Brain-Derived neurotrophic factor Val66Met induces female-specific changes in impulsive behaviour and alcohol self-administration in mice

Abstract

Substance use disorders are a debilitating neuropsychiatric condition, however it remains unclear why some individuals are at greater risk of substance use disorders than others and what genetic factors determine such individual differences. Impulsivity appears a promising candidate endophenotype to bridge the gap between genetic risk and addiction. Brain-derived neurotrophic factor (BDNF), and in particular the BDNFVal66Met polymorphism, has been suggested to be involved in both impulsivity and substance use disorders, however results so far have been inconsistent. To investigate the role of BDNF, and more specifically the BDNFVal66Met polymorphism, in both impulsivity and operant alcohol self-administration using the same animal model. Separate cohorts of humanized Val66Met transgenic mice were assessed for either trait impulsivity in the 5-choice serial reaction time (5-CSRT) touchscreen task, or propensity towards obtaining ethanol in an operant paradigm. It was found that female hBDNFVal/Val mice exhibited both greater impulsivity compared to hBDNFMet/Met mice of the same sex as shown by a higher number of premature responses at one of three increased inter-trial intervals tested in the 5-CSRT task, and a greater propensity toward stable ethanol self-administration relative to male mice of the same genotype in the operant paradigm. By contrast, male mice showed no difference between genotypes in impulsivity or stable ethanol self-administration. The hBDNFMet/Met genotype appears to sex-specifically alter aspects of both impulsive behaviour and addiction propensity. These results suggest that impulse behaviour may be a possible predictor of addiction risk.