TY - JOUR
T1 - Time course of the antipsychotic effect and the underlying behavioral mechanisms
AU - Li, Ming
AU - Fletcher, Paul J.
AU - Kapur, Shitij
N1 - Funding Information:
Dr Ming Li was supported by a fellowship from Ontario Mental Health Foundation. Dr Shitij Kapur is supported by Canada Research Chair program. We thank Jun Parkes for helping with Experiments 1 and 4.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
KW - Conditioned avoidance response
KW - Drug interoceptive state
KW - Haloperidol
KW - Olanzapine
KW - Risperidone
KW - Time course of antipsychotic effect
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U2 - 10.1038/sj.npp.1301110
DO - 10.1038/sj.npp.1301110
M3 - Article
C2 - 16738541
AN - SCOPUS:33846248766
SN - 0893-133X
VL - 32
SP - 263
EP - 272
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 2
ER -