Simple SummaryThe 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.AbstractBrain-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.