This is the second submission of a competing renewal for the research grant R01 DA15214, a project that originally activated on 07 February 2003. During the current funding period, our work focused on delineating the neuronal circuitry and associated neurotransmitter systems underlying cocaine priming-induced reinstatement of cocaine seeking. During the previous funding period we identified a practical application for the elucidation of the neuronal circuitry underlying cocaine reinstatement. Thus, we showed that deep brain stimulation (DBS), a technique increasingly used clinically for the treatment of neurological and psychiatric diseases, of the nucleus accumbens shell attenuated the reinstatement of cocaine seeking in rats. Here, we propose to assess the effect of DBS of other limbic nuclei on priming-induced reinstatement of cocaine seeking as well as cocaine cue-induced reinstatement. We also propose experiments designed to delineate the mechanism of action of DBS responsible for its effect on the reinstatement of cocaine seeking.
In Specific Aim 1 the effect of DBS of relevant limbic nuclei on priming- and cue-induced reinstatement of cocaine seeking will be examined. Although the mechanism of action of DBS remains unclear, it has been proposed that DBS suppresses neuronal activity in the targeted structure via inactivation. This hypothesis will be examined in Specific Aim 2 by comparing the effect of DBS of the subregions of the nucleus and medial prefrontal cortex (mPFC) on priming- and cue-induced reinstatement of cocaine seeking to the effects of pharmacological inactivators (i.e. baclofen/muscimol or lidocaine). It also has been proposed that DBS produces complex effects on the neural circuitry associated with the stimulated structure. In order to examine this hypothesis, in Specific Aim 3 c-Fos immunreactivity will be used to assess the influence of accumbens shell or core DBS on neuronal activity in the accumbens as well as shell afferents (i.e. mPFC, amygdala, hippocampus, VTA), efferents (i.e. ventral pallidum and VTA) and adjacent structures (i.e. shell/core, dorsal striatum, etc.). The proposed experiments will specifically examine potential mechanisms that account for the influence on DBS on the reinstatement of cocaine seeking. These results will more completely characterize the nuclei and circuits influenced by DBS in the context of addiction therapies and will provide important mechanistic information that will be important for the application of DBS to other psychiatric and neurological diseases.

Public Health Relevance

Cocaine addiction remains a major public health issue in the United Sates. The experiments described in this grant application are designed to further characterize deep brain stimulation (DBS) as a novel therapeutic for cocaine addiction using animal models. DBS of various relevant limbic nuclei will be assessed in an effort to guide clinical experiments focusing on DBS in the treatment of addiction. In addition, a series of experiments will be performed to identify the specific mechanisms responsible for the behavioral effects of DBS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA015214-12A1
Application #
8783483
Study Section
Special Emphasis Panel (ZRG1-BBBP-Y (03))
Program Officer
Volman, Susan
Project Start
2002-07-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$333,457
Indirect Cost
$121,957
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Polter, Abigail M; Bishop, Rachel A; Briand, Lisa A et al. (2014) Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. Biol Psychiatry 76:785-93
Vassoler, Fair M; White, Samantha L; Schmidt, Heath D et al. (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42-7
Pierce, R Christopher; Wolf, Marina E (2013) Psychostimulant-induced neuroadaptations in nucleus accumbens AMPA receptor transmission. Cold Spring Harb Perspect Med 3:a012021
Pierce, R Christopher; Vassoler, Fair M (2013) Deep brain stimulation for the treatment of addiction: basic and clinical studies and potential mechanisms of action. Psychopharmacology (Berl) 229:487-91
Graziane, Nicholas M; Polter, Abigail M; Briand, Lisa A et al. (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942-54
Briand, Lisa A; Lee, Francis S; Blendy, Julie A et al. (2012) Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice. Eur J Neurosci 35:932-9
Yee, Judy; Famous, Katie R; Hopkins, Thomas J et al. (2011) Muscarinic acetylcholine receptors in the nucleus accumbens core and shell contribute to cocaine priming-induced reinstatement of drug seeking. Eur J Pharmacol 650:596-604
Pierce, R Christopher; Vanderschuren, Louk J M J (2010) Kicking the habit: the neural basis of ingrained behaviors in cocaine addiction. Neurosci Biobehav Rev 35:212-9
Schmidt, Heath D; Pierce, R Christopher (2010) Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. Ann N Y Acad Sci 1187:35-75

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