Project 8A: Acquisition and extinction of methamphetamine- and cocaine-induced memories

K. Matthew Lattal, Ph.D., Principal Investigator

A common finding from studies of drug abuse is that exposure to the context in which drug use occurs can trigger relapse, resulting in an increase in drug-seeking behavior and subsequent drug use. A major goal of interventions designed to eliminate drug abuse therefore must be to eliminate the ability of contextual cues to elicit memories that result in relapse.

Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the context and the drug is severed, as a way to eliminate conditioned behavior. A major challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. Thus, extinction-based behavioral interventions must focus on ways to enhance the development of extinction, as well as methods to make the extinction memory long-lasting, causing persistent suppression of the original context-drug association.

At a molecular level, studies of memory and extinction have demonstrated the necessity of gene transcription for long-term memory storage. Our research has found that regulation of gene transcription necessary for long-term memory formation involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA.

Chromatin remodeling via histone modification (a form of epigenetic gene regulation) is emerging as a major molecular pathway involved in the transcriptional regulation of gene expression required for synaptic plasticity and memory storage. Chromatin remodeling has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level.

However, remarkably little is known about how chromatin remodeling affects extinction, particularly in tasks involving drug memories. The goal of this pilot project is to lay the behavioral groundwork for future experiments examining epigenetic mechanisms involved in extinction of drug-associated memories. In the two specific aims outlined in this pilot project, we will examine different protocols for establishing and extinguishing context-cocaine and context-methamphetamine memories. These data will be instrumental in designing future behavioral, pharmacological, and molecular experiments examining the role of chromatin remodeling in extinction.