This K01 Mentored Research Career Development Award is to train Caroline E. Bass, junior faculty in the Dept. Physiology & Pharmacology at Wake Forest Univ., to develop an independent hypothesis-driven research project to investigate addiction processes that are modulated by dopamine and cannabinoid receptors in the mesocorticolimbic system. Dr. Bass will apply her skills in the development of adenoassociated virus (AAV) vectors for the delivery of RNA interference (RNAi) transgenes to develop her own project focused on the knock down of D1, D2 and CB1 receptors in strategically defined brain loci, the impact this has on the reinforcing efficacy of cocaine, and how the cananbiniod and dopamine systems interact in a cocaine self-administration model of drug abuse. Dr. Bass's mentoring in cannabinoid pharmacology and gene expression changes will come from Dr. Allyn C. Howlett, and her mentoring in the behavioral models, particularly rat self-administration, will come from Dr. David C.S. Roberts, who are distinguished scientists in these respective areas. Other mentoring will cover all aspects of professional skills commensurate with academic promotion and national recognition. The following specific aims are proposed to meet the goals of this proposal: 1) Generate and characterize AAV vectors containing RNAi expression cassettes that cause the degradation of D1, D2 and CB1 receptor mRNA in rats and determine the compensatory changes in molecular components of dopamine and endocannabinoid neurotransmission resulting from this manipulation; 2) Investigate the site(s) of action of non-conditioned behavioral effects of THC by injecting the CB1 RNAi-AAV into the striatum and medulla and assessing the efficacy of THC in inducing antinociception, hypoactivity, hypothermia, and catalepsy; 3) delineate and define the contribution of D1 and D2 receptors in the ventral striatum, dorsal striatum and VTA in the reinforcing effects of cocaine by site specific injection of D1 or D2 RNAi-AAV in rats self-administering cocaine; 4) Characterize the impact of CB1 receptor ablation from the ventral striatum, dorsal striatum and VTA on cocaine self-administration. Specifically, the CB1 RNAi-AAV will be injected into these regions and the reinforcing efficacy of cocaine will be assessed. During all stages of these aims the compensatory mechanisms in cannabinoid and dopamine neurotransmission will be assessed to determine how these receptor systems are interacting in modulating cocaine intake. These studies will address fundamental gaps in our knowledge of dopamine receptor function in reinforcement and serve as a basis for understanding how cannabinoid and dopamine receptor systems interact to regulate addictive behaviors. These findings may lead to the development of novel and more effective therapeutic interventions for drug addiction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DA024763-01A1
Application #
7588997
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pilotte, Nancy S
Project Start
2008-09-30
Project End
2012-08-31
Budget Start
2008-09-30
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$138,143
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Bernosky-Smith, Kimberly A; Qiu, Yan-Yan; Feja, Malte et al. (2018) Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats. Behav Brain Res 341:129-134
Blume, Lawrence C; Patten, Theresa; Eldeeb, Khalil et al. (2017) Cannabinoid Receptor Interacting Protein 1a Competition with ?-Arrestin for CB1 Receptor Binding Sites. Mol Pharmacol 91:75-86
Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J et al. (2016) Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner. J Neurochem 139:396-407
Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P et al. (2016) Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors. Neuroscience 333:54-64
Peterson, Sean M; Pack, Thomas F; Wilkins, Angela D et al. (2015) Elucidation of G-protein and ?-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci U S A 112:7097-102
Urs, Nikhil M; Bido, Simone; Peterson, Sean M et al. (2015) Targeting ?-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease. Proc Natl Acad Sci U S A 112:E2517-26
Blume, Lawrence C; Eldeeb, Khalil; Bass, Caroline E et al. (2015) Cannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells. Cell Signal 27:716-726
Gompf, Heinrich S; Budygin, Evgeny A; Fuller, Patrick M et al. (2015) Targeted genetic manipulations of neuronal subtypes using promoter-specific combinatorial AAVs in wild-type animals. Front Behav Neurosci 9:152
Fenno, Lief E; Mattis, Joanna; Ramakrishnan, Charu et al. (2014) Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods 11:763-72
Anaclet, Christelle; Ferrari, Loris; Arrigoni, Elda et al. (2014) The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat Neurosci 17:1217-24

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