Sahr AE, Sindelar DK, Alexander-Chacko JT, Eastwood BJ, Mitch CH, Statnick MA. Activation of mesolimbic dopamine neurons during novel and daily limited access to palatable food is blocked by the opioid antagonist LY255582. Am J Physiol Regul Integr Comp Physiol 295: R463-R471, 2008. First published June 4, 2008 doi:10.1152/ajpregu.00390.2007.-An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the -, ␦-, and -opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/ high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake. opiate; nucleus accumbens; obesity; food intake; microdialysis INVOLVEMENT OF THE CENTRAL opioid system in the regulation of food intake is well established (for review, see Refs. 22 and 49). Many studies have demonstrated that agonists at all three opioid receptor subtypes, , ␦, and , increase food intake (26, 44), whereas antagonists decrease food intake (22, 49). More specifically, manipulations of the opioid system regulate hedonic feeding or the intake and response to highly palatable (HP) macronutrients (high-fat and/or high-sucrose) (5, 6, 33, 37). The acquisition of hedonic feeding appears to involve activation of the mesolimbic dopamine (DA) system, the dopaminergic projection from the ventral tegmental area to the nucleus accumbens (NAc) (8,11,17,21,41,42). This pathway is a key component of the brain reward circuit (33, 60) that consists of neural pathways strongly implicated in reward and reinforcement mechanisms of drugs of abuse, as well as vital behaviors, including feeding and sexual behavior. Several neurotransmitter and neuropeptide systems that modulate feeding do so, at least in part, by acting through the mesolimbic DA pathway (1, 36, 59). Endogenous opioids regulate the mesolimbic DA projection at both the level of the ventral tegmental area and NAc (30, 54), providing a potential mech...