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Reducing effect of the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in alcohol-preferring rats

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Abstract

Rationale and objectives

The positive allosteric modulator of the GABAB receptor, GS39783, has recently been found to suppress acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats exposed to the standard, homecage two-bottle “alcohol vs water” choice regimen. The present study was designed to extend the characterization of the “anti-alcohol” effects of GS39783 to oral self-administration of alcohol under an operant procedure.

Materials and methods

Two separate groups of male sP rats were trained to lever-press (on an FR4 schedule) to orally self-administer alcohol (15%, v/v) or sucrose (0.3%, w/v) in daily 30-min sessions. Once lever-pressing behavior reached stable levels, the effect of GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on responding for alcohol and sucrose was determined.

Results

Pretreatment with GS39783 resulted in a significant, dose-dependent reduction in responding for alcohol; at the dose of 100 mg/kg GS39783, the number of lever responses for alcohol was reduced by approximately 50% in comparison to vehicle-treated rats. The effect of GS39783 on alcohol self-administration was specific, as responding for sucrose was completely unaffected by pretreatment with GS39783.

Conclusions

These data demonstrate the capability of GS39783 to attenuate the reinforcing properties of alcohol in alcohol-preferring rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the GABAB receptor in the control of alcohol drinking and reinforcement.

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References

  • Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL, Gasbarrini G (2002) Baclofen efficacy in reducing alcohol craving and intake—a preliminary double-blind randomised controlled study. Alcohol Alcohol 37:504–508

    PubMed  CAS  Google Scholar 

  • Addolorato G, Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (2006) Baclofen in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus diazepam. Am J Med 119:276e13–276e18

    Article  Google Scholar 

  • Ameisen O (2005) Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician. Alcohol Alcohol 40:147–150

    PubMed  CAS  Google Scholar 

  • Anstrom KK, Cromwell HC, Markowski T, Woodward DJ (2003) Effect of baclofen on alcohol and sucrose self-administration in rats. Alcohol Clin Exp Res 27:900–908

    PubMed  CAS  Google Scholar 

  • Besheer J, Lepoutre V, Hodge CW (2004) GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174:358–366

    Article  PubMed  CAS  Google Scholar 

  • Binet V, Brajon C, Le Corre L, Acher F, Pin JP, Prezeau L (2004) The heptahelical domain of GABAB2 is activated directly by CGP7930, a positive allosteric modulator of the GABAB receptor. J Biol Chem 279:29085–29091

    Article  PubMed  CAS  Google Scholar 

  • Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383

    Article  PubMed  CAS  Google Scholar 

  • Brebner K, Phelan R, Roberts DC (2000) Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules. Psychopharmacology 148:314–321

    Article  PubMed  CAS  Google Scholar 

  • Bucknam W (2007) Suppression of symptoms of alcohol dependence and craving using high dose baclofen. Alcohol Alcohol (in press). DOI 10.1093/alcalc/agl091

  • Carai MAM, Colombo G, Froestl W, Gessa GL (2004) In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor. Eur J Pharmacol 504:213–216

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Phillips K, Minton G, Sher E (2005) GABAB receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area. Br J Pharmacol 144:926–932

    Article  PubMed  CAS  Google Scholar 

  • Chester JA, Cunningham CL (1999) Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice. Pharmacol Biochem Behav 63:325–331

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Agabio R, Carai MAM, Lobina C, Pani M, Reali R, Addolorato G, Gessa GL (2000) Ability of baclofen in reducing alcohol intake and withdrawal severity: I—preclinical evidence. Alcohol Clin Exp Res 24:58–66

    PubMed  CAS  Google Scholar 

  • Colombo G, Serra S, Brunetti G, Atzori G, Pani M, Vacca G, Addolorato G, Froestl W, Carai MAM, Gessa GL (2002) The GABAB receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats. Alcohol Alcohol 37:499–503

    PubMed  CAS  Google Scholar 

  • Colombo G, Serra S, Brunetti G, Vacca G, Carai MAM, Gessa GL (2003a) Suppression by baclofen of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats. Drug Alcohol Depend 70:105–108

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Vacca G, Serra S, Brunetti G, Carai MAM, Gessa GL (2003b) Baclofen suppresses motivation to consume alcohol in rats. Psychopharmacology 167:221–224

