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

Correspondence: Dr PJ Fletcher, Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8, Tel: +1 416 535 8501 X4058; Fax: +1 416 979 6942; E-mail: Paul_Fletcher@camh.net

⁵Current address: DRDC Suffield PO Box 4000, Station Main, Medicine Hat, Alberta, Canada T1A 8K6.

Received 9 June 2006; Revised 25 July 2006; Accepted 25 August 2006; Published online 18 October 2006.

Abstract

Exposure to repeated, intermittent, escalating doses of amphetamine in rats disrupts information processing in several tasks. Some of these deficits, notably impaired attentional set shifting, may reflect altered prefrontal cortex function. This study examined the effects of repeated treatment with amphetamine on performance in the 5-choice serial reaction time test. This test measures sustained visual attention, a behavior that is known to require the prefrontal cortex. Rats were trained to respond to a brief light stimulus presented randomly in one of five spatial locations, with 100 trials per session. Once performance had stabilized rats were treated with escalating doses of amphetamine (three injections per week for 5 weeks at 1–5 mg/kg per week); testing was continued on nondrug days, and for several weeks of withdrawal. During the amphetamine-treatment and withdrawal phases accuracy of responding was unaffected, but errors of omission increased. Lengthening the stimulus duration abolished this effect. Reducing the stimulus duration also reduced response accuracy and this effect was more marked in amphetamine-treated rats. Both reduced accuracy, and increased omissions, seen in amphetamine-treated rats were reversed by injecting the D1 receptor agonist SKF38393 into the medial prefrontal cortex. This treatment also prevented the decline in accuracy in control animals that resulted from reducing the stimulus duration. These results, indicating that exposure to amphetamine induces a long-lasting deficit in visual attention, add to a growing list of deficits suggesting that amphetamine-sensitized state may model the cognitive deficit state in schizophrenia. The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia.