T. E. Thiele^{1, 4}; M. Navarro⁴; I. Cubero⁵; D. J. Knapp^{2, 4}; G. R. Breese^{3, 4}
1. Psychology, University of North Carolina, Chapel Hill, NC, USA.
2. Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
3. Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
4. Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA.
5. Neurociencia Y Ciencias de la Salud, University of Almeria, Almeria, Spain.

Background: Ethanol is a caloric compound, and ethanol drinking and feeding involve both appetitive and consummatory behaviors. It is therefore possible that overlapping central pathways are involved with uncontrolled eating and excessive ethanol consumption. Neuropeptide Y (NPY) and the melanocortin (MC) peptides produce orexigenic and anorectic effects, respectively. Recent investigations have implicated NPY and MC neuropeptides in the regulation of ethanol consumption. The purpose of the present research was to determine if compounds targeting central NPY or MC receptors (MCR) would produce similar effects on behaviors associated with the ingestion of ethanol or food.

Methods: Subjects were non-dependent C57BL/6J mice. For studies involving central infusions, mice were implanted with cannulae aimed at the lateral ventricle (ICV). Mice were individually housed, had ad libitum access to food, and were presented with 24-h access to a water bottle and an ethanol bottle. To determine the contributions of the NPY Y1 receptor, mice were given intraperitoneal (IP) or ICV administration of the Y1 receptor antagonist (Y1RA), [(-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl) ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-tiazol-2-yl)ethyl]-4-morpholinopyridine]. To study the contributions of MCR signaling, mice were given ICV infusion of the non-selective MCR agonist melanotan II (MT-II), the non-selective MCR antagonist agouti-related protein (AgRP)-83-132, or the selective MC-4 receptor agonist (MC4RA), cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2. Additionally, we studied MC-3 receptor (MC3R) knockout mice to determine the role of this receptor.

Results: In C57BL/6J mice, IP (25-75 mg/kg) and ICV (100 g) administration of the NPY Y1RA significantly reduced ethanol drinking and food intake over a similar time-frame. Similarly, ICV infusion of MTII (1.0 g) reduced, while AgRP-(83-132) (0.05 or 5.0 g) increased, feeding and ethanol consumption. MC3R knockout mice showed normal ingestive behavior and showed normal MTII-induced reduction of feeding and ethanol intake. ICV infusion of the selective MC4RA (1.0 and 3.0 g) reduced food and ethanol intake, implicating the MC4R. Importantly, none of the drugs examined influenced ethanol metabolism.

Discussion: In non-dependent C57BL/6J mice, administration of compounds targeting NPY Y1 or MC receptor produced similar and concurrent effects on ethanol and food ingestion. These results are consistent with the hypothesis that there is overlapping neuropeptide control of ethanol consumption and food intake. Several important questions remain. It will be important to determine if the effects of these compounds are similar in dependent versus non-dependent mice. In fact, recent data suggest that NPY produces very different effects in ethanol-dependent animals, implying that different NPY circuits are recruited over the course of ethanol dependence. A second important issue requiring resolution is whether compounds targeting NPY or MC receptor control ethanol drinking through a mechanism involving the regulation of calories or by a mechanism that modulates the pharmacodynamic effects of ethanol (e.g., the reinforcing properties of ethanol). Finally, it will be important to determine if ethanol alters NPY and/or MC signaling during the development of ethanol dependence, and if such alterations have subsequent effects of feeding behaviors.