Project 6B: Medial Prefrontal Cortex and Extinction of Psychostimulant Self-administration

Matt Lattal, Ph.D., Principal Investigator

Modulation of transcription and translation via epigenetic regulation is emerging as an area of convergence between research on the neurobiology of memory and the neurobiology of substance abuse. 

We have found that epigenetic modulation of memory mechanisms can weaken drug seeking.  Behavioral approaches have identified extinction, which occurs when the relation between the drug and the environment or the drug-seeking response is severed. 

When an episode of extinction is paired with the delivery of a histone deacetylase (HDAC) inhibitor, this extinction process can be enhanced, resulting in a persistent suppression of previously learned behaviors, including drug seeking. 

My laboratory has shown this in several published studies involving extinction in fear conditioning and cocaine-induced conditioned place preference procedures.  This pilot project expands this approach to examine extinction of drug-seeking using a self-administration paradigm. 

The first goal of the project is to develop an intravenous self-administration procedure with rats that involves robust acquisition and extinction of a lever press response for methamphetamine.  This will allow us to broaden the scope of the behavioral questions that we can ask about drug seeking and will open the door for future interactions with researchers in the MARC who would like to ask experimental questions about methamphetamine self-administration. 

The second goal of this project is to collect preliminary data examining the effects of delivery of an HDAC inhibitor to the medial prefrontal cortex during extinction of methamphetamine self-administration. 

We hope this will ultimately lead to the development of mouse self-administration procedures, which would be a tremendous asset to the MARC for characterizing some of the lines that have been selected for methamphetamine phenotypes.