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      Repeated administration of the GABA B receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats

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          Abstract

          Rationale

          γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA B receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA B receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA B receptor agonists, GABA B receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists.

          Objectives and methods

          We examined whether the acute effects of the GABA B receptor positive modulator N-[(1 R,2 R,4 S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self-administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined.

          Results

          Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period.

          Conclusions

          These results showed that BHF177 selectively blocked nicotine self-administration and prevented cue-induced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA B receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans.

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          Most cited references66

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          Shape of the relapse curve and long-term abstinence among untreated smokers.

          To describe the relapse curve and rate of long-term prolonged abstinence among smokers who try to quit without treatment. Systematic literature review. Cochrane Reviews, Dissertation Abstracts, Excerpt Medica, Medline, Psych Abstracts and US Center for Disease Control databases plus bibliographies of articles and requests of scientists. Prospective studies of self-quitters or studies that included a no-treatment control group. Two reviewers independently extracted data in a non-blind manner. The number of studies was too small and the data too heterogeneous for meta-analysis or other statistical techniques. There is a paucity of studies reporting relapse curves of self-quitters. The existing eight relapse curves from two studies of self-quitters and five no-treatment control groups indicate most relapse occurs in the first 8 days. These relapse curves were heterogeneous even when the final outcome was made similar. In terms of prolonged abstinence rates, a prior summary of 10 self-quitting studies, two other studies of self-quitters and three no-treatment control groups indicate 3-5% of self-quitters achieve prolonged abstinence for 6-12 month after a given quit attempt. More reports of relapse curves of self-quitters are needed. Smoking cessation interventions should focus on the first week of abstinence. Interventions that produce abstinence rates of 5-10% may be effective. Cessation studies should report relapse curves.
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            Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure.

            The reinstatement model is widely used to study relapse to drug addiction. However, the model's validity is open to question. We assess the reinstatement model in terms of criterion and construct validity. We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model's criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication's effects on reductions in cocaine intake rather than relapse during abstinence. The model's construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.
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              Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence.

              The motivation to maintain nicotine self-administration and dependence may involve alterations in glutamatergic neurotransmission. Metabotropic glutamate (mGlu) 2/3 receptors regulate glutamate and dopamine release in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) shell, two brain areas critically involved in reward and motivational processes. We found that acute systemic, as well as intra-VTA or intra-NAc, administration of the mGlu2/3 receptor agonist LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] decreased nicotine, but not food, self-administration in rats. In addition, nicotine self-administration downregulated mGlu2/3 receptor function in corticolimbic rat brain sites including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/3 receptors to G-proteins in the [35S]GTPgammaS binding assay. Furthermore, repeated treatment with LY379268 reduced nicotine self-administration at the beginning of a 14 d treatment period; however, the number of nicotine infusions earned gradually returned to baseline levels, indicating tolerance to the effects of repeated LY379268 treatment. Finally, LY379268 administration decreased both cue-induced reinstatement of nicotine- and food-seeking behavior. Together, these findings indicate an important role for mGlu2/3 receptors in the posterior VTA and the NAc shell in the mediation of the rewarding effects of nicotine and potentially in cue-induced nicotine-seeking behavior.
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                Author and article information

                Contributors
                +1-858-5341572 , +1-858-5349917 , amarkou@ucsd.edu
                Journal
                Psychopharmacology (Berl)
                Psychopharmacology
                Springer-Verlag (Berlin/Heidelberg )
                0033-3158
                1432-2072
                22 December 2010
                22 December 2010
                May 2011
                : 215
                : 1
                : 117-128
                Affiliations
                [1 ]Department of Psychiatry, MC-0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603 USA
                [2 ]Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
                [3 ]Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA
                [4 ]Place Marie Jose 6, 1050 Brussels, Belgium
                [5 ]AC Immune SA, EPFL PSE B 1.7, 1015 Lausanne, Switzerland
                [6 ]Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
                Article
                2119
                10.1007/s00213-010-2119-x
                3072487
                21181127
                cc11e213-7368-4e23-a2ea-765091543ba6
                © The Author(s) 2010
                History
                : 4 July 2010
                : 26 November 2010
                Categories
                Original Investigation
                Custom metadata
                © Springer-Verlag 2011

                Pharmacology & Pharmaceutical medicine
                addictive drugs,nicotine dependence,medication,relapse prevention,smoking cessation,treatment

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