Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT 1A Receptor-Dependent Mechanism

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)—used as a pharmacological model of schizophrenia—disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15–4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT 2A and 5-HT 1A receptors (5-HT 2A R and 5-HT 1A R, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT 2A R and behaves as partial agonist in vivo at 5-HT 1A R. We used wild-type (WT) mice and 5-HT 1A R and 5-HT 2A R knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n =23, 13, 11, respectively; p <0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT 1A R antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT 1A R activation without the need to block 5-HT 2A R, as observed with clozapine-induced cortical dopamine release.