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Cataleptic effects of γ-hydroxybutyrate (GHB), its precursor γ-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348

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Abstract

Rationale

Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABAB receptor agonist baclofen.

Objective

To further study the role of GABAB receptors in the effects of GHB.

Materials and methods

The experiments examined the ability of the GABAB receptor antagonist CGP35348 to attenuate GHB-induced catalepsy in comparison with its ability to attenuate the cataleptic effects of GABAB receptor agonists.

Results

In C57BL/6J mice, GHB, the GHB precursor gamma-butyrolactone (GBL), and the GABAB receptor agonists baclofen and SKF97541 all produced catalepsy but differed in potency (i.e., SKF97541>baclofen>GBL>GHB) and in onset of action. The cataleptic effects of drug combinations were assessed at the time of peak effect of each compound, i.e., 60 min after CGP35348 and 60, 30, 30, and 15 min after baclofen, SKF97541, GHB, and GBL, respectively. At 100 mg/kg, CGP35348 shifted the dose–response curves of baclofen and SKF97541 to the right but not those of GHB and GBL; at 320 mg/kg, CGP35348 shifted the curves of all four compounds to the right.

Conclusions

The finding that CGP35348 was about threefold less potent to antagonize GHB and GBL than baclofen and SKF97541 is further evidence that the mechanisms mediating the effects of GHB and GABAB agonists are not identical. Differential involvement of GABAB receptor subtypes, or differential interactions with GABAB receptors, may possibly explain why GHB is effective for treating narcolepsy and is abused whereas baclofen is not.

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References

  • Benavides J, Rumigny JF, Bourguignon JJ, Cash C, Wermuth CG, Mandel P, Vincendon G, Maitre M (1982) High affinity binding sites for gamma-hydroxybutyric acid in rat brain. Life Sci 30:953–961

    Article  PubMed  CAS  Google Scholar 

  • Bonanno G, Raiteri M (1992) Functional evidence for multiple gamma-aminobutyric acid B receptor subtypes in the rat cerebral cortex. J Pharmacol Exp Ther 262:114–118

    PubMed  CAS  Google Scholar 

  • Carai MA, Colombo G, Brunetti G, Melis S, Serra S, Vacca G, Mastinu S, Pistuddi AM, Solinas C, Cignarella G, Minardi G, Gessa GL (2001) Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid. Eur J Pharmacol 428:315–321

    Article  PubMed  CAS  Google Scholar 

  • Carter LP, Flores LR, Wu H, Chen W, Unzeitig AW, Coop A, France CP (2003) The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies. J Pharmacol Exp Ther 305:668–674

    Article  PubMed  CAS  Google Scholar 

  • Carter LP, Wu H, Chen W, Cruz CM, Lamb RJ, Koek W, Coop A, France CP (2004) Effects of gamma-hydroxybutyrate (GHB) on schedule-controlled responding in rats: role of GHB and GABAB receptors. J Pharmacol Exp Ther 308:182–188

    Article  PubMed  CAS  Google Scholar 

  • Carter LP, Wu H, Chen W, Matthews MM, Mehta AK, Hernandez RJ, Thomson JA, Ticku MK, Coop A, Koek W, France CP (2005) Novel {gamma}-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABAB receptor agonists. J Pharmacol Exp Ther 313:1314–1323

    Article  PubMed  CAS  Google Scholar 

  • Carter LP, Chen W, Coop A, Koek W, France CP (2006) Discriminative stimulus effects of GHB and GABA(B) agonists are differentially attenuated by CGP35348. Eur J Pharmacol 538:85–93

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Agabio R, Lobina C, Reali R, Gessa GL (1998) Involvement of GABA(A) and GABA(B) receptors in the mediation of discriminative stimulus effects of gamma-hydroxybutyric acid. Physiol Behav 64:293–302

