Psychopharmacology

, Volume 174, Issue 3, pp 358–366 | Cite as

GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

  • Joyce Besheer
  • Veronique Lepoutre
  • Clyde W. Hodge
Original Investigation

Abstract

Rationale

A growing number of studies suggest that γ-aminobutyric acid type-B (GABAB) receptor agonists reduce alcohol use and craving.

Objectives

This study was designed to further clarify behavioral mechanism(s) by which GABAB agonists may decrease alcohol reinforcement.

Methods

Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABAB agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABAB agonists was examined in ethanol naive and self-administering mice.

Results

Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABAB agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABAB agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABAB agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.

Conclusions

GABAB agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABAB agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABAB positive modulation. These data question the safety of prescribing GABAB agonists to alcoholics since these drugs may potentiate ethanol’s sedative/hypnotic effects during relapse.

Keywords

Alcohol self-administration Reinforcement Mice GABAB agonist Baclofen SKF 97514 Locomotor activity Sedation 

Notes

Acknowledgements

This work was supported by grants AA09981 and AA011605 to C.W.H. from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies.

References

  1. Addolorato G, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (2000) Ability of baclofen in reducing alcohol craving and intake. II. Preliminary clinical evidence. Alcohol Clin Exp Res 24:67–71PubMedGoogle Scholar
  2. 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 randomized controlled study. Alcohol Alcohol 37:504–508CrossRefPubMedGoogle Scholar
  3. Agmo A, Giordano M (1985) The locomotor-reducing effects of GABAergic drugs do not depend on the GABAA receptor. Psychopharmacology 87:51–54PubMedGoogle Scholar
  4. Ågmo A, Soria P (1997) GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat. Psychopharmacology 129:372–381CrossRefPubMedGoogle Scholar
  5. Allan AM, Harris RA (1989) A new alcohol antagonist: phaclofen. Life Sci 45:1771–1779PubMedGoogle Scholar
  6. Allan AM, Burnett D, Harris RA (1991) Ethanol-induced changes in chloride flux are mediated by both GABA(A) and GABA(B) receptors. Alcohol Clin Exp Res 15:233–237PubMedGoogle Scholar
  7. Anstrom KK, Cromwell HC, Markowski T, Woodward DJ (2003) Effect of baclofen on alcohol and sucrose self-administration in rats. Alcohol Clin Exp Res 27:900–908CrossRefPubMedGoogle Scholar
  8. Broadbent J, Harless WE (1999) Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Psychopharmacology 141:197–205Google Scholar
  9. Chester JA, Cunningham CL (1999) Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice. Pharmacol Biochem Behav 63:325–331PubMedGoogle Scholar
  10. Colombo G, Agabio R, Carai MA, 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
  11. Colombo G, Serra S, Brunetti G, Atzori G, Pani M, Vacca G, Addolorato G, Froestl W, Carai MA, Gessa GL (2002) The GABA(B) receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats. Alcohol Alcohol 37:499–503CrossRefPubMedGoogle Scholar
  12. Colombo G, Serra S, Brunetti G, Vacca G, Carai MA, Gessa GL (2003a) Suppression by baclofen of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats. Drug Alcohol Depend 70:105–108CrossRefPubMedGoogle Scholar
  13. Colombo G, Vacca G, Serra S, Brunetti G, Carai MA, Gessa GL (2003b) Baclofen suppresses motivation to consume alcohol in rats. Psychopharmacology 167:221–224PubMedGoogle Scholar
  14. Cott J, Carlsson A, Engel J, Lindqvist M (1976) Suppression of ethanol-induced locomotor stimulation by GABA-like drugs. Naunyn Schmiedebergs Arch Pharmacol 295:203–209PubMedGoogle Scholar
  15. Cousins MS, Roberts DC, de Wit H (2002) GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Drug Alcohol Depend 65:209–220CrossRefPubMedGoogle Scholar
  16. 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 4:469–472CrossRefPubMedGoogle Scholar
  17. De Luca C, Massotti M (1990) Phaclofen antagonizes the antinociceptive but not the sedative effects of (−)-baclofen. Prog Neuropsychopharmacol Biol Psychiatry 14:597–607CrossRefPubMedGoogle Scholar
  18. Faigle JW, Keberle H (1972) The chemistry of lioresal. Postgrad Med J Suppl 5:9–13Google Scholar
