Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase-1 improves cognitive performance

Abstract

Background and Purpose: Insufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor-dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function. Experimental Approach: Cognitive performance of the D1 receptor agonist, SKF38393, was studied in the T-maze continuous alternation task and 5-choice serial reaction time task. D1 receptor/PDE1B double-immunohistochemistry was performed using human and rat prefrontal brain sections. The pharmacological activity of the PDE1 inhibitor, ITI-214, was assessed by measuring the increase in cAMP/cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on the modulation of prefrontal neuronal transmission by SKF38393 and ITI-214 were performed using extracellular recordings in brain slices. Key Results: SKF38393 improved working memory and attentional performance in rodents. D1 receptor/PDE1B co-expression was verified in both human and rat prefrontal brain sections. The pharmacological activity of ITI-214 on its target, PDE1, was demonstrated by its ability to increase prefrontal cAMP/cGMP. In addition, ITI-214 improved working memory performance. Both SKF38393 and ITI-214 facilitated neuronal transmission in prefrontal brain slices. Conclusion and Implications: We hypothesize that PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data, therefore, support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction.