A Rat Model of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Shows Attenuated Motivation for Alcohol Self-Administration and Diminished Propensity for Cue-Induced Relapse in Females

Simple Summary The growth factor brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. Val66Met is a common variant of the BDNF gene which reduces BDNF release in the brain. Val66Met has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, we investigated ethanol preference and ethanol seeking in a genetically modified rat model of the BDNF Val66Met variant, Val68Met rats. There was no effect of Val68Met genotype (Val/Val, Val/Met and Met/Met) on acquisition of stable lever pressing for a 10% ethanol solution or extinction of this behaviour. Met/Met rats of both sexes had slightly, but significantly lower motivation to lever press for ethanol. Following extinction of responding, females with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no changes in anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females. Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. The Val66Met polymorphism is a common variant of the BDNF gene (rs6265) which reduces activity-dependent BDNF release, and has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, this study aimed to investigate ethanol preference and ethanol seeking in a novel rat model of the BDNF Val66Met polymorphism, Val68Met rats. Male and female BDNF Val68Met rats of three genotypes (Val/Val, Val/Met and Met/Met) were trained to lever press for a 10% ethanol solution. There was no effect of Val68Met genotype on acquisition of stable response to ethanol or its extinction. Met/Met rats of both sexes had a slight, but significantly lower breakpoint during progressive ratio sessions while female rats with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no effects of Val68Met genotype on anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to continue to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females.

Automated summary

The Val66Met gene variant reduces the release of BDNF in the brain, leading to decreased preference and seeking for alcohol. Using a rat model, researchers found that rats with the Met/Met genotype had lower motivation to seek alcohol and a decreased propensity to relapse. This suggests a possible protective effect of the Met/Met genotype against alcohol use disorder, particularly in females.