Synaptic mechanisms underlying reward seeking and compulsive drug use

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Project title: “Early life adversity increases striatal density of dopamine D1 receptors and promotes social alcohol drinking in mice, especially males ” The brain’s reward circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. It is thought that adverse experiences early in life can increase vulnerability to substance use disorders, likely through alterations to this circuitry. Yet, the precise neurobiological mechanisms by which early life adversity acts are incompletely characterized. In this study, we use the limited bedding and nesting (LBN) paradigm as a translationally relevant model of fragmented maternal care in genetically-identical, C57BL/6J mice. After LBN-rearing, we assess the lasting behavioral and neurobiological impacts of this experience in adulthood. In robust sample sizes, our results validate previous findings of increased risk avoidance, enhanced acute response to alcohol, and greater voluntary alcohol drinking in LBN-reared mice, especially males, even when tested in social housing conditions. Further, we uncovered increases in the density of dopamine D1-like receptor in the striatum, which skews the balance of D1- to D2-like receptor density in LBN-reared mice, relative to cross-fostered controls. Interestingly, after voluntary alcohol drinking, we find a downregulation in D1-like receptor density that restores the balance of dopamine receptors in the LBN-reared mice. We posit that LBN-rearing conditions upregulate striatal density of dopamine D1-receptors, via both transcriptional and post-transcriptional mechanisms, and it alters risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. Overall, our findings uncover specific neurobiological mechanisms that promote alcohol consumption after early life adverse events and point towards complex interactions between early life experience, dopamine receptor regulation, alcohol, and sex-related factors in the mediation of AUD vulnerability.