title: Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice.
abstract: BACKGROUND
  In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.
  
  
  OBJECTIVE
  This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.
  
  
  METHODS
  Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.
  
  
  RESULTS
  Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).
  
  
  CONCLUSIONS
  Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects.
authors: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: José L
authors: JL
authors: Moreno
authors: Terrell
authors: T
authors: Holloway
authors: Adrienne
authors: A
authors: Umali
authors: Vinayak
authors: V
authors: Rayannavar
authors: Stuart C
authors: SC
authors: Sealfon
authors: Javier
authors: J
authors: González-Maeso
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000235:genetics; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D008238:Lysergic Acid Diethylamide; D003024:Clozapine; D006220:Haloperidol