clozapine and amperozide

A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperazines; Piperidines; Risperidone; Schizophrenia; Serotonin; Tryptophan

Neuroleptics are known to stimulate dopamine release in neostriatal terminal areas. In the present study, we have investigated by brain microdialysis in freely moving rats the effect of typical and atypical neuroleptics on dopamine transmission in the bed nucleus of stria terminalis, a dopamine terminal area belonging to the limbic system and recently assigned the so-called extended amygdala. Mean basal dialysate dopamine values were 14.3 f moles/20 microliters sample. Dopamine output in dialysates was increased dose-dependently by clozapine (max + 158%, 298%, and 461% of basal at 5, 10, and 20 mg/kg i.p., respectively), risperidone (max + 115% and 221% of basal at 1 and 3 mg/kg i.p., respectively), olanzapine (max + 138% and 235% of basal at 3 and 6 mg/kg i.p., respectively), BIMG 80 (max + 64% and 164% of basal at 3 and 5 mg/kg i.p., respectively), amperozide (max + 110% and 194% of basal at 3 and 6 mg/kg i.p., respectively). The selective dopamine D4 antagonist L-745,870 increased dialysate dopamine but at rather high doses and not as effectively as clozapine (max + 32%, 89%, and 130% of basal at 2.7, 5.4, and 10.8 mg/kg i.p., respectively). The typical neuroleptic haloperidol (0.1 and 0.5 mg/kg s.c.) and the selective D2 antagonist raclopride (0.14, 0.56, and 2.1 mg/kg s.c.), the serotonergic 5-HT2 antagonist ritanserin (0.5 and 1.5 mg/kg i.p.), and the adrenergic alpha 1 antagonist prazosin (0.91 and 2.73 mg/kg i.p.) did not affect dialysate dopamine in the bed nucleus of stria terminalis. Saline (1 ml/kg s.c. or 3 ml/kg i.p.) did not modify dialysate dopamine. Therefore, atypical neuroleptics share the ability of stimulating dopamine transmission in the bed nucleus of stria terminalis, but this property is not mimicked by any of the drug tested that selectively act on individual receptors among those that are affected by atypical neuroleptics. These observations raise the possibility that the property of increasing dopamine transmission in the bed nucleus of stria terminalis is the result of combined blockade of dopamine, serotonin, and noradrenaline receptors and that might be predictive of an atypical neuroleptic profile.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Dopamine; Kinetics; Male; Microdialysis; Olanzapine; Piperazines; Pirenzepine; Rats; Rats, Sprague-Dawley; Risperidone; Septal Nuclei

Serotonin (5-HT)(1A) receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT(1A) receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohe xanecarboxamide trihydrochloride (WAY100635), a selective 5-HT(1A) receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT(2A)/D(2) receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0. 03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01-1.0 mg/kg), potent D(2) receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1-0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT(2A) receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT(1A) receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT(2A) receptors. The significance of these results for EPS and antipsychotic action is discussed.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Dopamine; Fluorobenzenes; Haloperidol; Male; Microdialysis; Nucleus Accumbens; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Risperidone; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tritium

Classic neuroleptic drugs produce a syndrome of vacuous jaw movements in rats, and this syndrome has been offered as an animal model of early onset extrapyramidal side effects. The atypical antipsychotics do not produce elevations in vacuous jaw movements, or do so only at very high doses. The purpose of the present study was to determine the impact of the putative antipsychotic, amperozide, on vacuous jaw movements in rats. Groups of rats received daily injections of haloperidol (0.2, 0.4, or 0.8 mg/kg), clozapine (2.0, 4.0, 8.0 mg/kg), amperozide (2.0, 4.0, 8.0 mg/kg) or vehicle for 4 weeks. Once per week, rats were observed for the presence of vacuous jaw movements. Haloperidol increased vacuous jaw movements with increasing doses. Clozapine only produced elevations in vacuous jaw movements at the highest dose. In contrast, increasing doses of amperozide resulted in decreasing vacuous jaw movements for this portion of the dose-response curve. This is the first report of the effect of amperozide on vacuous jaw movements and results are discussed in terms of a potentially unique behavioral profile with respect to this behavior.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Extrapyramidal Tracts; Haloperidol; Jaw; Male; Movement Disorders; Piperazines; Rats; Rats, Sprague-Dawley

In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.

