Novel, Cell Type-Specific Roles for Nucleus Accumbens Amylin Receptors in Oxycodone Taking in Rats
The rise in prescription opioid use and availability in recent decades has led to widespread abuse and an overdose epidemic that still persists in the United States. Therefore, there is a critical need for research to investigate the neurobiological mechanisms of opioid use disorder and to identify molecular targets for pharmacotherapies that can reduce opioid abuse liability. Recent evidence suggests that one potential pharmaceutical target is the amylin system. Amylin is a glucoregulatory hormone that reduces oxycodone taking- and seeking-behaviors in rats when administered into the nucleus accumbens (NAc) shell, a brain region critical to opioid reinforcement. However, the cell type-specific mechanisms underlying amylin’s suppressive effects are unknown. The main cell populations in the NAc comprise dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). Evidence suggests that D1R-MSNs encode the reinforcing effects of opioids while D2R-MSNs encode aversive states such as withdrawal. This study sought to determine the functional significance of amylin receptors expressed on these two cell populations in oxycodone taking. Amylin receptor expression was selectively reduced in D1R- and D2R-MSNs using a knock-down virus. The results showed that reduced amylin receptor expression in D1R-MSNs, but not D2R-MSNs, facilitated the acquisition of oxycodone taking. These findings suggest that these two cell populations have different roles in the development of compulsive oxycodone-taking behavior. Furthermore, reduced amylin receptor expression in D1R- and D2R-MSNs attenuated amylin’s suppressive effects on oxycodone taking; thus, exogenous amylin reduces oxycodone taking via both cell types. Ultimately, the results from this study demonstrate that amylin receptors may serve as molecular targets to mitigate the compulsive behaviors that characterize opioid use disorder.