title: Effects of central activation of serotonin 5-HT2A/2C or dopamine D 2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test.
abstract: BACKGROUND
  Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect.
  
  
  OBJECTIVE
  The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats.
  
  
  METHODS
  2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested.
  
  
  RESULTS
  Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance.
  
  
  CONCLUSIONS
  Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC.
authors.affiliation: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Nan
authors.initials: N
authors.lastname: Sui
authors.forename: Ming
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003024:Clozapine / Q000008:administration & dosage*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017366:Serotonin Receptor Agonists; D003024:Clozapine