Clozapine, haloperidol, and the D4 antagonist PNU-101387G:: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release

With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D-4/D-2), haloperidol (D-2) and the selective D-4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A(10) neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A(9) 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 A(10) terminal fields, PFC and NAcc; DA release was not increased by clozapine within A, terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A(10) and A(9) 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 D-4 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 D-4 antagonist did not affect 5-HT release within either A(10) or A(9) 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 D-4 antagonist, PNU-101387G.