Activation of RMTg projections to the VTA reverse cocaine-induced molecular adaptation in the reward system

Abstract

The rostromedial tegmental nucleus (RMTg) plays a crucial role in regulating reward-related behavior by exerting inhibitory control over the ventral tegmental area (VTA). This modulation of dopamine neuron activity within the VTA is essential for maintaining homeostasis in the reward system. Recently we have shown that activation of RMTg projections to the VTA during the acquisition of cocaine-conditioned place preference (CPP) reduces the rewarding properties of cocaine and decreases VTA dopamine neuron activity. By inhibiting dopamine neurons in the VTA, we hypothesized that RMTg projections hold the potential to restore reward system homeostasis disrupted by repeated cocaine use, and attenuate molecular adaptations in the reward system, including alterations in signaling pathways. Our study demonstrates that enhancing the GABAergic inputs from the RMTg to the VTA can mitigate cocaine-induced molecular changes in key regions, namely the VTA, nucleus accumbens (NAc), and prefrontal cortex (PFC). Specifically, we found that cocaine-induced alteration in the phosphorylation state of ERK (pERK) and GluA1 on serine 845 (S845) and serine 831 (S831), that play a major role in plasticity by controlling the activity and trafficking of AMPA receptors, were significantly reversed following optic stimulation of RMTg afferents to the VTA. These findings highlight the therapeutic potential of targeting the RMTg-VTA circuitry for mitigating cocaine reward. Ultimately, this research may pave the way for novel therapeutic interventions that restore balance in the reward system and alleviate the detrimental effects of cocaine.