To investigate a possible link between some neuropeptides and depression, we analyzed their mRNA levels in brains of rats exposed to chronic mild stresses (CMS; a stress-induced anhedonia model), a commonly used model of depression. Rats exposed for 3 weeks to repeated, unpredictable, mild stressors exhibited an increased self-stimulation threshold, reflecting the development of an anhedonic state, which is regarded as an animal model of major depression. In situ hybridization was employed to monitor mRNA levels of neuropeptide Y (NPY), substance P and galanin in several brain regions. In the CMS rats, NPY mRNA expression levels were significantly decreased in the hippocampal dentate gyrus but increased in the arcuate nucleus. The substance P mRNA levels were increased in the anterodorsal part of the medial amygdaloid nucleus, in the ventromedial and dorsomedial hypothalamic nuclei and the lateral hypothalamic area, whereas galanin mRNA levels were decreased in the latter two regions. These findings suggest a possible involvement of these three peptides in mechanisms underlying depressive disorders and show that similar peptide changes previously demonstrated in genetic rat models also occur in the present stress-induced anhedonia model.

Neuropeptide Y (NPY) is a hexatriacontapeptide amide that is now well characterized as a neuromodulator in the central nervous system (CNS). When infused into the CNS, NPY produces both anxiolytic and orexigenic effects. NPY's anxiolytic effects appear to be mediated through receptors in the central amygdala, whereas its orexigenic effects are localized in discrete hypothalamic nuclei. Both food restriction and food deprivation produce increased levels of the peptide in the hypothalamus that are ameliorated by refeeding. However, the effects of alcohol consumption/deprivation on NPY levels remain unknown. The present study sought to determine if brain NPY levels were affected by either alcohol exposure and/or correlated with genetic differences in preference for drinking alcohol. In the first experiment, NPY-like immunoreactivity (NPY-LI) was compared in alcohol-naive, alcohol-preferring (P), and nonpreferring (NP) rats. After tissue extraction, NPY-LI was measured by radioimmunoassay: amygdala, hippocampus, frontal cortex, hypothalamus, and caudate. P rats were found to have significantly lower NPY-LI in amygdala (F = 4.69, p < 0.04), hippocampus (F = 7.03, p < 0.01), and frontal cortex (F = 4.7, p < 0.04), compared with NP rats. In the second experiment, heterozygous Wistar rats were exposed to alcohol for 14 hr/day for 7 weeks in alcohol vapor chambers (mean blood alcohol concentrations = 180 mg%) or control chambers. At 7 weeks of alcohol exposure, no significant changes in NPY-LI in were found. At 1 month after ethanol withdrawal, however, the ethanol-exposed animals had significantly higher NPY-LI in the hypothalamus (F = 4.78, p < 0.04) when compared with the nonexposed controls. Taken together, these studies suggest that exposure to chronic ethanol may affect NPY-LI at the level of the hypothalamus in a fashion similar to food restriction, because 4 weeks after alcohol withdrawal, significantly higher NPY levels are found. In addition, differences in NPY-LI in limbic areas and frontal cortex between alcohol-naive P and NP rats suggest that NPY may also play a role in risk for the development of alcohol preference either by modulating the "tension-reduction" properties of alcohol or by influencing consummatory behaviors.

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