    PubMed  CAS  Google Scholar 

  • Colombo G, Addolorato G, Agabio R, Carai MAM, Pibiri F, Serra S, Vacca G, Gessa GL (2004a) Role of GABAB receptor in alcohol dependence: Reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox Res 6:403–414

    Article  PubMed  Google Scholar 

  • Colombo G, Serra S, Vacca G, Gessa GL, Carai MAM (2004b) Suppression by baclofen of the stimulation of alcohol intake induced by morphine and WIN 55,212-2 in alcohol-preferring rats. Eur J Pharmacol 492:189–193

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Lobina C, Carai MAM, Gessa GL (2006a) Phenotypic characterization of genetically selected Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats. Addict Biol 11:324–338

    Article  PubMed  Google Scholar 

  • Colombo G, Serra S, Vacca G, Carai MAM, Gessa GL (2006b) Baclofen-induced suppression of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats exposed to different alcohol concentrations. Eur J Pharmacol 550:123–126

    Article  PubMed  CAS  Google Scholar 

  • Cott J, Carlsson A, Engel J, Lindqvist M (1976) Suppression of ethanol-induced locomotor stimulation by GABA-like drugs. Naunyn-Schmiedeberg’s Arch Pharmacol 295:203–209

    Article  CAS  Google Scholar 

  • Cryan JF, Kelly PH, Chaperon F, Gentsch C, Mombereau C, Lingenhoehl K, Froestl W, Bettler B, Kaupmann K, Spooren WP (2004) Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines. J Pharmacol Exp Ther 310:952–963

    Article  PubMed  CAS  Google Scholar 

  • Czachowski CL, Legg BH, Stansfield KH (2006) Ethanol and sucrose seeking and consumption following repeated administration of the GABAB agonist baclofen in rats. Alcohol Clin Exp Res 30:812–818

    Article  PubMed  CAS  Google Scholar 

  • Daoust M, Saligaut C, Lhuintre JP, Moore N, Flipo JL, Boismare F (1987) GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats. Alcohol 4:469–472

    Article  PubMed  CAS  Google Scholar 

  • File SE, Zharkovsky A, Gulati K (1991) Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat. Neuropharmacology 30:183–190

    Article  PubMed  CAS  Google Scholar 

  • Flannery BA, Garbutt JC, Cody MW, Renn W, Grace K, Osborne M, Crosby K, Morreale M, Trivette A (2004) Baclofen for alcohol dependence: a preliminary open-label study. Alcohol Clin Exp Res 28:1517–1523

    Article  PubMed  CAS  Google Scholar 

  • Humeniuk RE, White JM, Ong J (1994) The effects of GABAB ligands on alcohol withdrawal in mice. Pharmacol Biochem Behav 49:561–566

    Article  PubMed  CAS  Google Scholar 

  • Janak PH, Gill TM (2003) Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose. Alcohol 30:1–7

    Article  PubMed  CAS  Google Scholar 

  • Knapp DJ, Overstreet DH, Breese GR (2007) Baclofen blocks expression and sentization of anxiety-like behavior in an animal model of repeated stress and ethanol withdrawal. Alcohol Clin Exp Res 31:582–595

    PubMed  CAS  Google Scholar 

  • Leite-Morris KA, Czachowski CL (2006) Intra-ventral tegmental area microinjections of a GABA receptor agonist dose-dependently attenuate ethanol seeking in rats. Alcohol Clin Exp Res 30:182A

    Article  Google Scholar 

  • Lhuillier L, Mombereau C, Cryan JF, Kaupmann K (2007) GABAB receptor-positive modulation decreases selective molecular and behavioral effects of cocaine. Neuropsychopharmacology 32:388–398

    Article  PubMed  CAS  Google Scholar 

  • Liang JH, Chen F, Krstew E, Cowen MS, Carroll FY, Crawford D, Beart PM, Lawrence AJ (2006) The GABAB receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats. Neuropharmacology 50:632–639

    Article  PubMed  CAS  Google Scholar 

  • Maccioni P, Serra S, Vacca G, Orrù A, Pes D, Agabio R, Addolorato G, Carai MAM, Gessa GL, Colombo G (2005) Baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats. Alcohol 36:161–168

    Article  PubMed  CAS  Google Scholar 

  • Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF (2004) Genetic and pharmacological evidence of a role for GABAB receptors in the modulation of anxiety-and antidepressant-like behavior. Neuropsychopharmacology 29:1050–1062

