Acute cocaine exposure occludes long-term depression in ventral tegmental area GABA neurons
Neurochemistry International(2021)
摘要
The ventral tegmental area (VTA) in the midbrain is essential in incentive salience of reward behavior. Drugs of abuse increase midbrain dopamine cell activity and/or dopamine levels, and can alter endogenous VTA glutamate plasticity, leading to addiction or dependence. VTA dopamine cells are regulated by local inhibitory GABA cells, which exhibit a form of pre-synaptic cannabinoid receptor 1-dependent long-term depression of their glutamatergic inputs. Our current aim was to determine cocaine's influence on VTA GABA cell glutamate plasticity and circuity. Using whole cell voltage-clamp electrophysiology in VTA slices of GAD67-GFP knock-in mice, we recorded excitatory inputs on VTA GABA cells. Acute and chronic injections of cocaine were sufficient to occlude long-term depression. The plasticity could be reversed to the naïve state however, as long-term depression was again observed following a 7-day abstinence from acute cocaine exposure. Furthermore, chronic cocaine decreased AMPA/NMDA ratios at glutamate synapses onto VTA GABA cells, compared to vehicle injection controls, the opposite change noted in dopamine cells. Collectively, our data suggest the cellular mechanism of cocaine-mediated synaptic modification that may result in dependence/withdrawal could involve changes in glutamate input to VTA GABA circuitry in addition to VTA dopamine cells. Therefore VTA GABA cells may also play a role, possibly in a synergistic manner with the dopamine circuit, in cocaine-induced changes to the VTA reward pathway than previously known.
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关键词
Endocannabinoid,Plasticity,AMPA,NMDA,VTA,Chronic,LTD,Glutamate
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