Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 25, Issue 45, Pages 4799-4805Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1381612825666191216145153
Keywords
MC4R; melanocortin; alpha-MSH; alcohol use disorder; neuroinflammation; hypothalamus
Categories
Funding
- Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
- Programa de Investigacion Asociativa (PIA) Grant Anillo de Ciencia y Tecnologia [ACT1411]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1160710]
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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-1 beta), and tumor necrosis factor-alpha (TNF-alpha) 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-1 beta and TNF-alpha 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 alpha-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain.
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