This is the first resubmission of a competing renewal for the research grant R01 DA15214, a five-year project that 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 and, to a lesser extent, cocaine reinforcement. Our work indicates that D1-like and D2 dopamine receptors in the shell, but not core, subregion of the nucleus accumbens play critical roles in the reinstatement of cocaine seeking and cocaine reinforcement. In addition, we demonstrated that administration of cocaine directly into the medial prefrontal cortex (mPFC) reinstates cocaine-seeking behavior by increasing AMPA-mediated glutamate transmission in the nucleus accumbens. Our research, combined with that of others, demonstrates that a collection of limbic nuclei, including the ventral tegmental area (VTA), nucleus accumbens, mPFC, amygdala, hippocampus and ventral pallidum, underlie cocaine reinforcement and the reinstatement of cocaine seeking.
In Specific Aims 1 and 2 of the present application, we extend this circuitry to include the pedunculopontine tegmental nucleus (PPTg), which receives glutamatergic inputs from the mPFC and sends glutamatergic and cholinergic projections to the VTA that synapse on dopaminergic neurons. The overarching hypothesis of these experiments is that the serial circuit encompassing the mPFC, PPTg, VTA and nucleus accumbens is critically involved in cocaine reinforcement as well as cocaine priming-induced reinstatement of drug seeking. We also propose to examine a practical application for the emerging neuronal circuitry underlying cocaine reinforcement and reinstatement. Thus, in Specific Aim 3 we will assess the effect of reversible inactivation of various limbic nuclei on cocaine reinforcement and reinstatement of cocaine seeking. The novel aspect of this aim is the method of neuronal inactivation. We will utilize deep brain stimulation (DBS), a technique increasingly used clinically for the treatment of neurological diseases that has recently been tested as a potential treatment for a range of psychiatric disorders as well. Cocaine addiction remains a major public health issue in the United Sates. The experiments described in this grant application are designed to delineate the neuronal circuitry and associated neurotransmitter systems underlying influenced by cocaine using animal models. The overarching goal of this project is to identify novel therapeutic targets for cocaine craving and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015214-11
Application #
8217179
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Volman, Susan
Project Start
2002-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
11
Fiscal Year
2012
Total Cost
$305,550
Indirect Cost
$111,550
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Briand, Lisa A; Kimmey, Blake A; Ortinski, Pavel I et al. (2014) Disruption of glutamate receptor-interacting protein in nucleus accumbens enhances vulnerability to cocaine relapse. Neuropsychopharmacology 39:759-69
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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