Repeated social stress induces metaplasticity in ventral tegmental area dopaminergic neurons




Stelly, Claire Elizabeth

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Learned associations between environmental cues and drug reward are critical for reinforcing drug use and triggering relapse. Effective prevention and treatment of substance use disorders requires a detailed understanding of the synaptic plasticity mechanisms underlying these associations as well as their modulation by experience, environment, and genetic differences. Stressful experience increases susceptibility to addiction in humans and hastens the development of addiction-related behaviors in rodent models. The facilitating effects of stress persist beyond the duration of the stressful experience, suggesting that stress causes persistent cellular adaptations that promote drug-related learning processes. The data presented in this dissertation demonstrate that stress, via glucocorticoid receptor (GR) signaling, induces metaplasticity of N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). NMDAR-mediated transmission in these neurons is of particular importance as it is required for burst firing and subsequent phasic dopamine release, which is both necessary and sufficient for learning of reward-predictive cues. Repeated exposure to social defeat stress induces a persistent, PKA-dependent increase in the sensitivity of inositol 1,4,5-triphosphate (IP3) receptors. This sensitization of IP3Rs augments metabotropic glutamate receptor (mGluR) -dependent calcium (Ca²⁺) signaling, which then enhances induction of long-term-potentiation of NMDAR transmission (NMDAR-LTP). Repeated social defeat stress also enhanced acquisition of cocaine conditioned place preference (CPP), a form of associative learning driven by drug reward, and this effect required GR signaling as well. This dissertation provides the first demonstration of stress-induced metaplasticity in VTA DA neurons. These findings may illuminate one mechanism by which stress increases vulnerability to addiction, a chronic, relapsing disorder that is perpetuated by powerful memories of stimuli associated with drug reward.



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