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

被引:15
作者
Briand, Lisa. A. [1 ,2 ]
Lee, Francis S. [3 ]
Blendy, Julie A. [1 ]
Pierce, R. Christopher [2 ]
机构
[1] Univ Penn, Dept Pharmacol, Perelman Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA
[3] Cornell Univ, Dept Psychiat, Weill Med Coll, New York, NY 10021 USA
关键词
brain-derived neurotropic factor; cocaine; extinction; neurotrophin; self-administration; single-nucleotide polymorphism; MEDIAL PREFRONTAL CORTEX; CYCLOSERINE FACILITATES EXTINCTION; MESOLIMBIC DOPAMINE SYSTEM; HPA-AXIS REACTIVITY; FACTOR BDNF; CONDITIONED FEAR; SUBSTANCE-ABUSE; GENE-EXPRESSION; SPATIAL MEMORY; POLYMORPHISM;
D O I
10.1111/j.1460-9568.2012.08021.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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. BDNFMet/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 (BDNFVal/Val) animals to mice heterozygous for the Met allele (BDNFVal/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 BDNFVal/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.
引用
收藏
页码:932 / 939
页数:8
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