title: A sensitizing regimen of amphetamine impairs visual attention in the 5-choice serial reaction time test: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.
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.
authors.affiliation: Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, ON, Canada. Paul_Fletcher@camh.net
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Tenn
authors.forename: Judy
authors.initials: J
authors.lastname: Sinyard
authors.forename: Zoë
authors.initials: Z
authors.lastname: Rizos
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009483:Neuropsychological Tests; D010775:Photic Stimulation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D014796:Visual Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000661:Amphetamine; D004298:Dopamine