Topics: Animals; Antipsychotic Agents; Caudate Nucleus; Clozapine; Dopamine Antagonists; Haloperidol; Male; Nucleus Accumbens; Organ Specificity; Piperazines; Prefrontal Cortex; Protein Precursors; Putamen; Raclopride; Rats; Rats, Sprague-Dawley; RNA, Messenger; Salicylamides; Somatostatin; Tachykinins; Transcription, Genetic

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; CHO Cells; Clozapine; Corpus Striatum; COS Cells; Cricetinae; Dibenzothiazepines; Dopamine; Female; Guinea Pigs; Haloperidol; Indoles; Kidney; Male; Microdialysis; Neuroblastoma; Nucleus Accumbens; Olanzapine; Piperazines; Pirenzepine; Prefrontal Cortex; Pyridines; Quetiapine Fumarate; Radioligand Assay; Rats; Rats, Sprague-Dawley; Risperidone; Tritium; Tumor Cells, Cultured

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN). 2. Administration of risperidone (25-400 micrograms kg-1, i.v.) dose-dependently decreased 5-HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25-4.0 mg kg-1, i.v.), the putative antipsychotic drug amperozide (0.5-8.0 mg kg-1, i.v.) and the selective alpha 1-adrenoceptor antagonist prazosin (50-400 micrograms kg-1, i.v.). 3. The selective alpha 2-adrenoceptor antagonist idazoxan (10-80 micrograms kg-1, i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D2 and 5-HT2A receptor antagonists raclopride (25-200 micrograms kg-1, i.v.) and MDL 100,907 (50-400 micrograms kg-1, i.v.), respectively, were without effect. Thus, the alpha 1-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing. 4. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms kg-1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5-HT cells induced by risperidone, failed to prevent the prazosin-induced decrease in 5-HT cell firing. This finding argues against the notion that alpha 1-adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells. 5. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg kg-1, i.p., day-1 for 3 consecutive days) in comparison with drug naive animals. 6. Administration of risperidone (2.0 mg kg-1, s.c.) significantly enhanced 5-HT output in the DRN. 7. Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of firing, and is probably only to a minor extent caused by its alpha 1-adrenoceptor antagonistic action.

Topics: Adrenergic alpha-Antagonists; Animals; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Hydroxyindoleacetic Acid; Idazoxan; Male; Piperazines; Prazosin; Pyridines; Raclopride; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Serotonin; Risperidone; Salicylamides; Serotonin; Serotonin Antagonists

The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT2 receptors but only low affinity for dopamine (DA) D2 receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT2 receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D2 receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT2 receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1, 10 microM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 microM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT2 receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine; Male; Microdialysis; Neostriatum; Nucleus Accumbens; Piperazines; Prefrontal Cortex; Rats; Rats, Wistar; Ritanserin; Serotonin Antagonists; Synaptic Transmission

