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

Department of Pharmacology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 03/2012; 35(6):932-9. DOI: 10.1111/j.1460-9568.2012.08021.x
Source: PubMed


The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena.

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    • "is important for many types of plasticity, including drug-induced plasticity . For example, global upregulation of BDNF enhanced extinction training that in turn decreased drug-seeking behavior[81]. Since BDNF has been implicated in a number of types of plasticity, it is perhaps not surprising that it also affects the expression of PV and PNNs, but the relationship between BDNF and PNN expression is far from clear. "
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    • "When interpreting these latter results, however, it is important to address the potential confound of prior food self-administration in this study. While we, and others, utilize food self-administration prior to cocaine selfadministration in mice (Alsio et al. 2011; Briand et al. 2012; Fowler and Kenny 2011; Ozburn et al. 2012; Thomsen and Caine 2007), recent studies demonstrated how difficult food responding can be to extinguish in the continued presence of food-paired cues (Thomsen and Caine 2011; Xi et al. 2011). Because our experimental design incorporates the same light/ tone cues during the food and cocaine self-administration phases, we cannot separate out the contribution of food reinforcement from cocaine reinforcement during cue-induced reinstatement . "
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