Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that includes the neuropeptide Y (NPY) gene. Alcohol-preferring rats have lower levels of NPY in several brain regions compared with alcohol-non-preferring rats. We therefore studied alcohol consumption by mice that completely lack NPY as a result of targeted gene disruption. Here we report that NPY-deficient mice show increased consumption, compared with wild-type mice, of solutions containing 6%, 10% and 20% (v/v) ethanol. NPY-deficient mice are also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations do not differ significantly from those of controls. In contrast, transgenic mice that overexpress a marked NPY gene in neurons that usually express it have a lower preference for ethanol and are more sensitive to the sedative/hypnotic effects of this drug than controls. These data are direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.
Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.
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