Effects of clozapine on behavioral sensitization induced by cocaine.
Using cocaine-sensitized mice as a model for psychosis, this study investigated whether subchronic treatment with clozapine could affect the sensitized state of the animals and examined the accompanying molecular changes in the brain. To induce sensitization, ICR mice (n=44) were treated with cocaine for 5 days. After 7 days of withdrawal, sensitization was confirmed by a cocaine challenge. Then, the sensitized animals were treated with clozapine for 5 days and rechallenged with cocaine. The frontal cortices were removed from the mice (n=16) 24 h after the last challenge, and the phosphorylation status of some key signaling molecules was investigated. Compared with the sensitized mice receiving the vehicle treatment, the sensitized mice receiving subchronic clozapine showed less locomotor activity, with an activity level similar to that of non-sensitized mice. However, clozapine did not directly affect the stimulatory effect of cocaine. Clozapine also reversed some of the sensitization-induced biochemical changes, including increased phosphorylation of GSK-3beta and CREB, in the frontal cortex. Subchronic treatment with clozapine apparently de-sensitized the sensitized mice. The long-term effect of clozapine on stimulant-induced sensitization may be related to the therapeutic effect of the drug as an antipsychotic agent.
Park
Hye-Jean
HJ
Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, Republic of Korea.
Cui
Feng Ji
FJ
Hwang
Jae Yeon
JY
Kang
Ung Gu
UG
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D003024:Clozapine / Q000627:therapeutic use*; D003042:Cocaine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*
D014150:Antipsychotic Agents; D050882:CREB-Binding Protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D003042:Cocaine; D003024:Clozapine