Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.

Addiction is a characterized by compulsive drug use that persists in the face of negative consequences and desire to stop use (Kalivas & O'Brien, 2008; O'Brien, 2011). Conditioned drug craving elicited by drug-paired cues is among the many factors that contribute to this compulsive use. Addicts report that these conditioned cues are one of the most potent factors contributing to relapse (Heather et al., 1991). Understanding how to extinguish this cue-elicited craving is a major goal in addiction research. Genetically modified mice provide a useful model system to examine molecular mechanisms underlying cocaine extinction behavior and how this might lead to alterations in vulnerability in human populations. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of polypeptide growth factors, is widely expressed throughout the brain and is regulated in an activity dependent manner (Goodman et al., 1996; Egan et al., 2003). BDNF has been implicated in synaptic plasticity, learning, and addiction. Manipulations of BDNF levels in the brain have been demonstrated to modulate addictive behaviors, such as cocaine-induced locomotor activity (Pierce & Bari, 2001), cocaine conditioned place preference (Horger et al., 1999; Hall et al., 2003), and cocaine self-administration (Lu et al., 2004). Furthermore, upregulation of BDNF expression is observed in various limbic nuclei during abstinence from cocaine self-administration (Sadri-Vakili et al., 2010), and levels of BDNF expression correlate with measures of cue-elicited craving (Grimm et al., 2003). Along with this evidence from the preclinical literature, there is also a relationship between substance abuse and BDNF in human populations. At a genetic level, single nucleotide polymorphisms (SNPs) conferring vulnerability for polysubstance abuse were indentified flanking the BDNF gene (Uhl et al., 2001). More recently, a common SNP in the BDNF gene that leads to a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met) was linked to substance abuse vulnerability. A higher frequency of the Val allele is found among methamphetamine addicts compared to non-addicted individuals, suggesting the Met allele may confer resistance to addiction (Cheng et al., 2005). However, there is an increase in 66Met allele frequency in smokers and healthy Met carriers consume more alcohol per week than 66Val homozygotes (Lang et al., 2007; Colzato et al., 2011). Parsing the role of this SNP in addictive behavior using an animal model could provide unique insight into the pathophysiology of addiction. The current study utilized an inbred genetic knock-in mouse strain that expresses the variant BDNF allele to recapitulate the specific phenotypic properties of the human polymorphism in vivo. Previous work has demonstrated that the BDNF Val66Met genotype is associated with a resistance to the extinction of fear memories (Soliman et al., 2010). While there is considerable overlap between the neurocircuitry underlying the extinction of aversive and appetitive memories (Ressler et al., 2004; Davis et al., 2006; Peters et al., 2009; Myers & Carlezon, 2010b), it is clear that the mechanisms molecular mechanisms are not identical (Chhatwal et al., 2009; Ward et al., 2009; Bernardi & Lattal, 2010). The objective of this study was to assess the acquisition, stability and extinction of an appetitive behavior (cocaine self-administration) in Vall66Met knock-in mice.