, Volume 173, Issue 1–2, pp 105–111

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

  • Mark A. Smith
  • David L. Yancey
  • Drake Morgan
  • Yu Liu
  • Wolfgang Froestl
  • David C. S. Roberts
Original Investigation



Previous studies have strongly implicated a role for GABAB receptors in modulating the reinforcing effects of cocaine.


The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement.


Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined.


On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs.


These findings suggest that positive allosteric modulators of the GABAB receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.


CGP7930 Cocaine Discrete trials GABA GS39783 Fixed ratio Progressive ratio Self-administration 


  1. Arnold JM, Roberts DCS (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447PubMedGoogle Scholar
  2. Ashby CR Jr, Rohatgi R, Ngosuwan J, Borda T, Gerasimov MR, Morgan AE, Kushner S, Brodie JD, Dewey SL (1999) Implication of the GABA(B) receptor in gamma vinyl-GABA’s inhibition of cocaine-induced increases in nucleus accumbens dopamine. Synapse 31:151–153CrossRefPubMedGoogle Scholar
  3. Bischoff S, Leonhard S, Reymann N, Schuler V, Shigemoto R, Kaupmann K, Bettler B (1999) Spatial distribution of GABA(B)R1 receptor mRNA and binding sites in the rat brain. J Comp Neurol 412:1–16CrossRefPubMedGoogle Scholar
  4. Brebner K, Froestl, W, Andrews M, Phelan R, Roberts DCS (1999) The GABAB agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure. Neuropharmacology 38:1797–1804CrossRefPubMedGoogle Scholar
  5. Brebner K, Phelan R, Roberts DCS (2000a) Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio and progressive-ratio schedules. Psychopharmacology 148:314–321Google Scholar
  6. Brebner K, Phelan R, Roberts DCS (2000b) Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement. Pharmacol Biochem Behav 66:857–862Google Scholar
  7. Brebner K, Froestl W, Roberts DCS (2002) The GABAB antagonists CGP56433A attenuates the effect of baclofen on cocaine, but not heroin self-administration. Psychopharmacology 160:49–55CrossRefPubMedGoogle Scholar
  8. Caine SB, Koob GF (1994) Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther 270:209–218PubMedGoogle Scholar
  9. Campbell UC, Lac ST, Carroll ME (1999) Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats. Psychopharmacology 143:209–214PubMedGoogle Scholar
  10. Fitch T, Roberts DCS (1993) The effects of dose and access restrictions on the periodicity of cocaine self-administration in the rat. Drug Alcohol Depend 33:119–128PubMedGoogle Scholar
  11. Gudeman D, Shoptaw S, Majewska D, Scherf S, Yeats D, Ling W (1996) Preliminary report of baclofen as a cocaine craving medication. NIDA Res Monogr 174:183Google Scholar
  12. Hubner CB, Moreton JE (1991) Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat. Psychopharmacology 105:151–156PubMedGoogle Scholar
  13. Institute of Laboratory Animal Resources (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington D.C.Google Scholar
  14. Ling W, Shoptaw S, Majewska D (1998) Baclofen as a cocaine anti-craving medication: a preliminary clinical study. Neuropsychopharmacology 18:403–404Google Scholar
  15. Margeta-Mitrovic M, Mitrovic I, Riley RC, Jan LY, Basbaum AI (1999) Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. J Comp Neurol 405:299–321CrossRefPubMedGoogle Scholar
  16. Richardson NR, Roberts DCS (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11PubMedGoogle Scholar
  17. Roberts DCS, Andrews MM (1997) Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure. Psychopharmacology 131:271–277Google Scholar
  18. Roberts DCS, Goeders N (1989) Drug self-administration: experimental methods and determinants. In: Boulton AA, Baker GB, Greenshaw AJ (eds) Neuromethods: psychopharmacology (vol 13). Humana Press, Clifton, N.J., pp 349–398Google Scholar
  19. Roberts DCS, Andrews MM, Vickers GJ (1996) Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology 15:417–423Google Scholar
  20. Roberts DCS, Brebner K, Vincler M, Lynch WJ (2002) Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend 67:291–299PubMedGoogle Scholar
  21. Shoaib M, Swanner LS, Beyer CE, Goldberg SR, Schindler CW (1998) The GABAB agonist baclofen modifies cocaine self-administration in rats. Behav Pharmacol 9:195–206PubMedGoogle Scholar
  22. Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology 139:169–184PubMedGoogle Scholar
  23. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K (2001) Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) 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
  24. Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K (2003) GS39783 (N,N’-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) and structurally related compounds: novel allosteric enhancers of {gamma}-aminobutyric acidb receptor function. J Pharmacol Exp Ther 307:322–330CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mark A. Smith
    • 1
  • David L. Yancey
    • 1
  • Drake Morgan
    • 1
  • Yu Liu
    • 1
  • Wolfgang Froestl
    • 2
  • David C. S. Roberts
    • 1
  1. 1.Department of Physiology and PharmacologyWake Forest University School of MedicineWinston-SalemUSA
  2. 2.Therapeutic Area Nervous SystemNovartis Pharma AGBaselSwitzerland

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