Reducing effect of the positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari (CA), Italy.
European Journal of Pharmacology (Impact Factor: 2.68). 12/2005; 525(1-3):105-11. DOI: 10.1016/j.ejphar.2005.10.005
Source: PubMed

ABSTRACT The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.

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    • "l consumption . This drug entirely abolished alcohol intake during the initial ( 15 min ) period of the study , which may implicate its effects on eliminating alcohol " front - loading " and overall intake during the whole session . Interestingly , repeated treatment with CGP7930 , GS39783 or rac - BHFF resulted in a reduced daily alcohol intake ( Orrù et al . , 2005 ; Loi et al . , 2013 ) , with the most efficacious action observed for rac - BHFF ( up to a 7 - day treatment period ) , suggesting no tolerance to the inhibitory ef - fects . Most recent report by Hwa et al . ( 2014 ) showed that ADX 71441 markedly and specifically reduce alcohol consumption in mouse models of " binge " - like drinking"
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    ABSTRACT: γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted.
    Neuropharmacology 06/2014; 88. DOI:10.1016/j.neuropharm.2014.06.016 · 4.82 Impact Factor
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    • "It has been proposed that this feature enables PAMs to produce less adverse effects and leads to less tolerance than direct agonists (May and Christopoulos 2003; Langmead and Christopolous 2006; Perdona et al. 2011; Urwyler 2011). Preclinical findings support this proposal, as ethanol-suppressing effects of GABA B R PAMs are associated with compensatory increases in water drinking (Orrù et al. 2005; Loi et al. 2013), while having no effect on self-administration of sucrose (Maccioni et al. 2007, 2008b, 2009, 2010). Microinfusion of GS39783 into the ventral tegmental area reduces ethanol-seeking behavior in rats without concurrent changes in spontaneous locomotor activity (Leite-Morris et al. 2009). "
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    ABSTRACT: A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents. The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA). Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control. In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h. These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.
    Psychopharmacology 08/2013; 231(2). DOI:10.1007/s00213-013-3245-z · 3.99 Impact Factor
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    • "Printed in U.S.A. herbe et al., 2008), and BHF177 (Maccioni et al., 2009)], and in vivo results suggest them to have anxiolytic-and antidepressant-like properties (Cryan et al., 2004; Frankowska et al., 2007; Jacobson and Cryan, 2008). In addition, positive modulators of GABA B receptors reduce self-administration of alcohol (Orrù et al., 2005; Liang et al., 2006; Maccioni et al., 2008, 2009), cocaine (Filip et al., 2007), and nicotine (Mombereau et al., 2007; Paterson et al., 2008). Although all of these effects generally are thought to be mediated by positive modulation of GABA B receptors, to date such modulation has been examined almost exclusively in vitro. "
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    ABSTRACT: In vivo effects of GABA(B) receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA(B) receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA(B) receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by γ-hydroxybutyrate (GHB), which, like baclofen, has GABA(B) receptor agonist properties. In contrast with baclofen- and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA(B) receptors mediating loss of righting, but not at GABA(B) receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA(B) receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA(B) system.
    Journal of Pharmacology and Experimental Therapeutics 10/2010; 335(1):163-71. DOI:10.1124/jpet.110.171116 · 3.86 Impact Factor
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