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NEUROPHARMACOLOGY

Positive Modulation of GABA_B Receptors Decreased Nicotine Self-Administration and Counteracted Nicotine-Induced Enhancement of Brain Reward Function in Rats

Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, California (N.E.P., S.V., A.M.); and Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (S.G., K.K., W.F.)

Acute administration of -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. GABA_B 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 GABA_B 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 GABA_B receptor-positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA_B 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 GABA_B receptor-positive modulators, similarly to GABA_B receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA_B receptor agonists. Thus, GABA_B receptor-positive modulators may be useful antismoking medications.

Address correspondence to Dr. Athina Markou, Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Dr., M/C 0603, La Jolla, CA 92093-0603. E-mail: amarkou{at}ucsd.edu

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