Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs.
Brain research. Brain research reviews March 1, 2000 T H Svensson
Classical antipsychotics like haloperidol require about 75% dopamine D2 receptor occupancy to be effective, whereas clozapine is effective at only 45% occupancy. Using the phencyclidine (PCP) model of schizophrenia in rats, this paper investigates which other receptors mediate clozapine's atypical profile. NMDA-receptor antagonists caused dysregulation of mesocorticolimbic dopamine neurons: those projecting to the medial frontal cortex lost burst firing, while subcortically projecting neurons showed high-frequency firing and increased dopamine output. Drugs blocking 5-HT2A receptors restored burst firing in mesocortical neurons and potentiated the conditioned avoidance response suppressant effect of raclopride without increasing catalepsy. The alpha1-adrenoreceptor antagonist prazosin suppressed high-frequency firing and behavioral activation. AMPA-receptor antagonists also produced antipsychotic-like effects. The authors suggest that 5-HT2A and alpha1-adrenoreceptor blockade contribute to atypical antipsychotic effects, and AMPA-receptor antagonists may have an atypical profile.