benzofurans and Schizophrenia

This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia.. In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score.. SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated.. These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.

Topics: Adult; alpha7 Nicotinic Acetylcholine Receptor; Benzofurans; Female; Humans; Male; Middle Aged; Nicotinic Agonists; Outcome Assessment, Health Care; Quinuclidines; Schizophrenia; Severity of Illness Index; Young Adult

This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18-60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12). The primary efficacy outcome measure was the Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (P=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (P=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial agonists for cognitive dysfunction and negative symptoms in schizophrenia.

Topics: Adolescent; Adult; alpha7 Nicotinic Acetylcholine Receptor; Antipsychotic Agents; Benzofurans; Female; Humans; India; Male; Middle Aged; Nicotinic Agonists; Nootropic Agents; Quinuclidines; Schizophrenia; Schizophrenic Psychology; United States; Young Adult

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

Topics: Adult; Age Factors; Benzazepines; Benzofurans; Binding, Competitive; Carbon Radioisotopes; Dopamine Antagonists; Female; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Predictive Value of Tests; Prefrontal Cortex; Principal Component Analysis; Receptors, Dopamine D1; Schizophrenia; Tomography, Emission-Computed

Topics: Adult; Benzazepines; Benzofurans; Dopamine Antagonists; Follow-Up Studies; Humans; Male; Placebo Effect; Receptors, Dopamine D1; Schizophrenia; Treatment Outcome

SU-23397 is a unique new hybrid molecule, the animal profile being characteristic of neuroleptic activity. Although the trial was uncontrolled, there appears to be no doubt that SU-23397 exerts antipsychotic activity between 20 mg and 250 mg daily in severely ill schizophrenic patients. Seven of the ten subjects required at least transient antiparkinson medication. Two patients demonstrated premature ventricular contractions. One patient had infrequent PVCs at baseline which increased in frequency with rising dosage. The other patient developed frequent premature ventricular contractions only after active and medication was initiated and was subsequently withdrawn from the study.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzofurans; Clinical Trials as Topic; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds

Topics: Adult; Benzofurans; Clinical Trials as Topic; Humans; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Tranquilizing Agents

Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01mg/kg), clozapine (5mg/kg), haloperidol (0.2mg/kg), haloperidol (0.2mg/kg)+ORM-10921 (0.01mg/kg) or vehicle once daily for 14days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol+ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol+ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Benzofurans; Brain-Derived Neurotrophic Factor; Corpus Striatum; Disease Models, Animal; Drug Synergism; Haloperidol; Male; Prepulse Inhibition; Quinolizidines; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Social Isolation; Statistics, Nonparametric

The theme of this year's American Psychiatric Association (APA) meeting was 'Psychiatry: integrating body and mind, heart and soul', with special focus given to advances in basic and cognitive neuroscience and how these may contribute to integrated care of mental health and illness. The program featured numerous tracks and subtracks in areas of interest such as addiction psychiatry, child, adolescent and geriatric psychiatry, and psychosomatic medicine.

Topics: Alcoholism; Benzofurans; Canada; Drug Discovery; Humans; Indoles; Mental Disorders; Piperazines; Psychiatry; Quinolones; Schizophrenia; Thiophenes; Vilazodone Hydrochloride

