1. ¹Schizophrenia-PET program, Centre for Addiction and Mental Health, Toronto, ON, Canada
2. ²Biopsychology Section, Centre for Addiction and Mental Health, Toronto, ON, Canada
3. ³Department of Psychology, University of Toronto, Toronto, ON, Canada
4. ⁴Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Kapur, Centre for Addiction and Mental Health, Clarke Site, 250 College Street, Toronto, ON, Canada M5R 1T8, Tel: +1 416 535 8501 x6176; Fax: +1 416 260 4206; E-mail: shitij_kapur@camh.net

⁵Current address: Department of Psychology, 238 Burnett Hall, University of Nebraska-Lincoln, Lincoln, NE 68588-0308, USA

Received 6 February 2006; Revised 23 March 2006; Accepted 25 April 2006; Published online 31 May 2006.

Abstract

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.