Drug addiction is a devastating disease both for the addict and for society. Unfortunately there are few treatment options available that prevent relapse to drug use after a period of abstinence. Therefore, the overarching aim of this proposal is to extend our understanding of the neural circuitry underlying relapse behavior using in vivo microdialysis and the cocaine reinstatement model of relapse. The present proposal is based on the finding that cocaine-primed reinstatement is at least partially mediated by a decrease in GABA in the ventral pallidum (VP), and that the decrease in GABA is mediated by activation of mu opioid receptors. The mu antagonist CTAP infused into the VP blocked both the decrease in GABA and reinstatement behavior after a cocaine-priming injection. Therefore, the primary hypothesis of this proposal is that cocaine-priming after abstinence requires a decrease in GABA release in the VP to produce reinstatement, and interventions that increase GABA in the VP will prevent reinstatement. Therefore, several compounds that act on peptide receptors in the VP will be infused by reverse dialysis, and GABA concentrations will be measured using microdialysis and electrochemical detection. Compounds found to increase GABA will be tested in the cocaine-priming reinstatement model of drug relapse to determine if compounds that increase GABA in the VP will also block reinstatement. In addition, the finding that an opioid antagonist injected in the VP blocks reinstatement suggests that chronic cocaine and abstinence changes the way peptides like the endogenous opioids are released from the nucleus accumbens to the VP. In order to better understand how peptide release is altered after chronic cocaine in brain regions such as the VP, a reliable method needs to be developed to measure neuropeptides from microdialysis samples. Therefore, a second aim of this proposal is to develop a method for measuring peptides using mass spectrometry, which will ultimately be used to test the hypothesis that cocaine-priming causes a release of peptides, particularly the endogenous opioids, in the VP to produce relapse behavior. Ultimately, when the interactions between fast-acting neurotransmitters and peptides are fully understood, we will be able to find the best target for the prevention of relapse in drug addicts. This proposal is relevant to public health because it will increase our understanding of the changes that take place in the brain after chronic exposure to drugs of abuse that lead to such a strong propensity for an addict to relapse. Specific targets for the prevention of relapse will be determined and verified, leading to the development of potential pharmacotherapies for the prevention of drug relapse in addicted individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA022812-03
Application #
7739463
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2007-11-01
Project End
2009-11-30
Budget Start
2009-11-01
Budget End
2009-11-30
Support Year
3
Fiscal Year
2010
Total Cost
$4,447
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Torregrossa, Mary M; Sanchez, Hayde; Taylor, Jane R (2010) D-cycloserine reduces the context specificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens. J Neurosci 30:10526-33
Sanchez, Hayde; Quinn, Jennifer J; Torregrossa, Mary M et al. (2010) Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A. J Neurosci 30:4401-7
Barker, Jacqueline M; Torregrossa, Mary M; Arnold, Arthur P et al. (2010) Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors. J Neurosci 30:9140-4
Kimchi, Eyal Y; Torregrossa, Mary M; Taylor, Jane R et al. (2009) Neuronal correlates of instrumental learning in the dorsal striatum. J Neurophysiol 102:475-89
Torregrossa, Mary M; Tang, X-C; Kalivas, Peter W (2008) The glutamatergic projection from the prefrontal cortex to the nucleus accumbens core is required for cocaine-induced decreases in ventral pallidal GABA. Neurosci Lett 438:142-5
Torregrossa, Mary M; Kalivas, Peter W (2008) Neurotensin in the ventral pallidum increases extracellular gamma-aminobutyric acid and differentially affects cue- and cocaine-primed reinstatement. J Pharmacol Exp Ther 325:556-66
Torregrossa, Mary M; Kalivas, Peter W (2008) Microdialysis and the neurochemistry of addiction. Pharmacol Biochem Behav 90:261-72