Positive Modulation of GABAB 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, 9500 Gilman Dr., La Jolla, CA 92093-0603, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 08/2008; 326(1):306-14. DOI: 10.1124/jpet.108.139204
Source: PubMed


Acute administration of gamma-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.

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Available from: Neil E. Paterson
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    • "In the few studies in which baclofen and GABAB PAMs were concurrently tested (Liang et al., 2006; Maccioni et al., 2012), baclofen resulted to be more potent and effective in reducing lever-responding for alcohol; however, at variance with the results collected with baclofen, the reducing effect of GS39783, BHF177, and rac-BHFF (at least within a given dose-range for the latter compound) displayed the important feature of being highly selective for alcohol self-administration: indeed, treatment with these compounds did not alter lever-responding for a sucrose solution in independent sets of sP rats. Additional studies are needed to understand the bases of the differential selectivity of the “anti-alcohol” effects of baclofen and GABAB PAMs; nevertheless, these “selectivity” data are in close agreement with the results of several studies (Cryan et al., 2004; Malherbe et al., 2008; Paterson et al., 2008) suggesting the capacity of GABAB PAMs to produce the “desired” behavioral effects—anxiolysis or “anti-addictive” effects—at doses far lower than those inducing motor-impairment and sedation, displaying higher therapeutic index and better side-effect profile than baclofen. "
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    ABSTRACT: The present paper summarizes the preclinical and clinical studies conducted to define the "anti-alcohol" pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date-including case reports, retrospective chart reviews, and randomized placebo-controlled studies-suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several "anti-alcohol" effects of baclofen and display a higher therapeutic index (with larger separation-in terms of doses-between "anti-alcohol" effects and sedation).
    Full-text · Article · Jun 2014 · Frontiers in Neuroscience
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    • "cyclohepten-5,10-imine hydrogen maleate (MK-801)- and amphetamine-induced hyperactivity tests (Wieronska et al., 2011). In addition, they reduce self-administration of alcohol (Orru et al., 2005, 2012; Liang et al., 2006; Maccioni et al., 2007, 2008, 2009, 2010a, b, 2012; Agabio et al., 2012), cocaine (Filip et al., 2007), and nicotine (Mombereau et al., 2007; Paterson et al., 2008; Vlachou et al., 2011). GABA B receptorpositive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction, because they may have a better side-effect profile than GABA B receptor agonists, based on the notion that selective enhancement of activated receptors has effects that differ from indiscriminate activation of all receptors. "
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    ABSTRACT: GABA(B) receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABA(B) receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABA(B) receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABA(B) receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABA(B) receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA(B) receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABA(B) receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABA(B2) subunits of GABA(B) receptors. At a dose 10-fold lower than the training dose rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABA(B) receptor-positive modulators are not identical to those of GABA(B) receptor agonists. In addition, the results suggest that positive modulation of GABA(B) receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABA(B) receptors mediating the effects of baclofen and GHB are not identical.
    Preview · Article · Dec 2012 · Journal of Pharmacology and Experimental Therapeutics
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    • "In interpreting the results of our study it should be borne in mind that we only measured mRNA transcripts and not protein levels, however if decreased GABBR1 expression results in down-regulation of GABAB receptors our identical findings in alcoholics, cocaine addicts and alcohol-naïve P rats suggest that this may be a marker for vulnerability to addiction. Indeed, accumulating evidence from studies in mice and rats (including Indiana P rats) shows that in the reverse situation of GABAB receptor up-regulation by agonists such as baclofen, there is a reduction of drug-related behaviors including alcohol consumption, relapse-like drinking and re-instatement of cocaine seeking behavior [17], [18], [35], [36], [37]. Moreover, baclofen decreases alcohol consumption, craving and severity of alcohol withdrawal symptoms in humans [17], [19]. "
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    ABSTRACT: By performing identical studies in humans and rats, we attempted to distinguish vulnerability factors for addiction from neurobiological effects of chronic drug exposure. We focused on the GABAergic system within the hippocampus, a brain region that is a constituent of the memory/conditioning neuronal circuitry of addiction that is considered to be important in drug reinforcement behaviors in animals and craving and relapse in humans. Using RNA-Seq we quantified mRNA transcripts in postmortem total hippocampus from alcoholics, cocaine addicts and controls and also from alcohol-naïve, alcohol preferring (P) and non-preferring (NP) rats selectively bred for extremes of alcohol-seeking behavior that also show a general addictive tendency. A pathway-targeted analysis of 25 GABAergic genes encoding proteins implicated in GABA synthesis, metabolism, synaptic transmission and re-uptake was undertaken. Directionally consistent and biologically plausible overlapping and specific changes were detected: 14/25 of the human genes and 12/25 of the rat genes showed nominally significant differences in gene expression (global p values: 9×10⁻¹⁴, 7×10⁻¹¹ respectively). Principal FDR-corrected findings were that GABBR1 was down-regulated in alcoholics, cocaine addicts and P rats with congruent findings in NSF, implicated in GABAB signaling efficacy, potentially resulting in increased synaptic GABA. GABRG2, encoding the gamma2 subunit required for postsynaptic clustering of GABAA receptors together with GPHN, encoding the associated scaffolding protein gephryin, were both down-regulated in alcoholics and cocaine addicts but were both up-regulated in P rats. There were also expression changes specific to cocaine addicts (GAD1, GAD2), alcoholics (GABRA2) and P rats (ABAT, GABRG3). Our study confirms the involvement of the GABAergic system in alcoholism but also reveals a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction. Finally, the results of this study have therapeutic implications.
    Full-text · Article · Jan 2012 · PLoS ONE
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