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

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.