Current pharmacotherapies used to treat opioid use disorder have modest efficacy in promoting long-term abstinence. Thus, there is a critical need for the development of novel medications that improve chronic pain management while reducing opioid abuse liability.  Emerging evidence from our lab suggests that systemic administration of amylin, a neuropeptide and metabolic factor, reduces opioid reinforcement in rats. However, the circuit- and cell type-specific mechanisms that mediate amylin’s suppressive effects are still unknown. The mesolimbic dopamine system plays a critical role in the reinforcing effects of natural rewards and drugs of abuse. Specifically, the nucleus accumbens (NAc) is involved in decoding rewarding and aversive stimuli. The two main cell populations involved are dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). Recent studies from our lab show that amylin administration directly into the nucleus accumbens (NAc) shell reduces oxycodone taking- and seeking-behaviors in rats. In this study, we aimed to characterize the relative contribution of D1R- and D2R-MSNs to these suppressive effects of amylin. Using a Cre-dependent knock-down (KD) virus, we reduced amylin receptor expression selectively in D1R- and D2R-MSNs in the NAc shell. Our pilot studies show that amylin receptor KD in D1R- and D2R-MSNs respectively potentiated and attenuated the acquisition of oxycodone self-administration. We additionally demonstrate that amylin receptors in both D1R- and D2R-MSNs are implicated in the motivation to self-administer oxycodone and the reinstatement of oxycodone seeking. Finally, we reveal a novel role of endogenous amylin in the acquisition of oxycodone taking. Together, these findings suggest that amylin receptors may serve as molecular targets to reduce opioid abuse liability.