PubMed · 6958298
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H Rankin. 1982. Teaching assessment.. https://doi.org/10.1111/j.1360-0443.1982.tb02450.x
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Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.
The two inbred strains of mice C57BL/6 and DBA/2 mice have been shown to differ significantly in their preference for alcohol (EtOH). These strains of mice have been employed to study various aspects of pharmacological and behavioral effects of EtOH. We have previously demonstrated that chronic EtOH exposure down-regulated cannabinoid receptors (CB1) in mouse synaptic plasma membranes and enhanced the synthesis of endogenous cannabimimetic compound anandamide (AnNH) in human neuroblastoma cells. The purpose of the present study was to investigate whether there were differences in the density and the affinity of CB1 receptors in the brains of the two inbred C57BL/6 (alcohol-preferring) and DBA/2 (alcohol avoiding) mice. The results indicate the presence of specific CB1 receptors in the brain membranes of both the strains. It was also found that the CB1 receptor densities (B(max)) were 25% lower in C57BL/6 (0.66 +/- 0.15 pmol/mg protein) compared with that of DBA/2 (0.88 +/- 0.08 pmol/mg protein) mice. Significant differences in the affinity were also observed between the two lines (K(d), 0.68 +/- 0.15 nM for C57BL/6 and 2.21 +/- 0.56 nM for DBA/2). The competition studies with SR141716A, a CB1 receptor antagonist, and 2-arachidonylglycerol (2-AG) and anandamide (AnNH), known CB1 receptor agonists, all showed a substantial decrease in [(3)H]CP-55,940 binding in both strains of mice with a higher K(i) values in the DBA/2 mice. These results suggest that CB1 receptor signal transduction may play an important role in controlling the voluntary EtOH consumption by these strains of mice.
The authors used prospective data from two supplemental studies of the National Health Interview Survey, the 1988 Alcohol Supplement and the 1990 Health Promotion and Disease Prevention Supplement, to examine the relation between alcohol intake and mortality. Their study included 17,821 men and 25,874 women aged 40 years or older at baseline; during an average of 6 years of follow-up, 5,540 deaths occurred. The alcohol-mortality relation was U-shaped for men and J-shaped for women. On the basis of categorical analyses adjusted for age, race, smoking, and baseline diseases, men who drank 2 drinks per day had a significantly lower risk of death compared with abstainers (relative risk = 0.60, 95% confidence interval (CI): 0.45, 0.82). The relative risk was 0.75 (95% CI: 0.55, 1.03) after further adjustment for marital status, education, and self-perceived health status. For women, the corresponding relative risks were 0.69 (95% CI: 0.61, 0.78) and 0.79 (95% CI: 0.70, 0.90) for those who drank less than 1 drink per day. When drinking category was considered as an ordinal variable and fitted with a quadratic function in the Cox model, the estimated optimal alcohol intake was approximately less than 1 to 1 drink per day for men and lifetime infrequent to less than 1 drink per day for women. Data from these representative US cohorts demonstrated that less than 2 drinks per day for men and less than 1 drink per day for women are associated with the lowest all-cause mortality.