LAUSR

Rationale Cognitive dysfunction mediates functional impairment in patients with schizophrenia, necessitating the timely development of pro-cognitive therapeutics. An important initial step in this process is to establish what, if any, pro-cognitive agents and associated mechanisms can be identified using cross-species translational paradigms. For example, attentional deficits—a core feature of schizophrenia—can be measured across species using the 5-choice continuous performance test (5C-CPT). The psychostimulant, amphetamine, improves human and rodent 5C-CPT performance. Objective Here, we tested whether amphetamine would similarly improve 5C-CPT performance in the presence of dopamine D2 receptor blockade, since pro-cognitive treatments in schizophrenia would virtually always be used in conjunction with D2 receptor antagonists. Methods We established the dose-response effects of amphetamine (0, 0.1, 0.3, or 1.0 mg/kg) and haloperidol (0, 3.2, 10, or 32 μg/kg) on 5C-CPT performance in Long Evans rats, and then tested an amphetamine (0.3 mg/kg) × haloperidol (10 μg/kg) interaction; the low dose was chosen because higher doses exerted deleterious non-specific effects on performance. Results Amphetamine improved 5C-CPT performance in poorly performing rats by increasing target detection, independent of haloperidol pretreatment. Conclusions The pro-attentional effects of amphetamine were most likely mediated by dopamine release at D1-family receptors, since they persisted in the presence of acute D2 blockade. Alternative explanations for these findings are also discussed, as are their potential implications for future pro-cognitive therapeutics in schizophrenia.