olanzapine and amperozide

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

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

Five potential antipsychotics (i.e. risperidone, olanzapine, seroquel, ziprasidone and amperozide) were given daily for 21 days to rats and the effect on the number of spontaneously active dopamine neurons in ventral tegmental area and substantia nigra pars compacta was determined. Standard electrophysiological measurements (i.e. single unit recording technique) were used. Risperidone, olanzapine and amperozide showed some selectivity (at one particular dose) for decreasing the number of active dopamine neurons in the ventral tegmental area. However, risperidone induced a U-shaped dose-response curve. The highest dose of amperozide inhibited the activity in substantia nigra pars compacta, showing a liability to induce extrapyramidal side-effects. Seroquel and ziprasidone inhibited the activity in both areas indicating a classical antipsychotic profile (i.e. high liability to cause extrapyramidal side-effects).

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Dopamine; Dose-Response Relationship, Drug; Male; Mesencephalon; Neurons; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Rats; Rats, Wistar; Risperidone; Substantia Nigra; Thiazoles