Anhedonic-like effect induced by intranasal acute and repeated melanin-concentrating hormone and the influence of stress in male rats.

Increasing evidence highlights the involvement of melanin-concentrating hormone (MCH) in depression and its therapeutics. We previously demonstrated that acute MCH microinjection into serotonergic dorsal and median raphe and noradrenergic Locus Coeruleus (LC) induces depressive-like effects, while into the LC aggravated helpless behavior in stressed animals. Here, we investigated whether the depressive-like effect of MCH is maintained after acute and repeated intranasal (i.n.) administration, if stress exposure modulates it, and whether it is related to changes in monoamines. We assessed anhedonic-like behavior in the sucrose preference test after acute (7.5, 15 and 30 μg/30 μL i.n.) or repeated (15 μg/30 μL i.n.) MCH administration in male rats. A single swim session was used as a stressor. Noradrenaline, serotonin, and dopamine tissue levels were measured in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). MCH brain distribution was confirmed using rhodamine-labeled MCH (R-MCH). Stress exposure reduced sucrose preference after both acute and repeated saline administration. MCH-treated animals (15 μg) showed an anhedonic-like effect after acute and repeated (8 days) in non-stressed rats, however, this behavioral effect was not aggravated by stress exposure. Monoamine levels did not significantly change. Prolonged repeated MCH (15 days) reduced noradrenaline levels in both regions despite no behavioral changes. R-MCH reached the mPFC, NAc, hypothalamus, hippocampus, raphe, and LC confirming wide distribution following i.n. delivery. Overall, our findings support a prodepressive role of MCH and show that this profile is maintained across acute and repeated treatment, independently of prior stress exposure under the conditions tested.