Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference.

Endocannabinoid-mediated long-term depression of inhibitory synaptic transmission (I-LTD) in the ventral tegmental area (VTA) is implicated in cocaine-induced inhibitory synaptic plasticity and behavioral effects. It remains poorly understood, however, how this I-LTD is regulated and whether this regulation affects cocaine-seeking behavior. I-LTD requires cyclic adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase A (PKA) signaling, raising the possibility that modulators of cAMP/PKA signaling may regulate I-LTD and the reinforcement behavior. Phosphodiesterase (PDE) 4 hydrolyses cAMP and terminates cAMP/PKA signaling. Here, we report that selective PDE4 inhibitors rolipram and Ro 20-1724 blocked I-LTD and acute depression of inhibitory postsynaptic currents (IPSCs) induced by D₂ dopamine receptor and cannabinoid CB₁ receptor agonists in VTA dopamine neurons. We also show that intra-VTA microinjections of PDE4 inhibitor rolipram impaired the acquisition, but not the expression, of conditioned place preference (CPP) to cocaine. Systemic administration of rolipram also increased cAMP response element-binding protein (CREB) phosphorylation and activation in the VTA. Together, our results suggest that blockade of cocaine-induced inhibitory synaptic plasticity (I-LTD) and enhancement of CREB activation are two putative cellular mechanisms by which PDE4 inhibition impairs the acquisition of cocaine CPP.