Drugs of abuse alter neuronal signaling to reprioritize use over innate needs

Drugs of abuse, like cocaine and opioids, alter neuronal signaling in the nucleus accumbens (NAc), hijacking a key brain reward system involved with the fulfillment of innate needs for survival, according to a new study in mice. The findings provide mechanistic insights into the intensification of drug-seeking behaviors in substance use disorders. Persistent drug use is accompanied by a profound reprioritization of motivations, skewing decision-making behaviors toward a myopic focus on drug use over other innate needs, like eating or drinking water, often with little recognition of the adverse consequences. It’s thought that these impacts are driven, in part, by alterations in the brain’s reward systems, which normally function to identify and respond to the things essential for survival. However, the underlying physiological and molecular mechanisms linking the innate brain functions that become corrupted by drug use remain unclear. To address these unknowns, Bowen Tan and colleagues used whole-brain neuronal activity mapping, in vivo two-photon longitudinal calcium imaging, and single-cell sequencing to compare the response of key reward neural circuits activated by hunger and thirst to their response to morphine and cocaine in the mouse brain. Tan et al. discovered that the NAc plays a crucial role in motivated behavior and that, relative to other brain regions, activity in this region was increased in response to cocaine and morphine administration. Repeated exposure to these substances was found to drive functional and molecular changes that promote behavioral patterns underlying addiction and withdrawal. Tan et al. also identified Rheb – a gene that activates the mTOR pathway – as a molecular bridge that mediates cell-type-specific signaling in NAc and contributes to the ability of drugs to “hijack” natural reward processing. In vivo CRISPER perturbation of NAc-specific Rheb prevented the suppression of the natural reward responses induced by both cocaine and morphine. “Although these findings reveal how drugs can alter the neural circuitry that exists to satisfy survival needs, acute and chronic actions of drugs of abuse on decision-making extend beyond disrupting homeostatic needs,” write E. Zayra Millan and Gavan McNally. “Regardless, the findings by Tan et al. represent an important advance in understanding the brain mechanisms of addiction.”