Abstract
Acute administration of γ-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABAB receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABAB receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABAB receptor-positive modulator N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABAB receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotine- and food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine self-administration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine self-administration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine- but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABAB receptor-positive modulators, similarly to GABAB receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABAB receptor agonists. Thus, GABAB receptor-positive modulators may be useful antismoking medications.
Footnotes
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This work was supported by National Institutes of Health Grant U01 MH69062 (to A.M.). N.E.P. was supported by a Peter McManus research grant. S.V. was supported by the Propondis Foundation (Piraeus, Attiki, Greece). The data presented here have appeared in abstract form as follows: Vlachou S, Paterson NE, Guery S, Froestl W, Kaupmann K, Markou A (2007) GABA-B receptor positive modulators decrease nicotine self-administration in rats, in Society for Neuroscience Annual Meeting; 2007 Nov 3–7; San Diego, CA. Society for Neuroscience, Washington, DC.
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N.E.P. and S.V. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.139204.
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ABBREVIATIONS: CGP44532, (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid; GS39783, N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; BHF177, N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine; CGP7930, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol; ICSS, intracranial self-stimulation; FR, fixed ratio; TO, time-out; ANOVA, analysis of variance.
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↵1 Current affiliation: Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California.
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↵2 Current affiliation: GlaxoSmithKline S.p.A., Verona, Italy.
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↵3 Current affiliation: AC Immune SA, EPFL, Lausanne, Switzerland.
- Received March 19, 2008.
- Accepted April 28, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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