Schizophrenia is a severe psychiatric disorder characterized by three symptom domains, positive (hallucinations, obsession), negative (social withdrawal, apathy, self-neglect) and cognitive (impairment in attention, memory and executive function). Whereas current medication ameliorates positive symptomatology, negative symptoms as well as cognitive dysfunctions remain untreated. The development of improved therapies for negative symptoms has proven particularly difficult, in part due to the inability of mimicking these in rodents. Here, we address the predictive validity of combining an ethologically well preserved behavior in rodents, namely nest building activity, with an established animal model of schizophrenia, the sub-chronic PCP model, for negative symptoms. Decline in rodent nesting activity has been suggested to mirror domains of negative symptoms of schizophrenia, including social withdrawal, anhedonia and self-neglect, whereas repeated treatment with the NMDAR antagonist PCP induces and exacerbates schizophrenia-like symptoms in rodents and human subjects. Using a back-translational approach of pharmacological validation, we tested the effects of two agents targeting the nicotinic α7 receptor (EVP-6124 and TC-5619) that were reported to exert some beneficial effect on negative symptoms in schizophrenic patients. Sub-chronic PCP treatment resulted in a significant nest building deficit in mice and treatment with EVP-6124 and TC-5619 reversed this PCP-induced deficit. In contrast, the atypical antipsychotic drug risperidone remained ineffective in this assay. In addition, EVP-6124, TC-5619 and risperidone were tested in the Social Interaction Test (SIT), an assay suggested to address negative-like symptoms. Results obtained in SIT were comparable to results in the nest building test (NEST). Based on these findings, we propose nest building in combination with the sub-chronic PCP model as a novel approach to assess negative-like symptoms of schizophrenia in rodents.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzofurans; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hyperkinesis; Male; Mice; Mice, Inbred C57BL; Phencyclidine; Quinuclidines; Rotarod Performance Test; Schizophrenia; Schizophrenic Psychology; Social Behavior; Thiophenes

A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed.. The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [(11)C]SCH23390 and [(11)C]NNC112, may have contributed to these discrepancies reported in the literature.. Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [(11)C]SCH23390 and [(11)C]NNC112.. [(11)C]SCH23390 and [(11)C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed.. The results of this study suggest that differences in the binding of [(11)C]SCH23390 and [(11)C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers.

Topics: Adolescent; Adult; Benzazepines; Benzofurans; Carbon Radioisotopes; Case-Control Studies; Female; Humans; Male; Positron-Emission Tomography; Radioactive Tracers; Radiopharmaceuticals; Receptors, Dopamine D1; Schizophrenia; Young Adult

D₁ receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [¹¹C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF versus controls comparison. Furthermore, in the DF group, DF interval correlated positively with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be corrected and normalized by chronic antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Benzazepines; Benzofurans; Dopamine; Female; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Prefrontal Cortex; Radiopharmaceuticals; Receptors, Dopamine D1; Schizophrenia; Up-Regulation

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.

Topics: Animals; Benzofurans; Brain; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Kinetics; Memory, Short-Term; Models, Chemical; Piperidines; Rats; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Structure-Activity Relationship

Abnormality of cognitive function in schizophrenia has been suggested to be related to dopamine D1 receptor. However, the results of previous positron emission tomography (PET) studies of dopamine D1 receptor in schizophrenia were not consistent.. In this study, six patients with schizophrenia in severe residual phase with chronic antipsychotic treatment and twelve healthy age-matched controls participated. Two different radioligands, [11C]NNC112 and [11C]SCH23390, for dopamine D1 receptor were used on the same subjects. Binding of the ligands was measured by PET, and statistical analysis was performed using one-way analysis of covariate (ANCOVA) with age as covariate.. Good correlations between binding potential values (BP(ND)) and age were observed in all regions of interest (ROIs) with both ligands. ANCOVA with age as covariate of BP(ND) values of all ROIs revealed that the patient group showed significantly lower BP(ND) value compared with the control group in both ligands.. In patients with chronic schizophrenia in severe residual phase with chronic antipsychotic treatment, the binding potential values of both ligands were significantly lower in the striatum and cortical regions than those of healthy controls.

Topics: Adult; Antipsychotic Agents; Benzazepines; Benzofurans; Brain; Cerebral Cortex; Cognition; Corpus Striatum; Female; Humans; Ligands; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Receptors, Dopamine D1; Schizophrenia

A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Behavior, Animal; Benzofurans; Clozapine; Cognition Disorders; Exploratory Behavior; Female; Male; Maze Learning; Mice; Mice, Transgenic; Neurons; Nicotinic Agonists; Promoter Regions, Genetic; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Nicotinic; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Social Behavior; Tyrosine 3-Monooxygenase

Schizophrenia is a complex and debilitating disorder. Although effective therapeutic strategies are available, these are not without problems and are not universally efficacious. In this issue of the British Journal of Pharmacology, a trio of papers describe the characterisation of a potential, novel anti-psychotic medication, F15063. This compound combines antagonism of dopamine D(2)-like receptors with agonism at 5-HT(1A) receptors. Based on in vitro and in vivo profiles, the authors suggest that this compound approaches the 'optimal balance' for activity at these receptor systems.

