Alcoholism is a devastating disease that manifests as uncontrolled drinking. Consumption of alcohol is regulated by neurochemical systems within specific neural circuits, but endogenous systems that may counteract and thus suppress the behavioral effects of ethanol intake are unknown. Here we demonstrate that BDNF plays a role in reducing the behavioral effects of ethanol, including consumption, in rodents. We found that decreasing the levels of BDNF leads to increased behavioral responses to ethanol, whereas increases in the levels of BDNF, mediated by the scaffolding protein RACK1, attenuate these behaviors. Interestingly, we found that acute exposure of neurons to ethanol leads to increased levels of BDNF mRNA via RACK1. Importantly, acute systemic administration of ethanol and voluntary ethanol consumption lead to increased levels of BDNF expression in the dorsal striatum. Taken together, these findings suggest that RACK1 and BDNF are part of a regulatory pathway that opposes adaptations that lead to the development of alcohol addiction.

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol selfadministration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol selfadministration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF).

Prenatal alcohol exposure can affect brain development, leading to behavioral problems, including overactivity, motor dysfunction and learning deficits. Despite warnings about the effects of drinking during pregnancy, rates of fetal alcohol syndrome remain unchanged and thus, there is an urgent need to identify interventions that reduce the severity of alcohol's teratogenic effects. Insulin-like growth factor I (IGF-I) is neuroprotective against ethanol-related toxicity and promotes white matter production following a number of insults. Given that prenatal alcohol leads to cell death and white matter deficits, the present study examined whether IGF-I could reduce the severity of behavioral deficits associated with developmental alcohol exposure. Sprague-Dawley rat pups received ethanol intubations (5.25 g/kg/day) or sham intubations on postnatal days (PD) 4-9, a period of brain development equivalent to the third trimester. On PD 10-13, subjects from each treatment received 0 or 10 μg IGF-I intranasally each day. Subjects were then tested on a series of behavioral tasks including open field activity (PD 18-21), parallel bar motor coordination (PD 30-32) and Morris maze spatial learning (PD 45-52). Ethanol exposure produced overactivity, motor coordination impairments, and spatial learning deficits. IGF-I treatment significantly mitigated ethanol's effects on motor coordination, but not the other two behavioral deficits. These data indicate that IGF-I may be a potential treatment for some of ethanol's damaging effects, a finding that has important implications for children of women who drink alcohol during pregnancy.