This is competing renewal application of grant 1 U01 MH69062 in response to Program Announcement PAR-08-238 (NCDDDG). The main objectives of this project are now focused on the synthesis, and in vitro and in vivo characterization of novel y-aminobutyric acid (GABA) B receptor positive modulators for the treatment of nicotine dependence. The proposed program consists of three Scientific Projects and an Administrative Core (U19) (PD: A. Markou). Project 1 (PI: M.G. Finn, The Scripps Research Institute, La Jolla, California) will design, synthesize, and refine new GABAB receptor positive modulators, using both combinatorial and click chemistry. Project 2 (PI: P. Griffin, The Scripps Research Institute, Jupiter, Florida), will profile the in vitro pharmacology of candidate GABAB receptor positive modulators using cell-based functional G-protein coupled receptor (GPCR) assays for GABAB receptors. Project 2 will also assess the in vitro metabolism, and in vivo brain penetration and pharmacokinetic characteristics of selected compounds. Compounds with the desired combination of properties will be tested in Project 3 (PI: A. Markou, Univ of California San Diego, La Jolla, California) in well validated rat models of nicotine dependence. These in vivo models will include nicotine self-administration, reward-enhancing effects of nicotine in the intracranial self-stimulation procedure, cue-induced reinstatement of nicotine-seeking and anxiety-like behavior during nicotine withdrawal. Extensive work during the previously funded period resulted in the first highly selective positive modulators for GABAB receptors with the desired behavioral effects in rat models of nicotine dependence. Thus, strong preclinical proof-of-concept has been established for the unique and novel strategy of GABAB receptor positive modulation in the treatment of nicotine dependence, and potentially dependence on other drugs of abuse. With this application, we seek funding to build on our previous results by: (a) expanding the pipeline of drug-like active agents;(b) understanding the factors that promote selective positive modulation of GABAB receptors;and (c) assessing how the newly synthesized compounds affect behaviors in rat models of nicotine dependence. This multidisciplinary research program integrates the complementary expertise of the participating scientists to provide innovative potential therapeutics for nicotine dependence in humans.

Public Health Relevance

Tobacco smoking, partly attributable to the addictive properties of nicotine, continues to be a worldwide heath problem. This multidisciplinary research program will continue efforts to synthesize and provide in vitro and in vivo characterization of novel GABAB receptor positive modulators as innovative potential therapeutics to treat nicotine dependence in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DA026838-09
Application #
8485558
Study Section
Special Emphasis Panel (ZMH1-ERB-C (03))
Program Officer
Kline, Richard
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$1,413,468
Indirect Cost
$166,846
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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D'Souza, Manoranjan S; Markou, Athina (2013) The "stop" and "go" of nicotine dependence: role of GABA and glutamate. Cold Spring Harb Perspect Med 3:
Chirapu, Srinivas Reddy; Rotter, Charles J; Miller, Emily L et al. (2013) High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid. Curr Top Med Chem 13:837-42
Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea et al. (2013) Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. Neuropharmacology 70:156-67
Stoker, Astrid K; Markou, Athina (2013) Unraveling the neurobiology of nicotine dependence using genetically engineered mice. Curr Opin Neurobiol 23:493-9
Vlachou, Styliani; Guery, Sebastien; Froestl, Wolfgang et al. (2011) Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats. Psychopharmacology (Berl) 215:117-28
D'Souza, Manoranjan S; Markou, Athina (2011) Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments. Addict Sci Clin Pract 6:4-16
Vlachou, Styliani; Paterson, Neil E; Guery, Sebastien et al. (2011) Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats. Eur J Pharmacol 655:52-8
Wager-Smith, Karen; Markou, Athina (2011) Depression: a repair response to stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition? Neurosci Biobehav Rev 35:742-64