Topics: Antipsychotic Agents; Benzofurans; Benzylamines; Cyclopentanes; Dopamine D2 Receptor Antagonists; Humans; Schizophrenia; Serotonin 5-HT1 Receptor Agonists

F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) agonist, with little affinity (40-fold lower than for D(2) receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects.. Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'.. F15063 potently (ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats (flat body posture and forepaw treading: ED(50) >32 mg kg(-1) i.p.).. F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzofurans; Benzylamines; Cyclopentanes; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Mice, Inbred Strains; Models, Animal; Motor Activity; Piperazines; Prolactin; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; Receptors, Dopamine D4; Reflex, Startle; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Treatment Outcome

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

Topics: Aging; Animals; Avoidance Learning; Benzofurans; Central Nervous System Stimulants; Cognition Disorders; Dose-Response Relationship, Drug; Drinking; Electroencephalography; Histamine Antagonists; Hyperkinesis; Male; Maze Learning; Methamphetamine; Mice; Mice, Inbred DBA; Microdialysis; Neurons; Neurotransmitter Agents; Pyrrolidines; Rats; Rats, Inbred SHR; Receptors, Histamine H3; Reflex, Startle; Schizophrenia; Social Behavior

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Topics: Animals; Antipsychotic Agents; Benzofurans; Brain Chemistry; Cataplexy; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Synergism; Haloperidol; Histamine; Histamine Antagonists; Imidazoles; Ketoconazole; Male; Metabolic Clearance Rate; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Risperidone; Schizophrenia

Topics: Animals; Benzofurans; Cognition; Histamine Antagonists; Memory; Mice; Mice, Inbred DBA; Models, Animal; Pyrrolidines; Rats; Rats, Wistar; Receptors, Histamine H3; Schizophrenia

Recent positron emission tomography (PET) studies have assessed the level of dopamine (DA) D1 receptors in the prefrontal cortex (PFC) in patients with schizophrenia and have generated contradictory findings. In the PFC of patients with schizophrenia, the binding potential (BP) of [11C]NNC 112 has been reported as increased, while the BP of [11C]SCH 23390 was reported as decreased or unchanged. In this study, the effect of acute and subchronic DA depletion on the in vivo binding of [11C]NNC 112 and [3H]SCH 23390 was evaluated in rats. Acute DA depletion did not affect [11C]NNC 112 in vivo binding, but paradoxically decreased [3H]SCH 23390 in vivo binding. Subchronic DA depletion was associated with increased [11C]NNC 112 in vivo binding and decreased [3H]SCH 23390 in vivo binding. Together, these data demonstrate that the in vivo binding of these radiotracers is differentially affected by changes in endogenous DA tone, and suggest that alterations in the binding of these tracers in the PFC of patients with schizophrenia might reflect changes in D1 receptors secondary to sustained deficit in prefrontal DA function.

Topics: Adrenergic Uptake Inhibitors; alpha-Methyltyrosine; Animals; Benzazepines; Benzofurans; Binding Sites; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Antagonists; Enzyme Inhibitors; Hippocampus; Male; Prefrontal Cortex; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Reserpine; Schizophrenia; Time Factors; Tritium

Topics: Adolescent; Adult; Amitriptyline; Anthracenes; Antidepressive Agents; Azocines; Benzoates; Benzofurans; Bipolar Disorder; Clomipramine; Cyclothymic Disorder; Depression; Dibenzazepines; Dimethylamines; Dothiepin; Humans; Imipramine; Methylamines; Middle Aged; Personality Disorders; Propylamines; Schizophrenia