BIMG 80, a Novel Potential Antipsychotic Drug: Evidence for Multireceptor Actions and Preferential Release of Dopamine in Prefrontal Cortex

Authors


Address correspondence and reprint requests to Dr. F. Borsini at Department of Biology, Boehringer Ingelheim Italia S.p.A., Via Lorenzini 8, 20139 Milano, Italy.

Abstract

Abstract: 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 (α1) 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.

Abbreviations used: BIMG 80, 5-methoxy-3-[N-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6-tetrahydropyridin-3-ylmethyl]-1H-indole; CHO cells, Chinese hamster ovary cells; CS, corpus striatum; DA, dopamine (3,4-dihydroxyphenylethylamine); EPS, extrapyramidal side effects; HEK-293 cells, human embryonic kidney 293 cells; 5-HT, 5-hydroxytryptamine (serotonin); mPFC, medial prefrontal cortex; NAS, nucleus accumbens septi.

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