PROJECT SUMMARY
Substance use disorders (SUDs), particularly those involving opioids, have reached epidemic levels. SUDs
are hypothesized to be learning and memory disorders: the association of drug ‘reward’ with otherwise neutral
stimuli promotes continued or reinstated drug use (relapse) when similar stimuli are re-encountered. Relapse
rates are 40-60%, suggesting that previously learned drug associations are a constant risk for those recovering
from SUDs. Socially-mediated learning is ubiquitous across species, and social factors also modulate drug use.
However, how social factors influence drug-associated learning, and its expression once established, is unclear.
The nucleus accumbens (NAc) reward region is critical for both drug associative learning and for social influence
over behavior. We determined that microglia, the resident immune cells of the brain, mediate social development
via phagocytosis, or “pruning,” of synaptic proteins in the NAc core during early adolescence in male rats, and
pre-adolescence in females. Adolescent drug use increases SUD risk and social dysfunction later in life; in fact,
even prescription opioid use in adolescence increases opioid misuse later in life. The opioid morphine directly
activates a pro-phagocytic receptor on microglia, including on NAc microglia. These data raise the possibility
that adolescent opioid use increases SUD risk by changing microglia-mediated NAc and social development,
and in turn social influence over reward learning.
In this proposal, we will restrict short-term morphine exposure to each sex-specific NAc core pruning period
in adolescence to determine (1) how morphine affects ongoing developmental synaptic pruning activity, (2) social
development, and (3) socially-mediated reward learning. Our core hypothesis is that adolescent morphine
exposure exacerbates microglia-mediated pruning in the NAc core, causing abnormal social development and
increased social influence over reward learning. This proposal will be the first to examine a mechanistic
relationship between social development in adolescence and reward learning in adulthood, and may identify sex-
specific adolescent periods of vulnerability during which lifetime SUD risk and other mental health disorders can
be influenced.