    Article  PubMed  CAS  Google Scholar 

  • Mombereau C, Lhuillier L, Kaupmann K, Cryan J (2007) GABAB receptor positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens δFosB accumulation. J Pharmacol Exp Ther 321:172–177

    Article  PubMed  CAS  Google Scholar 

  • Onali P, Mascia FM, Olianas MC (2003) Positive regulation of GABAB receptors dually coupled to cyclic AMP by the allosteric agent CGP7930. Eur J Pharmacol 471:77–84

    Article  PubMed  CAS  Google Scholar 

  • Orrù A, Lai P, Lobina C, Maccioni P, Piras P, Scanu L, Froestl W, Gessa GL, Carai MAM, Colombo G (2005) Reducing effect of the positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats. Eur J Pharmacol 525:105–111

    Article  PubMed  CAS  Google Scholar 

  • Petry NM (1997) Benzodiazepine-GABA modulation of concurrent ethanol and sucrose reinforcement in the rat. Exp Clin Psychopharmacol 5:183–194

    Article  PubMed  CAS  Google Scholar 

  • Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442

    PubMed  CAS  Google Scholar 

  • Shen EH, Dorow J, Harland R, Burkhart-Kasch S, Phillips TJ (1998) Seizure sensitivity and GABAergic modulation of ethanol sensitivity in selectively bred FAST and SLOW mouse lines. J Pharmacol Exp Ther 287:606–615

    PubMed  CAS  Google Scholar 

  • Slattery DA, Markou A, Froestl W, Cryan JF (2005) The GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat. Neuropsychopharmacology 30:2065–2072

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, Yancey DL, Morgan D, Froestl W, Roberts DC (2004) Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats. Psychopharmacology 173:105–111

    Article  PubMed  CAS  Google Scholar 

  • Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K (2001) Positive allosteric modulation of native and recombinant γ-aminobutyric acidB receptors by 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol Pharmacol 60:963–971

    PubMed  CAS  Google Scholar 

  • Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K (2003) N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acid B receptor function. J Pharmacol Exp Ther 307:322–330

    Article  PubMed  CAS  Google Scholar 

  • Vacca G, Serra S, Brunetti G, Carai MAM, Samson HH, Gessa GL, Colombo G (2002) Operant self-administration of ethanol in Sardinian alcohol-preferring rats. Alcohol Clin Exp Res 26:1678–1685

    PubMed  CAS  Google Scholar 

  • Walker BM, Koob GF (2007) The γ-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats. Alcohol Clin Exp Res 31:11–18

    Article  PubMed  CAS  Google Scholar 

  • Weiss F, Porrino LJ (2002) Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 22:3332–3337

    PubMed  CAS  Google Scholar 

  • Zaleski MJ, Nunes Filho JR, Lemos T, Morato GS (2001) GABAB receptors play a role in the development of tolerance to ethanol in mice. Psychopharmacology 153:415–424

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Mrs. Carla Acciaro and Mrs. Maria Elena Vincis for animal breeding and care, and Mrs. Anne Farmer for language editing of the manuscript.

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Authors and Affiliations

  1. “Bernard B. Brodie” Department of Neuroscience, University of Cagliari, Viale Diaz 182, 09126, Cagliari, Italy

    Paola Maccioni, Daniela Pes & Alessandro Orrù

  2. C.N.R. Institute of Neuroscience, Viale Diaz, 182, 09126, Cagliari, CA, Italy

    Paola Maccioni, Daniela Pes, Gian Luigi Gessa, Mauro A. M. Carai & Giancarlo Colombo

  3. AC Immune SA, PSE Building B-EPFL, CH-1015, Lausanne, Switzerland

    Wolfgang Froestl

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  1. Paola Maccioni
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  2. Daniela Pes
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  3. Alessandro Orrù
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  4. Wolfgang Froestl
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  5. Gian Luigi Gessa
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  6. Mauro A. M. Carai
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  7. Giancarlo Colombo
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Correspondence to Giancarlo Colombo.

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Maccioni, P., Pes, D., Orrù, A. et al. Reducing effect of the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in alcohol-preferring rats. Psychopharmacology 193, 171–178 (2007). https://doi.org/10.1007/s00213-007-0776-1

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  • DOI: https://doi.org/10.1007/s00213-007-0776-1

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