Abstract
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.
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Acknowledgements
This work was supported by National Institutes of Health Grants DA024741.
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PZ, WW, and QSL designed the experiments. PZ, WW, FY, MN, and XJL performed the experiments, collected, and analyzed the data. PZ and QSL drafted the manuscript.
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Zhong, P., Wang, W., Yu, F. et al. Phosphodiesterase 4 Inhibition Impairs Cocaine-Induced Inhibitory Synaptic Plasticity and Conditioned Place Preference. Neuropsychopharmacol 37, 2377–2387 (2012). https://doi.org/10.1038/npp.2012.93
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DOI: https://doi.org/10.1038/npp.2012.93
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