New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

Abstract

Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood.

Ethanol Consumption Affects Neuronal Function: Role of the Mitochondria

“…Binge drinking is described as the intake of four drinks in women and five drinks in men in a period less than 2 h [118]. It is of great interest to understand the damaging effects of binge drinking in the brain [119], mainly because the adolescent brain is more sensitive to ethanol toxicity than that of the adult brain [120,121].…”

“…Persistent ethanol consumption also induced the loss of mitochondrial membrane potential and increased Ca +2 entries into the mitochondria that provoke the prolonged opening of mPTP and finally promote neurodegeneration. Interestingly, these mitochondrial alterations ethanol-associated may could occur mainly in glial cells, inducing inflammation and interfering with the glial-neuronal communication in specific brain areas [119]. The hippotalamus, important to ethanol dependence, and the hippocampus, associated to learning and memory, are particularly vulnerable; possibly due to the downregulation of melanocortin system induced by ethanol [119].…”

“…Interestingly, these mitochondrial alterations ethanol-associated may could occur mainly in glial cells, inducing inflammation and interfering with the glial-neuronal communication in specific brain areas [119]. The hippotalamus, important to ethanol dependence, and the hippocampus, associated to learning and memory, are particularly vulnerable; possibly due to the downregulation of melanocortin system induced by ethanol [119]. Therefore, the description of all these events highlights the importance of maintaining the function of the mitochondria to prevent the harmful effects of ethanol consumption and propose a new potential treatment for the pathological condition related to ethanol use and abuse.…”

Alcohol consumption during adolescence: A link between mitochondrial damage and ethanol brain intoxication

“…Even though binge drinking is becoming an increasingly common consumption pattern (Schulteis, Archer, Tapert, & Frank, ), and little is known about its effects and the mechanism involved in ethanol toxicity. Therefore, it is important to understand the harmful effects of this consumption (Orellana et al, ), since the adolescent brain is more vulnerable to ethanol toxicity (Slawecki, Thorsell, & Ehlers, ; Spear, ) and the cellular impairment could persist over time and affects the brain function in adulthood.…”

DNA Methylation of the Leptin Gene Promoter is Altered by Chronic Alcohol Exposure in an Animal Model for Alcohol Dependence

“…Leptin is also considered to take part in alcohol dependence [10] as it directly acts as part of the HPA axis. The derivatives of POMC, especially the melanocortin hormones adrenocorticotropic hormone and alpha-melanocyte-stimulating-hormone (alpha-MSH), are current subjects of research in the context of alcohol addiction [11]. Leptin has an inhibiting effect on the central actors of the HPA axis, the corticotropin-releasing factor expression in hypothalamus as well as adrenocorticotropic hormone expression in the anterior lobe of pituitary gland [12,13], which are known to be associated with higher craving for alcohol when diminished [14,15].…”