The long-term goal of research with animal models of substance abuse is to extrapolate findings from the laboratory to improve human treatments. A major limitation in making effective translations from the animal lab to the clinic is the differnt time elapsed between drug exposure and testing of potential treatments. In animal models of substance abuse, manipulations occur relatively soon after initial exposure;whereas in humans, intervention and relapse can occur long after initial drug exposure. A popular paradigm in studying drug abuse is conditioned place preference (CPP), wherein a drug is paired with a specific context, and later drug-associated motivation is assessed by evaluating the animal's preference for the drug-paired context. This paradigm is useful for studying the associative learning that underlies extinction (reduced responding over repeated CS presentations) of drug-induced associations. Much research has established that contextual learning depends upon the hippocampus for a short time after training, but later the memory consolidates to become hippocampus independent. In general, this suggests that recent contextual memories (1-7 days old) depend on different substrates for retrieval than remote memories (>28 days old). This may suggest that substrates supporting extinction of these memories differ as well. Remarkably little is known about the differences between recent and remote memories that are associated with drugs of abuse. The proposed research will determine whether recent (new) memories for drug-context associations are supported by different substrates than remote (old) memories. By increasing our understanding of the differences between recent and remote drug associations, this research has clear translational implications, because extinction of drug-associations may rely on different neural and epigenetic mechanisms at recent and remote time points. Thus, Aim 1 will investigate regional epigenetic modification (histone acetylation) and gene expression following extinction of recent or remote cocaine-induced CPP, to determine if extinction at different time points results in different patterns of gene expression. While, Aim 2 will use infusion HDAC and HAT inhibitors to examine if different epigenetic mechanisms within the hippocampus support extinction of recent and remote CPP.
These aims will determine if there are epigenetic differences between extinction of recent and remote CPP. Abbreviations: CPP: Conditioned place preference;DH: Dorsal hippocampus;NaBut Sodium Butyrate;HDAC: Histone Deacetylase;HAT: Histone Acetyltransferase.
Relapse is a major concern of any treatment for substance abuse. Although relapse often occurs long after initial exposure to substance, very little is known about the neural systems involved in retrieving and maintaining recent and remote cocaine-associated memories. This work will generate novel behavioral paradigms to facilitate the discovery of effective pharmacotherapies for drug addiction.
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