Many methamphetamine (meth) addicts suffer cognitive impairments that may perpetuate the addiction cycle. Although, meth impacts several cognitive domains (e.g., attention, impulsivity, memory), the relationship between impaired cognitive function, addiction, and relapse is not well understood. Repeated meth use results in maladaptive brain changes in areas involved in recognition memory and relapse including cortical and subcortical structures. For example, the perirhinal cortex (PRH) is the primary neural substrate involved in recognition memory and directs the flow of information in and out of the parahippocampal structure. The medial prefrontal cortex (mPFC) mediates inhibitory control over behaviors like risk-taking and drug over-consumption; and, the nucleus accumbens (NA) regulates reward-related behaviors. Meth induced impairments in these areas result in memory deficits, loss of inhibitory control, and biased reward processing of drug-associated cues that precipitate a relapse episode. In this proposal, we will study the relationship between motivated drug taking, meth induced cognitive dysfunction, and relapse using a long access (LA) meth self-administration (SA) regimen that reliably establishes recognition memory deficits and results in robust relapse to drug seeking. Given that the PRH is the primary substrate involved in recognition memory, combined with our previous reports of a meth-induced dysregulation of glutamate physiology in this area, we hypothesis that meth impairs recognition memory through PRH projection neurons loss of communication with the mPFC. We also suggest that the pathway encompassing prelimbic (PL) and infralimbic (IL) outputs of the mPFC that project to the NAcore and NAshell are dysregulated by meth resulting in the reinstated responding to conditioned drug cues. As such these separate pathways, PRH-mPFC and mPFC-NA, suggest that recognition memory deficits and relapse are distinct domains of the addiction pathology. However, the PRH-NAcore is a relatively unexplored circuit and the behavioral relevance of this connection has not been determined. We hypothesize that this connection may be the unifying pathway between meth-induced recognition memory dysfunction and relapse.
Our Specific Aims will determine whether meth causes functional changes within the pathways involved in recognition memory and cued reinstatement.
Specific Aim 1 will test the hypothesis that meth causes functional changes within the PRH-mPFC circuitry that result in recognition memory deficits.
Specific Aim 2 will test the hypothesis that functional changes within the mPFC-NA circuitry mediate cued reinstatement of meth seeking using a rodent model of reinstatement.
Specific Aim 3 will determine the functional and behavioral relevance of the PRH-NAcore pathway. We hypothesize that this pathway is involved in recognition memory and relapse to meth seeking. Upon completion of our aims we will have a more complete understanding of the pathways involved in recognition memory and cued drug-seeking to better inform treatment approaches for meth addiction.

Public Health Relevance

Although an accumulation of research reports a decline in cognitive function during methamphetamine (meth) withdrawal, little is known about the relationship between these impairments and the propensity towards relapse, and even less is understood about the underlying neural circuitry mediating these aspects of addiction pathology. Here, we propose that chronic self-administered meth results in recognition memory deficits mediated by an inability of the perirhinal cortex to process sensory information and relay that information to the prefrontal cortex and the nucleus accumbens. Using a pathway approach to discern the circuits involved in recognition memory and relapse, we will provide information to inform treatment approaches aimed at improving cognitive function with the ultimate goal of reducing relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA033049-06A1
Application #
9594601
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Grant, Steven J
Project Start
2012-09-15
Project End
2023-06-30
Budget Start
2018-08-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
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