Document Detail

Role of gamma-aminobutyric acid (GABA) and metabotropic glutamate receptors in nicotine reinforcement: potential pharmacotherapies for smoking cessation.
MedLine Citation:
PMID:  15542754     Owner:  NLM     Status:  MEDLINE    
Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self-administration. Male Wistar rats were allowed to self-administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self-administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: gamma-vinyl-GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (-)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (-)baclofen dose-dependently decreased nicotine self-administration on the fixed-ratio schedule, but also decreased food-maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive-ratio schedule. MPEP dose-dependently decreased nicotine self-administration with no effect on food-maintained responding in rats. MPEP also decreased nicotine self-administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self-administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine- versus food-maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti-smoking medications for humans.
Athina Markou; Neil E Paterson; Svetlana Semenova
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  1025     ISSN:  0077-8923     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-11-15     Completed Date:  2005-02-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  491-503     Citation Subset:  IM    
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
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MeSH Terms
Dose-Response Relationship, Drug
Excitatory Amino Acid Antagonists / pharmacology
GABA Agonists / pharmacology
Nicotine / administration & dosage*
Receptors, GABA-B / agonists,  physiology*
Receptors, Metabotropic Glutamate / antagonists & inhibitors,  physiology*
Reinforcement Schedule*
Self Administration
Smoking Cessation*
gamma-Aminobutyric Acid / pharmacology
Grant Support
Reg. No./Substance:
0/Excitatory Amino Acid Antagonists; 0/GABA Agonists; 0/Receptors, GABA-B; 0/Receptors, Metabotropic Glutamate; 54-11-5/Nicotine; 56-12-2/gamma-Aminobutyric Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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