    Article  PubMed  CAS  Google Scholar 

  • Fassio A, Bonanno G, Cavazzani P, Raiteri M (1994) Characterization of the GABA autoreceptor in human neocortex as a pharmacological subtype of the GABAB receptor. Eur J Pharmacol 263:311–314

    Article  PubMed  CAS  Google Scholar 

  • Froestl W, Mickel SJ, Hall RG, von Sprecher G, Strub D, Baumann PA, Brugger F, Gentsch C, Jaekel J, Olpe HR, Rihs G, Vassout A, Waldmeier PC, Bittiger H (1995a) Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists. J Med Chem 38:3297–3312

    Article  PubMed  CAS  Google Scholar 

  • Froestl W, Mickel SJ, von Sprecher G, Diel PJ, Hall RG, Maier L, Strub D, Melillo V, Baumann PA, Bernasconi R, Gentsch C, Hauser K, Jaekel J, Karlssen G, Klebs K, Maitre L, Marescaux C, Pozza MF, Schmutz M, Steinmann MW, van Riezen H, Vassout A, Mondadori C, Olpe H-R, Waldmeier PC, Bittiger H (1995b) Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J Med Chem 38:3313–3331

    Article  PubMed  CAS  Google Scholar 

  • Fuller DE, Hornfeldt CS (2003) From club drug to orphan drug: sodium oxybate (Xyrem) for the treatment of cataplexy. Pharmacotherapy 23:1205–1209

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez A, Nutt DJ (2005) Gamma hydroxy butyrate abuse and dependency. J Psychopharmacol 19:195–204

    Article  PubMed  CAS  Google Scholar 

  • Goodwin AK, Froestl W, Weerts EM (2005) Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacology (Berl) 180:342–351

    Article  CAS  Google Scholar 

  • Itzhak Y, Ali SF (2002) Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB. Ann N Y Acad Sci 965:451–460

    Article  PubMed  CAS  Google Scholar 

  • Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, Schmutz M, Froestl W, van der PH, Mosbacher J, Brauner-Osborne H, Waldmeier P, Bettler B (2003) Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice. Eur J Neurosci 18:2722–2730

    Article  PubMed  Google Scholar 

  • Koek W, Flores LR, Carter LP, Lamb RJ, Chen W, Wu H, Coop A, France CP (2004) Discriminative stimulus effects of gamma-hydroxybutyrate in pigeons: role of diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors. J Pharmacol Exp Ther 308:904–911

    Article  PubMed  CAS  Google Scholar 

  • Koek W, Wu H, Coop A, France CP (2006) Discriminative stimulus effects of gamma-hydroxybutyrate: role of training dose. J Pharmacol Exp Ther 317:1–9

    Google Scholar 

  • Lanza M, Fassio A, Gemignani A, Bonanno G, Raiteri M (1993) CGP 52432: a novel potent and selective GABAB autoreceptor antagonist in rat cerebral cortex. Eur J Pharmacol 237:191–195

    Article  Google Scholar 

  • Lingenhoehl K, Brom R, Heid J, Beck P, Froestl W, Kaupmann K, Bettler B, Mosbacher J (1999) Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology 38:1667–1673

    Article  PubMed  CAS  Google Scholar 

  • Maitre M (1997) The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog Neurobiol 51:337–361

    Article  PubMed  CAS  Google Scholar 

  • Mamelak M, Escriu JM, Stokan O (1977) The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 12:273–288

    PubMed  CAS  Google Scholar 

  • Mathivet P, Bernasconi R, De BJ, Marescaux C, Bittiger H (1997) Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist. Eur J Pharmacol 321:67–75

    Article  PubMed  CAS  Google Scholar 

  • Mehta AK, Ticku MK (1987) Baclofen induces catatonia in rats. Neuropharmacology 26:1419–1423

    Article  PubMed  CAS  Google Scholar 

  • Navarro JF, Pedraza C, Martin M, Manzaneque JM, Davila G, