PubMed · 8313256
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R Garlick. 1994-02-15. Abstinence or controlled drinking?. https://pubmed.ncbi.nlm.nih.gov/8313256/
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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.
To define the molecular basis of alcohol drinking behaviors, the effects of voluntary ethanol intake on the expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and on the expression and phosphorylation of cAMP responsive element binding protein (CREB) [corrected] in the nucleus accumbens (NAc), central amygdala, and frontal cortex of rats were investigated. Voluntary ethanol intake significantly decreased the expression of CaM kinase IV and CREB phosphorylation but not of CREB protein levels [corrected], specifically in the shell of NAc. These changes were not observed in the core of NAc, central amygdala and frontal cortex. Mianserin treatment significantly attenuated ethanol intake and antagonized the voluntary ethanol-induced reduction in expression of CaM kinase IV and CREB phosphorylation in the shell of NAc. This is the first evidence to suggest that decreased CaM kinase IV-dependent CREB phosphorylation in the shell region of NAc may play a role in the reward mechanisms of alcohol drinking.
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