The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation

Abstract

Background The Val66 to Met polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release, and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders. Methods We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF), and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology. Results We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type Val68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice, or by systemic administration of the TrkB agonist, LM22A-4. Conclusions Our findings suggest that carrying the Met66BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, TrkB. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele.

The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

“…p75NTR signals through the other members of the NGF family of neurotrophic factors (Kraemer et al, 2014a), and thus we cannot exclude the possibility that p75NTR's actions to drive excessive alcohol intake are mediated via other neurotrophic factors. p75NTR signals through downstream cytoplasmic effectors (Kraemer et al, 2014b), activating several pathways, including nuclear factor-B (Carter et al, 1996), Jun kinase (Casaccia-Bonnefil et al, 1996), the small G-proteins RhoA (Sun et al, 2012;Orefice et al, 2016) and RAC (Tian et al, 2014), as well as via ceramide signaling (Dobrowsky et al, 1994). Thus, it is likely that in response to excessive alcohol intake, membranal p75NTR recruits these effectors or others, and the involvement of downstream mediators of p75NTR signaling merits further investigation.…”

A Critical Role of Brain-Derived Neurotrophic Factor in Alcohol Consumption

“…In this issue of Biological Psychiatry , Warnault et al (1) investigated the role of a point mutation in the brain-derived neurotrophic factor (BDNF) gene from valine 68 (Val68) to methionine (Met68) (mouse homolog of human Met66BDNF allele) in the risk of developing alcoholism using a knock-in approach in C57BL/6 mice. The mice expressing Met68BDNF showed excessive alcohol consumption compared with wild type Val68BDNF mice.…”

“…(1) report novel findings demonstrating a direct role of Valine 68 to Methionine BDNF gene polymorphism (Met68BDNF) in excessive alcohol drinking behaviors in mice. This polymorphism generally causes decreased activity-dependent release of BDNF leading to its decreased function (1, 8).…”

“…(1) report novel findings demonstrating a direct role of Valine 68 to Methionine BDNF gene polymorphism (Met68BDNF) in excessive alcohol drinking behaviors in mice. This polymorphism generally causes decreased activity-dependent release of BDNF leading to its decreased function (1, 8). Met68BDNF in mice is homologous to the human Met66BDNF that has been implicated in the predisposition of several psychiatric disorders, including addiction (1, 8).…”

Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors

“…Additionally, local infusions of 7,8-DHF into the IL enhance the extinction of cocaine-CPP (Otis et al, 2014), while systemic 7,8-DHF treatment has apparently no effects on the acquisition of cocaine-CPP in typical rodents (Tzeng et al, 2013). Another trkB agonist, LM22A-4, decreases compulsive-like alcohol consumption in mice (Warnault et al, 2015; see for further discussion, Logrip et al, 2015). These findings together highlight the possible utility of pairing trkB-based interventions with therapies for drug use disorders, though further research is certainly necessary.…”