Involvement of alpha-melanocyte stimulating hormone (alpha-MSH) in differential ethanol exposure and withdrawal related depression in rat: neuroanatomical-behavioral correlates.

We investigated the involvement of alpha-melanocyte stimulating hormone (alpha-MSH) following acute, chronic and withdrawal treatments of ethanol with reference to depression. The degree of depression was evaluated using Porsolt's forced swim test. While intracerebroventricular (i.c.v.) alpha-MSH (100-400 ng/rat) dose-dependently increased the immobility, opposite response was observed following administration of selective MC4 receptor antagonist HS014 (0.01-0.07 ng/rat, i.c.v.). The anti-immobility effect of acute ethanol (1-2 g/kg), injected via intra-peritoneal route (i.p.), was suppressed by central administration of alpha-MSH (100 ng/rat, i.c.v.), but was enhanced following pretreatment with HS014 (0.01 ng/rat, i.c.v.). Chronic ethanol resulted in increased immobility time, while further augmentation in immobility was noticed following ethanol withdrawal. However, concomitant HS014 (0.01 ng/rat, i.c.v.) treatment prevented tolerance as well as attenuated enhanced immobility in ethanol-withdrawn rats. Acute administration of HS014 (0.01-0.03 ng/rat, i.c.v.), at 24h post-withdrawal time point, also antagonized the ethanol withdrawal immobility in rats. The profile of alpha-MSH-immunoreactivity in the paraventricular (PVN), arcuate (ARC), paraventricular thalamic (PVT), dorsomedial hypothalamic-dorsal (DMNd) and -ventral (DMNv) nuclei, lateral hypothalamus (LH) and central nucleus of amygdala (CeA) was investigated with immunocytochemistry. Acute ethanol significantly reduced the alpha-MSH-immunoreactivity in the cells and fibers of ARC, and fibers in the PVN, DMNd, DMNv and CeA. While chronic ethanol treatment significantly increased the alpha-MSH-immunoreactivity as compared to the pair-fed control group, further augmentation was noticed following 24 h ethanol withdrawal. However, the alpha-MSH-immunoreactive profile in the PVT and LH did not respond. alpha-MSH in discrete areas may play a role in ethanol-induced antidepressant-like response and withdrawal-induced depression.