Chronic methamphetamine (meth) self-administration in rats provides a translational animal model for the study of cognitive and motivational deficits of meth addiction in humans. This project consists of a multidisciplinary approach to study meth-induced cognitive and motivational dysfunctions, determine their critical neurobiological substrates in cortical glutamatergic circuitry, and reverse meth-induced changes with chronic pharmacotherapy. Specifically, we will first assess object recognition memory deficits in novel object and object-in-place recognition memory in rats with a history of chronic meth self-administration, withdrawal, and renewed drug-seeking. We hypothesize that chronic meth intake will negatively affect memory performance and that deficits will be related to altered glutamate receptors (AMPA, NMDA, mGluR2/3, and mGluR5) and glutamate receptor dependent neuron activity in the prefrontal and perirhinal cortices. We will also examine the ability of potential cognitive enhancers to reverse chronic meth-induced memory deficits by acting on glutamate receptors. We predict that chronic modafinil or an mGluR5 allosteric modulator (CDPPB) will reverse meth-induced cognitive deficits and reduce drug-seeking by acting on the aforementioned substrates. Finally, we will determine the impact of chronic meth SA on prefrontal cortex dependent attentional processing using a novel operant based attentional set-shifting task. These studies are significant in that they will provide novel insighs on chronic meth-induced changes in cognitive performance and neuroplasticity using a multifaceted assembly of behavioral, neurochemical, and neurophysiological techniques in a translationally relevant model of meth addiction. Ultimately, this project will advance our understanding of the neural substrates of cognitive deficits in meth addiction and the development of neurobiologically derived treatments for meth addiction.

Public Health Relevance

The major goals of this project are to study the neurobiology of chronic meth-induced cognitive deficits and relapse, and the attenuation of these factors by targeting cortical glutamate receptor function. We have closely aligned the animal model with important clinical issues both conceptually (e.g., cognitive deficits linked to meth addiction) and methodologically (e.g., analogous behavioral assessments). These studies will provide relevant and insightful data on the neurobiology of meth addiction and guidance to experimental and treatment approaches in human meth addicts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA033049-01A1
Application #
8317853
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Volman, Susan
Project Start
2012-09-15
Project End
2017-05-31
Budget Start
2012-09-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$331,875
Indirect Cost
$106,875
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Mishra, Devesh; Pena-Bravo, Jose Ignacio; Leong, Kah-Chung et al. (2016) Methamphetamine self-administration modulates glutamate neurophysiology. Brain Struct Funct :
Bernheim, Aurelien; See, Ronald E; Reichel, Carmela M (2016) Chronic methamphetamine self-administration disrupts cortical control of cognition. Neurosci Biobehav Rev 69:36-48
Leong, Kah-Chung; Berini, Carole R; Ghee, Shannon M et al. (2016) Extended cocaine-seeking produces a shift from goal-directed to habitual responding in rats. Physiol Behav 164:330-5
Peters, Jamie; Scofield, Michael D; Ghee, Shannon M et al. (2016) Perirhinal Cortex mGlu5 Receptor Activation Reduces Relapse to Methamphetamine Seeking by Restoring Novelty Salience. Neuropsychopharmacology 41:1477-85
Scofield, Michael D; Trantham-Davidson, Heather; Schwendt, Marek et al. (2015) Failure to Recognize Novelty after Extended Methamphetamine Self-Administration Results from Loss of Long-Term Depression in the Perirhinal Cortex. Neuropsychopharmacology 40:2526-35
Reichel, Carmela M; Gilstrap, Meghin G; Ramsey, Lauren A et al. (2014) Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N-methyl-D-aspartate receptor expression. Drug Alcohol Depend 134:115-22
Parsegian, Aram; See, Ronald E (2014) Dysregulation of dopamine and glutamate release in the prefrontal cortex and nucleus accumbens following methamphetamine self-administration and during reinstatement in rats. Neuropsychopharmacology 39:811-22
Mahler, Stephen V; Moorman, David E; Feltenstein, Matthew W et al. (2013) A rodent "self-report" measure of methamphetamine craving? Rat ultrasonic vocalizations during methamphetamine self-administration, extinction, and reinstatement. Behav Brain Res 236:78-89
Reichel, Carmela M; See, Ronald E (2012) Chronic modafinil effects on drug-seeking following methamphetamine self-administration in rats. Int J Neuropsychopharmacol 15:919-29
Reichel, Carmela M; Ramsey, Lauren A; Schwendt, Marek et al. (2012) Methamphetamine-induced changes in the object recognition memory circuit. Neuropharmacology 62:1119-26