Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs)

Yan Li,Qing-Song Liu,Fanxing Zeng,Laikang Yu,Li Zhao

doi:10.1038/s41598-017-16034-9

Abstract

Resveratrol is a natural phytoalexin synthesized by plants, including grapes. It displays a wide range of neuroprotective benefits associated with anti-aging. Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. The goal of the present study is to investigate whether and how resveratrol alters basal inhibitory synaptic transmission and cocaine-induced inhibitory synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA). We report that resveratrol elevated cAMP levels by itself and further potentiated a forskolin-induced increase in cAMP levels in midbrain slices, consistent with reported effects of inhibition of phosphodiesterases (PDEs). Resveratrol potentiated GABAA and GABAB-mediated inhibitory postsynaptic currents (IPSCs) in VTA dopamine neurons, and these effects were mediated by a protein kinase A (PKA)–dependent enhancement of presynaptic GABA release. In addition, we found that resveratrol blocked endocannabinoid-mediated long-term synaptic depression in VTA dopamine neurons. Resveratrol pretreatments attenuated cocaine-induced conditioned place preference and blocked the cocaine-induced reduction of GABAergic inhibition in VTA dopamine neurons. Together, these results provide evidence that resveratrol modulates basal inhibitory synaptic transmission, cocaine-induced synaptic plasticity, and drug-cue associative learning.

Highlights

Resveratrol (3,4′,5-trihydroxy-trans-stilbene), a constituent of red wine, produces a wide range of health benefits associated with anti-aging, including protection against type 2 diabetes, obesity, cancer, heart disease, and neurodegenerative diseases[1]
Having shown that resveratrol enhanced the amplitude of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs), we examined whether resveratrol affected I-LTD in ventral tegmental area (VTA) dopamine neurons
The present study has shown that resveratrol increased cAMP levels in midbrain slices

Summary

Introduction

Resveratrol (3,4′,5-trihydroxy-trans-stilbene), a constituent of red wine, produces a wide range of health benefits associated with anti-aging, including protection against type 2 diabetes, obesity, cancer, heart disease, and neurodegenerative diseases[1]. A recent study has identified phosphodiesterases (PDEs) as a direct target for resveratrol, and both resveratrol and the selective PDE4 inhibitor rolipram ameliorate aging-related metabolic phenotypes through inhibition of PDEs7. Selective PDE4 inhibitors such as rolipram significantly reduce cocaine-induced increases in locomotor activity, behavioral sensitization, conditioned place preference (CPP) and self-administration[13,14,15,16,17]. Resveratrol has been shown to enhance AMPAR expression via AMP-activated protein kinase-mediated protein translation in cultured neurons[18], it was unknown whether resveratrol modulates inhibitory synaptic transmission and plasticity. We have shown that endocannabinoid-mediated I-LTD is required for the cocaine-induced reduction of GABAergic inhibition to VTA dopamine neurons[19,20]. We investigated whether systemic administration of resveratrol altered cocaine-induced CPP and reduction of GABAergic inhibition in VTA dopamine neurons

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