Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release |
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| Authors: | P. A. Broderick M. F. Piercey |
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| Affiliation: | (1) Department of Physiology and Pharmacology, The City University of New York Medical School, and Doctoral Program, Department of Biology and Department of Psychology, The City University of New York Graduate School, New York, NY, and,;(2) CNS Research, The Pharmacia and Upjohn Co., Inc., Kalamazoo, MI, USA, US |
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| Abstract: | ![]()
Summary. With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D4/D2), haloperidol (D2) and the selective D4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A10 and A9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D4 antagonist did not affect 5-HT release within either A10 or A9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D4 antagonist, PNU-101387G. Received January 13, 1998; accepted April 27, 1998 |
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| Keywords: | : Neuroleptics antipsychotic agents extrapyramidal symptoms (EPS) motor disorders schizophrenia psychosis dopamine receptor antagonists serotonin receptor antagonists dopamine serotonin prefrontal cortex nucleus accumbens caudate putamen (dorsal striatum) A10 neural pathways A9 neural pathways in vivo microvoltammetry in vivo electrochemistry carbon paste microelectrodes clozapine haloperidol PNU-101387G D4 receptor D2 receptor 5-HT2 receptor. |
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