Cocaine self‐administration abolishes endocannabinoid‐mediated long‐term depression of glutamatergic synapses in the ventral tegmental area
Cocaine self‐administration abolishes low‐frequency stimulation‐induced long‐term depression (LFS‐LTD) of glutamatergic synapses onto dopaminergic neurons in the ventral tegmental area. The LFS‐LTD is mediated by presynaptic endocannabinoid signaling. Cocaine self‐administration reduces CB1 receptor function, blocks LFS‐LTD, and enhances dopamine release, which could be one of the cellular mechanisms underlying the addictive effects of cocaine.
Drugs of abuse, including cocaine, alter the mechanisms underpinning synaptic plasticity, including long‐term potentiation of glutamatergic synapses in the mesolimbic system. These effects are thought to underlie addictive behaviors. In the ventral tegmental area (VTA), glutamatergic synapses also exhibit long‐term depression (LTD), a type of plasticity that weakens synaptic strength. This form of synaptic plasticity is induced by low‐frequency stimulation and mediated by endocannabinoid (eCB) signaling, which also modulates addictive behaviors. However, it remains unknown whether eCB‐LTD in the VTA could be altered by cocaine use. Therefore, the goal of the present study was to examine the impact of cocaine self‐administration on eCB‐LTD of glutamatergic synapses onto VTA dopaminergic (DA) neurons. To that end, male rats underwent cocaine (0.75 mg/kg/infusion) or saline self‐administration under the fixed ratio 1 schedule for 6–9 days. One day after the last self‐administration session, the magnitude of eCB‐LTD was examined using ex vivo whole‐cell recordings of putative VTA DA neurons from naïve rats and rats with saline or cocaine self‐administration. The results revealed that cocaine self‐administration abolished eCB‐LTD. The cocaine‐induced blockade of eCB‐LTD in the VTA was mediated by an impaired function of presynaptic CB1 receptors. Collectively, these findings indicate that cocaine exposure blunts eCB‐mediated synaptic plasticity in midbrain DA neurons. This effect could be one of the cellular mechanisms that mediate, at least in part, addictive behaviors.