Environmental and behavioral controls of the expression of clozapine tolerance: Evidence from a novel across-model transfer paradigm

Min Feng, Nan Sui, Ming Li

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Repeated administration of antipsychotic drugs induces a sensitization-like or tolerance-like effect in many behavioral tasks, including the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion, two rodent models with high predictive validity for antipsychotic activity. This study investigated the impacts of contextual and behavioral variables on the expression of clozapine tolerance using a recently validated across-model transfer paradigm (Zhang and Li, 2012 [1]). Male Sprague-Dawley rats were first repeatedly treated with clozapine (2.5-10.0. mg/kg, sc) in the CAR model or PCP (1.6. mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another 5 days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response. Clozapine tolerance and its situational specificity may be related to the drug's low extrapyramidal motor side effect, its superior therapeutic efficacy and/or emergence of clozapine withdrawal syndrome.

Original languageEnglish (US)
Pages (from-to)178-187
Number of pages10
JournalBehavioural Brain Research
Volume238
Issue number1
DOIs
StatePublished - Feb 1 2013

Keywords

  • Clozapine
  • Conditioned avoidance response
  • Contextual control
  • Motor activity
  • Phencyclidine
  • Tolerance

ASJC Scopus subject areas

  • Behavioral Neuroscience

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