Y do we drink

The observation of increased ethanol preference in NPY-KO mice raises the possibility that the regulation of reward pathways may be included among the many actions of this neuropeptide. This possible role of NPY had received little attention despite the expression of NPY and its Y1 and Y2 receptor subtypes in the amygdala and nucleus accumbens. These structures are components of the mesolimbic dopamine system, a pathway believed to mediate the rewarding aspects of food, alcohol, and other drugs of abuse (reviewed in Koob 1992xKoob, G.F. Trends Pharmacol. Sci. 1992; 13: 177–184Abstract | Full Text PDF | PubMed | Scopus (1647)See all ReferencesKoob 1992; Heilig et al. 1994xHeilig, M, Koob, G.F, Ekman, R, and Britton, K.T. Trends Neurosci. 1994; 17: 80–85Abstract | Full Text PDF | PubMed | Scopus (277)See all ReferencesHeilig et al. 1994). For example, NPY facilitates dopamine release in the nucleus accumbens (Ault et al. 1998xAult, D.T, Radeff, J.M, and Werling, L.L. J. Pharmacol. Exp. Ther. 1998; 284: 553–560PubMedSee all ReferencesAult et al. 1998) and enhances the extent to which animals will work to receive food rewards (Jewett et al. 1992xJewett, D.C, Cleary, J, Levine, A.S, Schaal, D.W, and Thompson, T. Pharmacol. Biochem. Behav. 1992; 42: 207–212Crossref | PubMed | Scopus (35)See all ReferencesJewett et al. 1992). Moreover, local injections of NPY into the nucleus accumbens may be rewarding, as indicated by a preference of animals for the environment in which the effects of such injections were experienced (Josselyn and Beninger 1993xJosselyn, S.A and Beninger, R.J. Pharmacol. Biochem. Behav. 1993; 46: 543–552Crossref | PubMed | Scopus (64)See all ReferencesJosselyn and Beninger 1993). Based on these findings, one might predict that the rewarding effects of alcohol would be blunted in NPY mutant mice.How, then, can we account for the elevated ethanol preference of mice lacking NPY? Although this result could reflect an increased sensitivity of mutants to the rewarding properties of alcohol, the converse interpretation, diminished sensitivity to ethanol reward, must also be considered. In the latter case, elevated ethanol consumption may be required for animals to obtain pharmacological effects equivalent to those of wild-type mice. It is also important to consider the possibility that animals were not drinking to intoxication during the preference assay. It is known that factors independent of the pharmacological effects of ethanol, such as taste and novelty, may influence preference (Cicero 1980xCicero, T.J. See all ReferencesCicero 1980).Thus, further studies will be required to clarify the mechanisms underlying the increased preference displayed by the mutant mice. For example, detailed analysis of diurnal patterns of ethanol ingestion will be helpful here. Overconsumption in the form of intermittent prolonged drinking bouts would be more likely to produce pharmacological effects than a diffusely elevated pattern of ingestion. Ultimately, blood alcohol determinations during preference testing will be required to determine whether animals attain levels sufficient to achieve pharmacological effects. In addition, operant conditioning procedures in which animals work for ethanol access will clarify the impact of the NPY gene mutation on the rewarding properties of ethanol.As for all null mutant models, it will be important to determine the extent to which the adult mutant phenotype reflects the normal role for a gene product in the mature nervous system, rather than an indirect consequence of perturbed development. In this case, supporting evidence for the former possibility is provided by the observation of reduced ethanol preference and elevated sensitivity to the sedative effects of ethanol in NPY-overexpressing transgenic mice. The development of NPY receptor–selective agonists and antagonist compounds will provide complementary pharmacological approaches for assessing the modulatory effects of NPY systems on alcohol intake and for determining the identity and anatomical location of the NPY receptors mediating these effects. The development of new mouse lines designed for region-specific and inducible regulation of an NPY gene mutation will also aid these efforts.In summary, the findings described above illustrate the power of genetic methods to provide novel entry points into the biology of complex neural systems. In particular, this work has succeeded in focusing attention on a potentially important neuropeptide system for the regulation of alcohol intake. Future studies that build on these findings may provide the exciting prospect for novel strategies for the treatment of alcoholism.