Time course of the antipsychotic effect and the underlying behavioral mechanisms

Ming Li, Paul J. Fletcher, Shitij Kapur

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Antipsychotic drugs work for patients only when given repeatedly. The overall temporal pattern of symptom improvement is not clear. Some recent data question the traditional 'delayed-onset' hypothesis and suggest that the onset of antipsychotic response may be relatively early, and the improvement may grow with repeated treatment. The present study systematically examined the time course of the antipsychotic effect and the underlying behavioral mechanisms using a conditioned avoidance response (CAR) model. Rats repeatedly treated with either typical (haloperidol) or atypical (olanzapine, risperidone) antipsychotics, but not anxiolytics (chlordiazepoxide), show an early-onset, progressive across-session decline in avoidance responding, which re-emerges when the treatment is stopped. This effect is dose-dependent, transferable between antipsychotics, and cannot be attributed to simple sedation or motor side effects. Furthermore, we found that the pattern of this drug-induced decline depends on the number of exposures to the conditioned stimulus in the presence of the drug, and is best understood as the result of drug-induced attenuation of the reinforcing effectiveness of the conditioned stimulus. We also found that repeated drug exposure can create a drug interoceptive state that allows the attenuated reinforcing property of the stimulus to be maintained over time. Together, these data provide preclinical support for the newly postulated 'early-onset' hypothesis, and suggest that the repeated antipsychotic CAR model may be useful for understanding the neurochemical and behavioral mechanisms underlying the clinical effects of antipsychotics in patients with schizophrenia.

Original languageEnglish (US)
Pages (from-to)263-272
Number of pages10
Issue number2
StatePublished - Feb 2007


  • Conditioned avoidance response
  • Drug interoceptive state
  • Haloperidol
  • Olanzapine
  • Risperidone
  • Time course of antipsychotic effect

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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