Central administration of NPY or an NPY-Y5 selective agonist increase in vivo extracellular monoamine levels in mesocorticolimbic projecting areas

Selective NPY-Y5 antagonists are known to reduce NPY-evoked increase of food intake under free feeding conditions and drug-reinforced operant responding in rodents suggesting that NPY-Y5 receptors can regulate reinforcers, potentially by modulating the hypothalamic-limbic reward system. However, evidence published to date has revealed a limited expression of NPY-Y5 in the limbic areas. Thus, the first aim of the present study was to investigate the distribution of NPY-Y5 receptor binding sites in rat mesocorticolimbic projection areas such as the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and lateral hypothalamus (LH). Since mesocorticolimbic release of monoamines has been typically associated to the rewarding and motivational significance of reinforcers, we then compared the ability of NPY and an NPY-Y5 selective agonist, cPP1–7,NPY19–23,Ala31,Aib32,Gln34]hPP, to evoke changes in extracellular monoamines from these brain regions using in vivo microdialysis techniques. Intracerebral doses of each compound were selected on the basis of those previously demonstrated to trigger food intake in a separate set of animals. We found that NPY-Y5 receptors were widely distributed in both the NAc and mPFC but not in the LH nuclei. Central administration of either NPY (4.5 nmol/rat) or the NPY-Y5 agonist (0.6 nmol/rat) induced a significant increase of dopamine (DA) output of up to 150% of basal values in the NAc. In addition, NPY induced a stepped increase of norepinephrine (NE) outflow in the NAc area. Also extracellular levels of NE levels were increased by both treatments in the mPFC (150% vs basal concentration). Hypothalamic monoamine levels were unaffected by both treatments. Extracellular serotonin (5-HT) levels were also unchanged in all regions. Given the NPY-Y5 agonist paralleled the in vivo ability of NPY to increase DA, these data suggest that the release of NPY may modulate behaviours associated to accumbal DA release such reward and reinforcement by, at least in part, acting on mesocorticolimbic NPY-Y5 receptors.