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 seeking 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 modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in the transcriptional regulation of gene expression required for synaptic plasticity and memory storage. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in maintained gene expression, which is thought to drive persistent changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant application is to modulate learning and memory pathways in order to extinguish context-drug associated memories. We will use a combined behavioral, pharmacological, and genetic strategy to examine ways to enhance the development of extinction of cocaine-induced conditioned place preferences to cause persistent suppression of the original context-drug association.
In Specific Aim 1, we will determine the best temporal pattern of context presentations to extinguish context-cocaine associations using the conditioned place preference (CPP) procedure.
In Specific Aim 2, we will examine the behavioral and molecular consequences of administration of systemic or intra-hippocampal drugs that relax chromatin structure, thereby enhancing gene transcription during extinction of cocaine-induced CPP.
In Specific Aim 3, we will examine the effects of inhibiting a chromatin modifying enzyme called CREB-binding protein (CBP), which relaxes chromatin structure, through genetic mutations and focal deletions of CBP, thereby inhibiting transcription during extinction of cocaine-induced CPP. This novel approach promises to elucidate behavioral and epigenetic mechanisms of extinction and will allow us to identify further molecular targets and brain systems for pharmacological interventions.
Cocaine addiction is a major public health problem in the United States. In this project, we examine behavioral and pharmacological interventions in a mouse model of cocaine seeking that may help reverse cocaine seeking and reduce relapse.
|Hitchcock, Leah N; Cunningham, Christopher L; Lattal, K Matthew (2014) Cue configuration effects in acquisition and extinction of a cocaine-induced place preference. Behav Neurosci 128:217-27|
|Delamater, Andrew R; Lattal, K Matthew (2014) The study of associative learning: mapping from psychological to neural levels of analysis. Neurobiol Learn Mem 108:1-4|
|Raybuck, J D; Lattal, K M (2014) Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory. Neurosci Lett 569:1-5|
|Bolkan, Scott S; Lattal, K Matthew (2014) Opposing effects of D-cycloserine on fear despite a common extinction duration: interactions between brain regions and behavior. Neurobiol Learn Mem 113:25-34|
|Kwapis, Janine L; Wood, Marcelo A (2014) Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci 37:706-20|
|Tipps, Megan E; Raybuck, Jonathan D; Lattal, K Matthew (2014) Substance abuse, memory, and post-traumatic stress disorder. Neurobiol Learn Mem 112:87-100|
|Abraham, Antony D; Neve, Kim A; Lattal, K Matthew (2014) Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol Learn Mem 108:65-77|
|Raybuck, Jonathan D; Lattal, K Matthew (2014) Bridging the interval: theory and neurobiology of trace conditioning. Behav Processes 101:103-11|
|White, Andre O; Wood, Marcelo A (2014) Does stress remove the HDAC brakes for the formation and persistence of long-term memory? Neurobiol Learn Mem 112:61-7|
|Vogel-Ciernia, Annie; Wood, Marcelo A (2014) Examining object location and object recognition memory in mice. Curr Protoc Neurosci 69:8.31.1-8.31.17|
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