen; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Rodentia; Schizophrenia; Tomography, Emission-Computed