Psychopharmacology

, Volume 193, Issue 2, pp 171–178

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

  • Paola Maccioni
  • Daniela Pes
  • Alessandro Orrù
  • Wolfgang Froestl
  • Gian Luigi Gessa
  • Mauro A. M. Carai
  • Giancarlo Colombo
Original Investigation

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.

Keywords

Positive allosteric modulator of the GABAB receptor GS39783 Baclofen Alcohol self-administration Alcohol reinforcing properties Sardinian alcohol-preferring (sP) rats 

References

  1. 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 37:504–508PubMedGoogle Scholar
  2. 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 119:276e13–276e18CrossRefGoogle Scholar
  3. 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 40:147–150PubMedGoogle Scholar
  4. Anstrom KK, Cromwell HC, Markowski T, Woodward DJ (2003) Effect of baclofen on alcohol and sucrose self-administration in rats. Alcohol Clin Exp Res 27:900–908PubMedGoogle Scholar
  5. Besheer J, Lepoutre V, Hodge CW (2004) GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174:358–366PubMedCrossRefGoogle Scholar
  6. 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 279:29085–29091PubMedCrossRefGoogle Scholar
  7. Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383PubMedCrossRefGoogle Scholar
  8. 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 148:314–321PubMedCrossRefGoogle Scholar
  9. Bucknam W (2007) Suppression of symptoms of alcohol dependence and craving using high dose baclofen. Alcohol Alcohol (in press). DOI 10.1093/alcalc/agl091
  10. 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 504:213–216PubMedCrossRefGoogle Scholar
  11. 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 144:926–932PubMedCrossRefGoogle Scholar
  12. Chester JA, Cunningham CL (1999) Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice. Pharmacol Biochem Behav 63:325–331PubMedCrossRefGoogle Scholar
  13. 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 24:58–66PubMedGoogle Scholar
  14. 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 37:499–503PubMedGoogle Scholar
  15. 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 70:105–108PubMedCrossRefGoogle Scholar
  16. Colombo G, Vacca G, Serra S, Brunetti G, Carai MAM, Gessa GL (2003b) Baclofen suppresses motivation to consume alcohol in rats. Psychopharmacology 167:221–224PubMedGoogle Scholar
  17. 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 6:403–414PubMedCrossRefGoogle Scholar
  18. 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 492:189–193PubMedCrossRefGoogle Scholar
  19. 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 11:324–338PubMedCrossRefGoogle Scholar
  20. 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 550:123–126PubMedCrossRefGoogle Scholar
  21. Cott J, Carlsson A, Engel J, Lindqvist M (1976) Suppression of ethanol-induced locomotor stimulation by GABA-like drugs. Naunyn-Schmiedeberg’s Arch Pharmacol 295:203–209CrossRefGoogle Scholar
  22. 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 310:952–963PubMedCrossRefGoogle Scholar
  23. 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 30:812–818PubMedCrossRefGoogle Scholar
  24. 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 4:469–472PubMedCrossRefGoogle Scholar
  25. File SE, Zharkovsky A, Gulati K (1991) Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat. Neuropharmacology 30:183–190PubMedCrossRefGoogle Scholar
  26. 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 28:1517–1523PubMedCrossRefGoogle Scholar
  27. Humeniuk RE, White JM, Ong J (1994) The effects of GABAB ligands on alcohol withdrawal in mice. Pharmacol Biochem Behav 49:561–566PubMedCrossRefGoogle Scholar
  28. 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 30:1–7PubMedCrossRefGoogle Scholar
  29. 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 31:582–595PubMedGoogle Scholar
  30. 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 30:182ACrossRefGoogle Scholar
  31. Lhuillier L, Mombereau C, Cryan JF, Kaupmann K (2007) GABAB receptor-positive modulation decreases selective molecular and behavioral effects of cocaine. Neuropsychopharmacology 32:388–398PubMedCrossRefGoogle Scholar
  32. 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 50:632–639PubMedCrossRefGoogle Scholar
  33. 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 36:161–168PubMedCrossRefGoogle Scholar
  34. 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 29:1050–1062PubMedCrossRefGoogle Scholar
  35. 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 321:172–177PubMedCrossRefGoogle Scholar
  36. 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 471:77–84PubMedCrossRefGoogle Scholar
  37. 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 525:105–111PubMedCrossRefGoogle Scholar
  38. Petry NM (1997) Benzodiazepine-GABA modulation of concurrent ethanol and sucrose reinforcement in the rat. Exp Clin Psychopharmacol 5:183–194PubMedCrossRefGoogle Scholar
  39. Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442PubMedGoogle Scholar
  40. 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 287:606–615PubMedGoogle Scholar
  41. 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 30:2065–2072PubMedCrossRefGoogle Scholar
  42. 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 173:105–111PubMedCrossRefGoogle Scholar
  43. 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 60:963–971PubMedGoogle Scholar
  44. 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 307:322–330PubMedCrossRefGoogle Scholar
  45. 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 26:1678–1685PubMedGoogle Scholar
  46. 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 31:11–18PubMedCrossRefGoogle Scholar
  47. Weiss F, Porrino LJ (2002) Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 22:3332–3337PubMedGoogle Scholar
  48. 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 153:415–424PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Paola Maccioni
    • 1
    • 2
  • Daniela Pes
    • 1
    • 2
  • Alessandro Orrù
    • 1
  • Wolfgang Froestl
    • 3
  • Gian Luigi Gessa
    • 2
  • Mauro A. M. Carai
    • 2
  • Giancarlo Colombo
    • 2
  1. 1.“Bernard B. Brodie” Department of NeuroscienceUniversity of CagliariCagliariItaly
  2. 2.C.N.R. Institute of NeuroscienceCagliariItaly
  3. 3.AC Immune SALausanneSwitzerland

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