Sildenafil promotes dual memory effects in young rats: involvement of dopamine reuptake

Sildenafil, a phosphodiesterase-5 inhibitor, crosses the blood-brain barrier, enhancing cGMP signaling, dopamine neurotransmission, and hippocampal plasticity-key mechanisms for learning and memory.

This study aimed to (1) determine whether sildenafil influences hippocampal dopamine levels by modulating dopamine transporter (DAT) function in naïve young rats; (2) assess sildenafil-induced dopamine increases by evaluating its impact on hippocampal-dependent memories in non-aversive and aversive tasks; and (3) examine the effects of acute sildenafil administration on hippocampal synaptic plasticity.

DAT function was assessed through ex-vivo dopamine reuptake analysis in the hippocampus and nucleus accumbens of rats sacrificed 2 h post-administration. Memory effects were evaluated by administering sildenafil 2 h before training in non-aversive (novel object recognition-NOR, Y-maze, Barnes maze) and aversive (step-down inhibitory avoidance, fear conditioning) tasks. To examine D3 receptor (D3R) involvement, a subset of animals received the selective D3R antagonist FAUC-365 before NOR training. Synaptic plasticity was analyzed via electrophysiology and dendritic spine density.

Sildenafil reduced dopamine reuptake, likely by inhibiting DAT. It impaired NOR performance, an effect prevented by D3R antagonism, while leaving working and long-term spatial memory unaffected. Additionally, sildenafil enhanced aversive memory expression, facilitated hippocampal long-term potentiation, and increased dendritic spine density.

Sildenafil differentially affected hippocampal-dependent memory, potentially by increasing dopamine transmission. In young, healthy individuals, sildenafil may impair recognition memory and alter responses to non-threatening stimuli, influencing cognitive and emotional processes.