cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement.
Reinstatement of previously extinguished conditioned place preference (CPP) is precipitated by stress or drug exposure. Here, we show that acute exposure to forced swim stress (FS), in a context distinct from conditioning, induces reinstatement of cocaine CPP in wild-type mice. This behavior is accompanied by a pattern of phosphorylated cAMP response element-binding protein (pCREB) activation in discrete brain regions that is distinct from the pattern observed after cocaine-induced reinstatement. For example, previous cocaine conditioning increases pCREB levels in the amygdala, and acute exposure to FS, but not to cocaine, further augments these changes. In contrast, previous cocaine conditioning does not alter levels of pCREB in the nucleus accumbens, but acute exposure to FS increases pCREB levels in this region on reinstatement day. Furthermore, to determine whether these alterations of CREB are necessary in FS or cocaine-induced reinstatement, we examined the effect of these stimuli on reinstatement behavior in mice deficient in alpha and Delta isoforms of CREB. The CREB(alphaDelta) mutant mice show deficits in FS-induced reinstatement of conditioned place preference. In contrast, they show robust cocaine-induced reinstatement. This deficit in stress but not drug-induced reinstatement indicates a specific requirement for CREB in stress-induced behavioral responses to drugs of abuse.
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Arati S
AS
Kreibich
Julie A
JA
Blendy
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D003433:Crosses, Genetic; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011897:Random Allocation; D012054:Reinforcement, Psychology; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000523:psychology*; D013550:Swimming
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D003042:Cocaine