Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent
maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of
alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in
the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption,
such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury.
Objectives: In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide
prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression
in the hippocampus and hypothalamus.
Methods: Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days
for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide
in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6),
interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus
and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of
MC4R in the hippocampus and the hypothalamus.
Results: Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The
administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and
prefrontal cortex, to those observed in control rats that did not drink alcohol.
Conclusion: High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and
hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by
alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the
effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the
ethanol-induced inflammatory response in the brain.