Skip to main content

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

Psychopharmacology volume 174, pages 358–366 (2004)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  • 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 24:67–71

    CAS  PubMed  Google Scholar 

  • 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 37:504–508

    Article  CAS  PubMed  Google Scholar 

  • Agmo A, Giordano M (1985) The locomotor-reducing effects of GABAergic drugs do not depend on the GABAA receptor. Psychopharmacology 87:51–54

    CAS  PubMed  Google Scholar 

  • Ågmo A, Soria P (1997) GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat. Psychopharmacology 129:372–381

    Article  PubMed  Google Scholar 

  • Allan AM, Harris RA (1989) A new alcohol antagonist: phaclofen. Life Sci 45:1771–1779

    CAS  PubMed  Google Scholar 

  • 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 15:233–237

    PubMed  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

    Article  PubMed  Google Scholar 

  • 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 141:197–205

    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

    CAS  PubMed  Google Scholar 

  • 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 24:58–66

    CAS  PubMed  Google Scholar 

  • 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 37:499–503

    Article  CAS  PubMed  Google Scholar 

  • 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 70:105–108

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 65:209–220

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • De Luca C, Massotti M (1990) Phaclofen antagonizes the antinociceptive but not the sedative effects of (−)-baclofen. Prog Neuropsychopharmacol Biol Psychiatry 14:597–607

    Article  PubMed  Google Scholar 

  • Faigle JW, Keberle H (1972) The chemistry of lioresal. Postgrad Med J Suppl 5:9–13

    Google Scholar 

  • 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 560:84–91

    Article  CAS  PubMed  Google Scholar 

  • 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 207:859–869

    CAS  PubMed  Google Scholar 

  • Grech DM, Balster RL (1993) Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology 110:295–301

    PubMed  Google Scholar 

  • 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 19:1486–1493

    CAS  PubMed  Google Scholar 

  • Levy RA, Proudfit HK (1977) The analgesic action of baclofen [beta-(4-chlorophenyl)-gamma-aminobutyric acid]. J Pharmacol Exp Ther 202:437–445

    CAS  PubMed  Google Scholar 

  • Lewis JL, Westerberg VS, LaBella FS (1989) Mechanisms of general anaesthesia: brain regional responses to baclofen. Physiol Behav 46:3–8

    Article  CAS  PubMed  Google Scholar 

  • 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 261:88–95

    PubMed  Google Scholar 

  • Martz A, Deitrich RA, Harris RA (1983) Behavioral evidence for the involvement of gamma-aminobutyric acid in the actions of ethanol. Eur J Pharmacol 89:53–62

    CAS  PubMed  Google Scholar 

  • McBride WJ, Le AD, Noronha A (2002) Central nervous system mechanisms in alcohol relapse. Alcohol Clin Exp Res 26:280–286

    Article  PubMed  Google Scholar 

  • Mead AJ, Little HJ (1995) Do GABAB receptors have a role in causing behavioural hyperexcitability, both during ethanol withdrawal and in naive mice? Psychopharmacology 117:232–239

    Google Scholar 

  • Mehta AK, Ticku MK (1990) Are GABAB receptors involved in the pharmacological effects of ethanol? Eur J Pharmacol 182:473–480

    CAS  PubMed  Google Scholar 

  • Middaugh LD, Frackelton WF, Boggan WO, Onofrio A, Shepherd CL (1992) Gender differences in the effects of ethanol on C57BL/6 mice. Alcohol 9:257–260

    Article  CAS  PubMed  Google Scholar 

  • 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 408:169–174

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ, Depaulis A (1982) GABAergic influences on defensive fighting in rats. Pharmacol Biochem Behav 17:451–456

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • 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 221–248

  • Shellenberger MK, Groves L, Shah J, Novack GD (1999) A controlled pharmacokinetic evaluation of tizanidine and baclofen at steady state. Drug Metab Dispos 27:201–204

    CAS  PubMed  Google Scholar 

  • Shelton KL, Balster RL (1994) Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. Behav Pharmacol 5:441–451

    PubMed  Google Scholar 

  • Smith BR, Robidoux J, Amit Z (1992) GABAergic involvement in the acquisition of voluntary ethanol intake in laboratory rats. Alcohol Alcohol 27:227–231

    CAS  PubMed  Google Scholar 

  • 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 17:231–240

    Article  CAS  PubMed  Google Scholar 

  • VanDierendonk DR, Dire DJ (1999) Baclofen and ethanol ingestion: a case report. J Emerg Med 17:989–993

    Article  CAS  PubMed  Google Scholar 

  • 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 153:415–424

    Article  CAS  PubMed  Google Scholar 

  • Zarrindast MR, Hosseini-Nia T, Allah-Maddadi S (1989) Food intake suppressant effect of baclofen in rats. Gen Pharmacol 20:701–703

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

  1. Bowles Center for Alcohol Studies, Department of Psychiatry, Thurston-Bowles Building, University of North Carolina at Chapel Hill, CB#7178, Chapel Hill, NC 27599, USA

    Joyce Besheer, Veronique Lepoutre & Clyde W. Hodge

Authors
  1. Joyce Besheer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Veronique Lepoutre
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clyde W. Hodge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joyce Besheer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Besheer, J., Lepoutre, V. & Hodge, C.W. GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174, 358–366 (2004). https://doi.org/10.1007/s00213-003-1769-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1769-3

Keywords

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