Glutamate Receptor Plasticity in the Nucleus Accumbens Core After Social Choice-Induced Voluntary Abstinence: Implications for Synaptic Adaptations in Addiction

Preclinical studies on drug addiction and relapse often overlooked volitional social interactions despite their critical importance in human addiction. Recently, it has been demonstrated that social choice-based voluntary abstinence (SVA) prevents the incubation of methamphetamine craving in rats, yet the underlying neurobiological mechanisms remain poorly understood. Here, we interrogated excitatory synaptic transmission onto medium spiny neurons (MSN) of NAc core of rats, to understand how it is differentially shaped by SVA compared to forced abstinence (FA). Our findings reveal that SVA restores basal glutamatergic activity, renormalizes synaptic strength, and prevents the increase in excitatory drive observed in FA. A key mechanism driving cue-induced drug craving is the accumulation of calcium-permeable AMPAR (CP-AMPARS) in the Nac during abstinence. However, while SVA blocks the incubation of methamphetamine craving, our findings suggest that this mechanism is independent from CP-AMPAR accumulation, suggesting the involvement of alternative mechanisms at glutamatergic synapses onto MSN. Finally, our findings highlight the therapeutic potential of positive social interactions as a non-pharmacological intervention to reduce relapse vulnerability in methamphetamine use disorder, suggesting that SVA counteracts maladaptive synaptic plasticity and exerts a positive effect by preserving neurophysiological homeostasis in the NAc.