One of the biggest impediments to the successful treatment of cocaine addiction is the high rate of relapse, following even extended periods of drug abstinence. Exposures to stress, drug-paired cues, and cocaine itself have all been shown to increase reports of craving in human drug users and to elicit a reinstatement of drug-seeking behavior in animal models of relapse. However, there is a lacuna in our understanding of the neural circuitry and neuropharmacology via which these stimuli produce their behavioral effects. Without such information, adequate pharmacotherapies for the treatment of cocaine addiction are unlikely. It is the goal of the proposed project to identify the neural circuitry and examine the neurochemistry underlying stress-induced relapse in cocaine self-administration, particularly within the prefrontal cortex, an area important for behavioral responses to stress. In order to accomplish this goal, rats trained to self-administer cocaine will undergo behavioral extinction and then will be tested for their propensity to reinstate drug-taking behavior following exposure to foot shock stress. In some experiments, rats will have one of several target structures reversibly inactivated by GABA agonist treatment prior to reinstatement testing in order to identify the structures that form the requisite circuitry for stress-induced reinstatement. Following identification of the circuit, the relative importance of prefrontal cortex (PFC) glutamate (GLU) afferents to the nucleus accumbens (NA) in stress-induced reinstatement will be assessed by 1) antagonism of NA GLU or dopamine (DA) receptors during reinstatement; or 2) microdialysis for DA and GLU in the NA combined with antagonism of DA, norepinephrine (NE) or corticotropin-releasing factor (CRF) receptors in the PFC. Finally the source of PFC activation will be determined by combining microdialysis for GABA, NE, GLU or DA in the PFC with inactivation techniques. The hypotheses are that 1) limbic structures (including the central extended amygdala and ventral tegmental area) are important for processing stressful stimuli and transmitting information to motor structures (PFC, NA, ventral pallidum) responsible for activating behavioral output; 2) a rise in accumbal GLU mediates behavioral reinstatement; and dopaminergic activation of the PFC from the ventral tegmental afferents is responsible for activating the glutamatergic projection to the NA.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015851-04
Application #
7214201
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Frankenheim, Jerry
Project Start
2004-04-10
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$173,044
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
29425
Reissner, Kathryn J; Uys, Joachim D; Schwacke, John H et al. (2011) AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis. J Neurosci 31:5648-58
Uys, Joachim D; Grey, Angus C; Wiggins, Armina et al. (2010) Matrix-assisted laser desorption/ionization tissue profiling of secretoneurin in the nucleus accumbens shell from cocaine-sensitized rats. J Mass Spectrom 45:97-103
Pacchioni, Alejandra M; Kalivas, Peter W (2009) The Role of AMPAR Trafficking Mediated by Neuronal Pentraxins in Cocaine-induced Neuroadaptations. Mol Cell Pharmacol 1:183-192
Kalivas, Peter W (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561-72
Kalivas, Peter W; Lalumiere, Ryan T; Knackstedt, Lori et al. (2009) Glutamate transmission in addiction. Neuropharmacology 56 Suppl 1:169-73
Pacchioni, Alejandra M; Vallone, Joseph; Worley, Paul F et al. (2009) Neuronal pentraxins modulate cocaine-induced neuroadaptations. J Pharmacol Exp Ther 328:183-92
Shen, Haowei; Sesack, Susan R; Toda, Shigenobu et al. (2008) Automated quantification of dendritic spine density and spine head diameter in medium spiny neurons of the nucleus accumbens. Brain Struct Funct 213:149-57
Torregrossa, Mary M; Kalivas, Peter W (2008) Microdialysis and the neurochemistry of addiction. Pharmacol Biochem Behav 90:261-72
Gregory, Mary L; Szumlinski, Karen K (2008) Impoverished rearing impairs working memory and metabotropic glutamate receptor 5 expression. Neuroreport 19:239-43
Kalivas, Peter W (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9:389-97