Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT1A Receptor-Dependent Mechanism

Abstract

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)Fused as a pharmacological model of schizophreniaFdisrupts 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 ¼ 23, 13, 11, respectively; po0.0003). 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.

Serotonin modulation of cortical neurons and networks

“…Likewise, the reversal of this effect by two antipsychotic drugs with different primary targets strongly suggests a relationship with their therapeutic action. Despite its low in vitro affinity for 5-HT 1A receptors, the reversal by clozapine of PCP effects depends on the in vivo stimulation of such receptors (Kargieman et al, 2012), as previously observed for the antipsychotic-evoked release of dopamine in mPFC (Diaz-Mataix et al, 2005). …”

The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats

“…The 5-HT 1A effect, which parallels the post-mortem data cited in the "Introduction", suggest the possibility that subchronic PCP treatment impairs cortical 5-HT release, leading to an upregulation of post-synaptic 5-HT 1A receptors, which may contribute to the efficacy of 5-HT 1A agonists in this model. It is noteworthy that the efficacy of clozapine to prevent PCPinduced desynchronization of PFC is dependent upon 5-HT 1A activation, but not 5-HT 2A blockade (Kargieman et al 2011), a further evidence for the important role of 5-HT 1A agonism to ameliorate hypoglutamatergic deficits. The results reported here also indicate that the combination of 5-HT 1A partial agonism and 5-HT 2A antagonism is insufficient to reverse the PCP-induced NOR deficit.…”

Classics in Chemical Neuroscience: Aripiprazole

“…124–125 More recently, it was shown that the ability of clozapine to reverse phencyclidine-elicited cortical desynchronization—a model of neural activity underlying negative symptoms— requires activation of 5-HT 1A receptors. 126 …”