Dopamine D1 receptor modulation of set shifting: the role of stress exposure.

Chronic stress exerts detrimental effects on higher order executive functions that are governed by the prefrontal cortex. Experimental data suggest that dopamine D1 receptor-mediated hypodopaminergic dysfunction may underlie stress-induced cognitive deficits. However, although the involvement of D1 receptors in working memory is well established, less is known about their role in the modulation of set-shifting ability. Therefore, the aim of the present study was to examine the impact of the selective D1 receptor agonist, SKF 81297, on the attentional set-shifting task performance of rats subjected to repeated restraint stress and of unrestrained controls. The acute administration of SKF 81297 to control rats facilitated extradimensional set-shifting. However, only intermediate doses (0.1 and 0.3 mg/kg) were effective, whereas no effect was observed after the administration of either lower (0.01 mg/kg) or higher (1 mg/kg) doses. This dose-response curve was shifted to the left in stressed animals as the effectiveness of SKF 81297 (as compared with either vehicle-treated controls or stressed animals) was found only after the administration of lower drug doses (0.01 and 0.1 mg/kg). The beneficial effects of SKF 81297 on the attentional set-shifting task performance of stressed rats may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders.