title: Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short- and long-term withdrawal from this antipsychotic.
abstract: Clozapine is a prototype of atypical antipsychotics that has a profile not only to block D(2)/5-HT(2A) receptors but also to enhance N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. This study hypothesized different effects between a single and repeated administration of clozapine on NMDA receptor-mediated neurotransmission, and examined effects of these treatments of clozapine on a non-competitive NMDA receptor antagonist, phencyclidine (PCP)-induced hyperlocomotion and acute increases in glutamate levels in the medial prefrontal cortex (mPFC), after short- and long-term withdrawal from this antipsychotic. Locomotor activity and extracellular levels of glutamate were measured by an infrared sensor and in vivo microdialysis respectively. A single administration of clozapine attenuated PCP-induced hyperlocomotion and blocked PCP-induced increases in glutamate levels in the mPFC at 48 hours, but not 11 days after the injection of clozapine. Repeated administration of clozapine attenuated PCP-induced hyperlocomotion not only at 48 hours, but also 11 days after the last injection of clozapine, with blocking PCP-induced increases in glutamate levels in the mPFC. Both a single and repeated administration of clozapine had no effect on methamphetamine (METH)-induced hyperlocomotion at 48 hours or 11 days after the treatment of clozapine. Considering fast dissociation of clozapine from dopamine D(2) receptors and no effect of a single or repeated administration of clozapine on METH-induced hyperlocomotion, the attenuated PCP-induced hyperlocomotion by a single and repeated clozapine treatments cannot be explained by clozapine occupancy of dopamine D(2) receptors. Repeated but not a single administration of clozapine inhibited a 5-HT(2A/2C) agonist, DOI-induced increases in the mPFC 11 days after the last injection of clozapine. These findings suggest that subchronically treated clozapine-induced long-lasting downregulation of 5-HT(2A) receptors may block the enhanced PCP-induced neurochemical and behavioral changes.
authors: Department of Psychiatry, Graduate School of Medicine, Hokkaido University, 060-8638 Sapporo, Japan. tabekawa@med.hokudai.ac.jp
authors: Tomohiro
authors: T
authors: Abekawa
authors: Koki
authors: K
authors: Ito
authors: Tsukasa
authors: T
authors: Koyama
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D010622:Phencyclidine; D003024:Clozapine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine