Neuropeptide Y receptor modulation of dopamine transmission in the nucleus accumbens core

The mesolimbic dopamine (DA) system is a central regulator of reward processing, motivation, and affective state. Neuropeptide Y (NPY), one of the most abundant neuropeptides in the brain, is highly expressed within the nucleus accumbens (NAc), a key node of the mesolimbic pathway. Although NPY signaling has been implicated in stress resilience, affective behavior, and reward processing, its mechanistic influence on accumbal DA transmission remains poorly defined. Here, we examined receptor-specific NPY modulation of DA release within the NAc core using fast-scan cyclic voltammetry (FSCV) in acute mouse brain slices. Bath application of NPY significantly increased evoked DA release in female but not male mice. The selective Y1 receptor agonist [Leu³¹,Pro³⁴]NPY similarly enhanced DA release in females, and these effects were abolished by the Y1 receptor antagonist BIBO 3304, confirming Y1 receptor specificity. In contrast, Y1 receptor agonists had no significant effect on DA release in males, whereas Y1 receptor antagonism led to an increase in DA release. Complementary experiments demonstrated that antagonism of Y5 receptors with L-152,804 increased DA release in both sexes. These data highlight NPY receptors as potent modulators of NAc core dopamine function and provide mechanistic insight to how NPY signaling could serve as a critical interface linking stress, affective state, and DA-dependent behaviors.