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Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTOR(loxP/loxP) mice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics, and cocaine-induced synaptic plasticity and rewarding effects. We find that targeted deletion of mTOR in the VTA had no significant effects on soma size and dendritic morphology of VTA neurons but significantly decreased dopamine release and reuptake in the nucleus accumbens (NAc) shell, a major target region. Western blot analysis revealed that mTOR deletion led to decreases in phosphorylated tyrosine hydroxylase (pTH-Ser40) levels in the VTA and dopamine transporter expression in the NAc. mTOR deletion had no significant effects on basal excitatory transmission in VTA dopamine neurons but caused an increase in GABAergic inhibition because of an increase in VTA GABAergic neuron firing. Furthermore, mTOR deletion attenuated conditioned place preference to cocaine and cocaine-induced potentiation of excitation and reduction of GABAergic inhibition in VTA dopamine neurons. Taken together, these results suggest that loss of mTOR in the VTA shifts the balance of excitatory and inhibitory synaptic transmission and decreases dopamine release and reuptake in the NAc. In addition, VTA mTOR signaling regulates cocaine-cue associative learning and cocaine-induced synaptic plasticity in VTA dopamine neurons.

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.