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.

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

“…There is accumulating evidence that repeated passive exposure to psychostimulants leads to deficits in tasks that depend on intact prefrontal cortex function (Fletcher et al, 2005(Fletcher et al, , 2007Roesch et al, 2007;Schoenbaum et al, 2004;Schoenbaum and Setlow, 2005). Moreover, withdrawal from repeated passive cocaine or amphetamine treatments also decreases firing rate and bursting activity of dmPFC neurons (Nogueira et al, 2006;Homayoun and Moghaddam, 2007) and abolishes dopamine D 2 receptor-mediated regulation of dmPFC excitability (Nogueira et al, 2006) and membrane bistability of dmPFC neurons (Trantham et al, 2002).…”

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…Repeated administration of psychostimulants has been shown to model important neurobiological, behavioral, and cognitive aspects of schizophrenia, including a sensitized mesolimbic dopamine system and impairments in attentional performance Goldman-Rakic, 1999, 2003;Castner et al, 2004Castner et al, , 2005Crider et al, 1982;Dalley et al, 2005;Featherstone et al, 2007;Fletcher et al, 2005Fletcher et al, , 2007Kapur, 2003;Martinez et al, 2005;Robinson and Becker, 1986;Russig et al, 2002;Tenn et al, 2003Tenn et al, , 2005. Based on extensive evidence indicating the crucial role of the cortical cholinergic input system for attention Parikh et al, 2007;Sarter et al, 2006Sarter et al, , 2005a, the attentional symptoms of schizophrenia have been proposed to be mediated via abnormalities in the regulation and activity of this neuronal system Raedler et al, 2003Raedler et al, , 2007Sarter et al, 2005b).…”

Dissociation between long-lasting behavioral sensitization to amphetamine and impulsive choice in rats performing a delay-discounting task

“…For example, rats that exhibit behavioral sensitization have been shown to have deficits in tasks measuring attentional set-shifting , sustained visual attention (Fletcher et al 2007), pre-pulse and latent inhibition (Tenn et al 2003, and, in primates, working memory (Castner et al 2005). Rats that self-administered AMPH over five different cycles of five days each, which were interspersed with a nine day drug-free period when they were tested in a five-choice serial reaction time task, exhibited deficits in visuospatial attention and no significant effects on perseverative (compulsive) or premature (impulsive) responding compared to yoked, saline-infused controls (Dalley et al 2005).…”