  19. Frye GD, Taylor L, Trzeciakowski JP, Griffith WH (1991) Effects of acute and chronic ethanol treatment on pre- and postsynaptic responses to baclofen in rat hippocampus. Brain Res 560:84–91CrossRefPubMedGoogle Scholar
  20. Gianutsos GMK (1978) Tolerance to the effects of baclofen and gamma-butyrolactone on locomotor activity and dopaminergic neurons in the mouse. J Pharmacol Exp Ther 207:859–869PubMedGoogle Scholar
  21. Grech DM, Balster RL (1993) Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology 110:295–301PubMedGoogle Scholar
  22. Hodge CW, Chappelle AM, Samson HH (1995) GABAergic transmission in the nucleus accumbens is involved in the termination of ethanol self-administration in rats. Alcohol Clin Exp Res 19:1486–1493PubMedGoogle Scholar
  23. Levy RA, Proudfit HK (1977) The analgesic action of baclofen [beta-(4-chlorophenyl)-gamma-aminobutyric acid]. J Pharmacol Exp Ther 202:437–445PubMedGoogle Scholar
  24. Lewis JL, Westerberg VS, LaBella FS (1989) Mechanisms of general anaesthesia: brain regional responses to baclofen. Physiol Behav 46:3–8CrossRefPubMedGoogle Scholar
  25. Mandema JW, Heijligers-Feijen CD, Tukker E, De Boer AG, Danhof M (1992) Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures. J Pharmacol Exp Ther 261:88–95PubMedGoogle Scholar
  26. Martz A, Deitrich RA, Harris RA (1983) Behavioral evidence for the involvement of gamma-aminobutyric acid in the actions of ethanol. Eur J Pharmacol 89:53–62PubMedGoogle Scholar
  27. McBride WJ, Le AD, Noronha A (2002) Central nervous system mechanisms in alcohol relapse. Alcohol Clin Exp Res 26:280–286CrossRefPubMedGoogle Scholar
  28. Mead AJ, Little HJ (1995) Do GABAB receptors have a role in causing behavioural hyperexcitability, both during ethanol withdrawal and in naive mice? Psychopharmacology 117:232–239Google Scholar
  29. Mehta AK, Ticku MK (1990) Are GABAB receptors involved in the pharmacological effects of ethanol? Eur J Pharmacol 182:473–480PubMedGoogle Scholar
  30. Middaugh LD, Frackelton WF, Boggan WO, Onofrio A, Shepherd CL (1992) Gender differences in the effects of ethanol on C57BL/6 mice. Alcohol 9:257–260CrossRefPubMedGoogle Scholar
  31. Munzar P, Kutkat SW, Miller CR, Goldberg SR (2000) Failure of baclofen to modulate discriminative-stimulus effects of cocaine or methamphetamine in rats. Eur J Pharmacol 408:169–174CrossRefPubMedGoogle Scholar
  32. Petry NM (1997) Benzodiazepine-GABA modulation of concurrent ethanol and sucrose reinforcement in the rat. Exp Clin Psychopharmacol 5:183–194CrossRefPubMedGoogle Scholar
  33. Rodgers RJ, Depaulis A (1982) GABAergic influences on defensive fighting in rats. Pharmacol Biochem Behav 17:451–456PubMedGoogle Scholar
  34. 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
  35. Samson HH (1987) Initiation of ethanol-maintained behavior: a comparison of animal models and their implication to human drinking. In: Thompson T, Dews PB, Barrett JE (eds) Adv Behav Pharmacol, vol 6. Neurobehavioral Pharmacology. Lawrence Erlbaum, Hillsdale, NJ, pp 221–248Google Scholar
  36. Shellenberger MK, Groves L, Shah J, Novack GD (1999) A controlled pharmacokinetic evaluation of tizanidine and baclofen at steady state. Drug Metab Dispos 27:201–204PubMedGoogle Scholar
  37. Shelton KL, Balster RL (1994) Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. Behav Pharmacol 5:441–451PubMedGoogle Scholar
  38. Smith BR, Robidoux J, Amit Z (1992) GABAergic involvement in the acquisition of voluntary ethanol intake in laboratory rats. Alcohol Alcohol 27:227–231PubMedGoogle Scholar
  39. Smith BR, Boyle AE, Amit Z (1999) The effects of the GABA(B) agonist baclofen on the temporal and structural characteristics of ethanol intake. Alcohol 17:231–240CrossRefPubMedGoogle Scholar
  40. VanDierendonk DR, Dire DJ (1999) Baclofen and ethanol ingestion: a case report. J Emerg Med 17:989–993CrossRefPubMedGoogle Scholar
  41. Zaleski MJ, Nunes Filho JR, Lemos T, Morato GS (2001) GABA(B) receptors play a role in the development of tolerance to ethanol in mice. Psychopharmacology 153:415–424CrossRefPubMedGoogle Scholar
  42. Zarrindast MR, Hosseini-Nia T, Allah-Maddadi S (1989) Food intake suppressant effect of baclofen in rats. Gen Pharmacol 20:701–703CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Joyce Besheer
    • 1
  • Veronique Lepoutre
    • 1
  • Clyde W. Hodge
    • 1
  1. 1.Bowles Center for Alcohol Studies, Department of PsychiatryThurston-Bowles Building, University of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations