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Nicotine Self-Administration in an Animal Model

Institution: Scripps Research Institute
Investigator(s): George Koob, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0095 Award: $720,434
Subject Area: Nicotine Dependence
Award Type: Research Project Awards

Initial Award Abstract
Tobacco addiction is a serious health problem in the United States, accounting for over 400,000 premature deaths per year. Work in our laboratory during the previous funding period has established an animal model of nicotine addiction that has strong resemblance to the human condition. Animals increase their nicotine intake via intravenous self-administration with intermittent availability of access, which produces nicotine dependence and increased sensitivity to nicotine deprivation and nicotinic agents. Preliminary results have provided evidence that part of the dependence on nicotine involves a hyperactivity of the brain stress system involving the neurotransmitter corticotropin-releasing factor (CRF). CRF in the brain controls various aspects of the stress response of the body depending on its distribution, with CRF in the hypothalamus controlling the pituitary hormonal response to stressors, CRF in the brainstem controlling sympathetic responses to stressors, and CRF in the amygdala controlling emotional responses to stressors.

The present proposal is designed to test the hypothesis that the brain CRF systems contribute to the increased nicotine intake associated with dependence and that antagonists of CRF receptors may have efficacy in decreasing the stress component of nicotine-seeking in dependent animals. In a unique collaboration between our neuropharmacology and chemistry laboratories at The Scripps Research Institute, novel compounds will be developed with potential efficacy in the treatment of nicotine addiction that ultimately may provide a novel, previously unexplored, treatment for tobacco addiction.

Addiction and the brain antireward system.
Periodical: Annual Review of Psychology Index Medicus:
Authors: Koob GF; Le Moal M ART
Yr: 2008 Vol: Nbr: 59 Abs: Pg: 29-53

A role for brain stress systems in addiction.
Periodical: Neuron Index Medicus:
Authors: Koob GF ART
Yr: 2008 Vol: Nbr: 59 Abs: Pg: 11-34

Neurobiological mechanisms for opponent motivational processes in addiction.
Periodical: Philosophical Transactions of the Royal Society of London Series B: Biological Sciences Index Medicus:
Authors: Koob GF; Le Moal M ART
Yr: 2008 Vol: Nbr: 363 Abs: Pg: 3113-3123

Neurobiological substrates for the dark sid eof compulsivity in addiction.
Periodical: Neuropharmacology Index Medicus:
Authors: Koob GF ART
Yr: 2009 Vol: Nbr: 56 Abs: Pg: 18-31

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Grieder TE, George 0, Tan H, George SR, Le Foll B, Laviolette SR, van der Kooy D ART
Yr: 2012 Vol: 109 Nbr: Abs: PMCID:PMC3 Pg: 3101-3106

Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats.
Periodical: Psychopharmacology Index Medicus:
Authors: Goeders NE, Cohen A, Fox BS, Azar MR, George 0, Koob GF ART
Yr: Vol: Nbr: Abs: I Pg:

Effects of the_x000D_ specific a4~2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice.
Periodical: Psychopharmacology Index Medicus:
Authors: Tobey KM, Walentiny DM, Wiley JL, Carroll FI, Damaj MI, Azar MR, Koob GF, George 0, Harris ART
Yr: Vol: Nbr: Abs: Pg:

Robust escalation of nicotine intake with extended access to nicotine self-administration and_x000D_ intermittent periods of abstinence.
Periodical: Neuropsychopharmacology Index Medicus:
Authors: Cohen A, Koob GF, George 0. ART
Yr: Vol: Nbr: Abs: Pg: