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

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 forskolininduced increase in cAMP levels in midbrain slices, consistent with reported effects of inhibition of phosphodiesterases (PDEs). Resveratrol potentiated GABA A and GABA B -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.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 . Since the discovery that resveratrol mimics the life-span extending effects of calorie restriction in budding yeast 2 , this compound has attracted great interest. However, past research has focused on its role in protecting against aging-related diseases 1 . Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. Acute resveratrol treatment enhances cocaine-induced increases in dopamine D 1 receptor signaling and locomotor activity in mice, presumably via mechanisms involving the inhibition of monoamine oxidases 3 . In contrast, acute resveratrol treatment is ineffective at altering methamphetamine-induced hyperactivity in mice, while repeated resveratrol treatments decrease methamphetamine-induced hyperactivity in mice and dopamine overflow from rat striatal slices 4 . There are conflicting reports regarding whether resveratrol alters cocaine-induced conditioned place preference (CPP). Resveratrol has been shown to enhance cocaine CPP by activating the NAD(+)-dependent histone deacetylase sirtuins 5 . However, another study has shown that resveratrol is ineffective in altering CPP but attenuates cocaine withdrawal-induced anxiety 6 . A recent study has identified phosphodiesterases (PDEs) as a direct target for resveratrol, and both resveratrol and the selective PDE4 inhibitor rolip...

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…Interestingly, acute RSV treatment enhanced cocaine-induced dopamine neurotransmission and behavioral responses suggesting that RSV promotes drug addiction [49,50]. However, RSV is also shown to protect against drug addiction through an unknown mechanism [51,52]. Consistent with the dichotomic effects discussed above, RSV protects against Wallerian degeneration [53], but it also abolishes neuroprotection mediated through Wallerian-slow degeneration mutants [25].…”

Inhibitory Plasticity of Mesocorticolimbic Circuits in Addiction and Mental Illness

“…Reversing maladaptive plasticity at inhibitory synapses holds potential for treating various neuropsychiatric disorders, including addiction, depression, and anxiety. While the translational relevance of this approach remains to be examined, an increasing number of studies show that pharmacologic targeting of inhibitory synaptic plasticity can prevent or block various aberrant behaviors in animal models of pathology [26, 31, 32, 59, 61, 64, 89]. A form of inhibitory plasticity that has gained increasing attention involves long-lasting alterations in the transmembrane Cl − gradient.…”

Resveratrol Modulates the Gut-Brain Axis: Focus on Glucagon-Like Peptide-1, 5-HT, and Gut Microbiota

“…Several studies have mentioned the neurological role of resveratrol in depression and anxiety (Yu et al, 2013;Li et al, 2017) and the gut homeostasis-related role of resveratrol in stress-induced irritable bowel syndrome (Xu Y. et al, 2018).…”

“…Bastien -Dionne et al, 2011;Daitoku et al, 2011;Dao et al, 2011;Lee et al, 2012Lee et al, , 2014Samson and Bajaj, 2013;Xu et al, 2014;Shi and Huang, 2018;Zhuang et al, 2019 Resveratrol and 5- HT Xu et al, 2010;Yu et al, 2013Yu et al, , 2019Enck et al, 2016;Li et al, 2017;Nabavi et al, 2017;Peng et al, 2018;Xu L. et al, 2018 Resveratrol and gut microbiota Dao et al, 2011;Wu et al, 2011;Amri et al, 2012;Rotches-Ribalta et al, 2012;Bode et al, 2013;Qiao et al, 2014;Hsieh et al, 2015;Basholli-Salihu et al, 2016;Ling et al, 2016;Bird et al, 2017;Carrera-Quintanar et al, 2018;Hu et al, 2019 Ripken et al suggested that serotonin treatment could boost GLP-1 release, and the blocking of 5-HT receptor could affect the production of GLP-1 (Ripken et al, 2016).…”