Activation of mesolimbic dopamine neurons during novel and daily limited access to palatable food is blocked by the opioid antagonist LY255582

Lilly Research Laboratories, Indianapolis, Indiana Submitted 5 June 2007 ; accepted in final form 3 June 2008 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 µ-, -, 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 Address for reprint requests and other correspondence: M. A. Statnick, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0403 (e-mail: m.statnick{at}lilly.com )