NIH Reporter #1ZIAAA000421-18

Synaptic mechanisms underlying reward seeking and compulsive drug use

This NIH-funded project investigates how early life adversity affects dopamine receptor density in the brain's reward circuitry, promoting alcohol consumption in mice, especially males. Using a mouse model of fragmented maternal care, the study finds increased dopamine D1 receptor density linked to higher alcohol drinking behavior, revealing neurobiological mechanisms underlying vulnerability to substance use disorders.

Description

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. This study uses 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, the lasting behavioral and neurobiological impacts of this experience in adulthood are assessed. 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. Increases in the density of dopamine D1-like receptor in the striatum were uncovered, skewing the balance of D1- to D2-like receptor density in LBN-reared mice relative to cross-fostered controls. After voluntary alcohol drinking, a downregulation in D1-like receptor density restores the balance of dopamine receptors in the LBN-reared mice. The study posits that LBN-rearing conditions upregulate striatal density of dopamine D1-receptors via both transcriptional and post-transcriptional mechanisms, altering risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. 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.

View original record