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.
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Lucila
L
Kargieman
Maurizio S
MS
Riga
Francesc
F
Artigas
Pau
P
Celada
D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010622:Phencyclidine; D003024:Clozapine