This is a 5 year competitive renewal that builds upon nearly a decade of previously funded research that has identified the projection from the prefrontal cortex to the nucleus accumbens, and then to the ventral pallidum as a key brain circuit underlying relapse to cocaine use. Relapse is modeled in rats trained to self-administer cocaine and then undergone extinction training, and is defined as the reinstatement of cocaine seeking in response to a conditioned cue, a noncontingent injection of cocaine, or after inhibition of the infralimbic cortex that is hypothesized to disinhibit extinguished responding. In the first aim of the present proposal we will use the recent development of genetically targeted light- activated proteins to validate the role of this circuitry in the reinstatement of cocaine seeking. Previous pharmacological or electrical stimulation techniques used to define brain circuitry suffer caveats such affecting fibers of passage and/or multiple projections from a given nucleus, and these weaknesses are largely circumvented using in vivo light activation of virally transfected channels or transporters. Thus, the first aim is devoted to refining this new technology and validating, or not, previous circuitry studies by our group and others identifying the PFC-accumbens-pallidal circuit as important in relapse. The remaining 3 aims focus on our recent finding that dendritic spine morphology in the nucleus accumbens undergoes rapid and profound changes during a cocaine-primed reinstatement of drug seeking. Firstly, in Aim 2 we will fully characterize these morphological changes in both the core and shell subcompartments of the accumbens in response to different modalities of inducing cocaine seeking (e.g. cue, cocaine and inhibition of infralimbic cortex). Then in Aim 3 we will determine which afferents to the nucleus accumbens are mediating the reinstatement-associated morphological changes, with a focus on glutamatergic inputs from the prefrontal cortex and amygdala, and dopaminergic inputs from the ventral tegmental area. Finally in Aim 4 we conduct experiments to determine if the changes in spine morphology are necessary for reinstating cocaine seeking, or if they are protective and inhibit reinstatement. Accordingly, we will test the capacity of 3 different inhibitors of actin dynamics to simultaneously inhibit primed reinstatement and reinstatement-associated spine morphology. Interestingly, preliminary data presented in the proposal indicates that the rapid morphological changes may be protective rather than causal in reinstating cocaine seeking.

Public Health Relevance

The social and criminal ramifications of psychostimulant abuse are an enormous problem in North America. This project defines the circuitry underlying relapse to cocaine use in an animal model using new genetically targeted light-activated protein technology. Furthermore, neuronal plasticity in relapse circuitry will be examined to determine if the changes in brain structure accompanying chronic cocaine use are protective and helping to inhibit relapse or if they are causal and facilitating relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012513-15
Application #
8635997
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2000-02-10
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
15
Fiscal Year
2014
Total Cost
$304,034
Indirect Cost
$97,909
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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McClure, Erin A; Gipson, Cassandra D; Malcolm, Robert J et al. (2014) Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 28:95-106
Gipson, Cassandra D; Kupchik, Yonatan M; Kalivas, Peter W (2014) Rapid, transient synaptic plasticity in addiction. Neuropharmacology 76 Pt B:276-86
Kalivas, Peter W; Gipson, Cassandra D (2014) "Mourning" a lost opportunity. Psychopharmacology (Berl) 231:3921-2
Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya et al. (2014) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol 19:49-60
Reissner, Kathryn J; Brown, Robyn M; Spencer, Sade et al. (2014) Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology 39:499-506
Smith, Alexander C W; Kupchik, Yonatan M; Scofield, Michael D et al. (2014) Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nat Neurosci 17:1655-7
Stefanik, Michael T; Moussawi, Khaled; Kupchik, Yonatan M et al. (2013) Optogenetic inhibition of cocaine seeking in rats. Addict Biol 18:50-3
Gipson, Cassandra D; Kupchik, Yonatan M; Shen, Haowei et al. (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867-72
Smith, Rachel J; Lobo, Mary Kay; Spencer, Sade et al. (2013) Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr Opin Neurobiol 23:546-52

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