Behavioural, biochemical and electrophysiological studies suggest that amperozide affects mesolimbic dopamine neurotransmission. Amperozide is a potent 5-HT2, receptor antagonist with only a moderate affinity for rat brain dopamine D2 receptors. The brain regional dopamine D2 receptor binding properties of amperozide were investigated by using in vitro and in vivo radioligand binding techniques. Amperozide displaced [3H]spiroperidol binding from rat striatal and limbic dopamine D2 receptors with moderate affinity (Ki = 540 +/- 118 nM and Ki = 403 +/- 84 nM, respectively). The dopamine D2 receptor antagonist l-sulpiride and the agonist dopamine did not show different affinity in the two brain regions. Amperozide potently displaced in vivo [3H]spiroperidol binding in rat frontal cortex (ID50 = 1.4 mg/kg s.c.) but was devoid of effect in striatum, olfactory tubercle and nucleus accumbens (ID50 > 100 mg/kg s.c.). Chronic administration of amperozide (5 mg/kg p.o.) for three weeks did not result in any change of maximal dopamine D2 receptor number in either striatal or limbic tissue. The effects of amperozide on dopamine neurotransmission are thus not likely to occur by a direct interaction with dopamine D2 receptors in either striatal or limbic tissue. The functional limbic selectivity might rather be mediated by serotoninergic pathways.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Clozapine; Dopamine; In Vitro Techniques; Limbic System; Male; Neostriatum; Piperazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Spiperone; Sulpiride

The aim of the present study was to investigate whether amperozide, an antipsychotic drug which possesses anti-aggressive and anxiolytic-like properties, stimulates the secretion of oxytocin and if so, by which receptor mechanism. For this purpose, female or male Sprague Dawley rats were given amperozide (0.5, 2.5 and 5.0 mg/kg IP), ritanserin (5.0 mg/kg), raclopride (2.0 mg/kg) and prazosin (1.0 mg/kg) and were subsequently decapitated for collection of blood (30 and 120 min) after injection. Oxytocin levels were measured with radioimmunoassay. Amperozide 2.5 and 5 mg/kg increased plasma levels of oxytocin significantly (P < 0.05 and < 0.001). The effect appeared maximal about 30 min after injection of the drug and oxytocin levels were almost back to basal within 120 min. Similar effects were obtained in female and male rats as well as in animals that were freely fed or food deprived for 24 h. CSF levels of oxytocin were also increased. Ritanserin, a 5-HT2-receptor antagonist but not the D2 receptor antagonist raclopride or the alpha 1-adrenoceptor antagonist prazosin stimulated oxytocin release. In addition, clozapine, a neuroleptic with potent HT2-antagonistic properties, was a potent releaser of oxytocin, whereas haloperidol was without effect. A possible role for oxytocin in the behavioural effects of amperozide and clozapine remains to be explored.

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Female; Haloperidol; Male; Oxytocin; Piperazines; Raclopride; Rats; Rats, Sprague-Dawley; Salicylamides; Serotonin Antagonists

Amperozide, a new putatively antipsychotic compound, has been evaluated for its effect on conditioned avoidance response and food-reinforced lever-pressing. Given alone, amperozide was almost equipotent to clozapine, but less potent than haloperidol in both test models. It was found that there was a statistically significant synergism, in these two models, between amperozide and classical neuroleptics. Since amperozide is inactive in behavioural tests reflecting striatal dopaminergic mechanisms, the synergistic effect could be of great therapeutic value in the treatment of psychotic disorders.

Topics: alpha-Methyltyrosine; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Butyrophenones; Chlorpromazine; Clozapine; Conditioning, Operant; Drug Synergism; Female; Food; Haloperidol; Male; Methyltyrosines; Piperazines; Psychotropic Drugs; Rats; Rats, Inbred Strains; Reinforcement Schedule

The ability of amperozide (N-ethyl-4-[4,4-bis(p-fluorophenyl)butyl]-1-piperazinecarboxamide) , a potentially antipsychotic agent, to activate the tuberoinfundibular dopamine (TIDA) neurons was studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase. The activity of the TIDA neurons was markedly elevated in a dose-related manner after treatment with amperozide (1 and 10 mg/kg). A significant stimulation was also found following treatment with the atypical antipsychotic agent clozapine (20 mg/kg) while the typical antipsychotic drug haloperiodol had no effect on TIDA neuron activity. The stimulatory effect of amperiozide on the TIDA neurons is suggested to be mediated by a non-dopaminergic mechanism.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Clozapine; Dihydroxyphenylalanine; Dopamine; Haloperidol; Male; Median Eminence; Neurons; Piperazines; Psychotropic Drugs; Rats; Rats, Inbred Strains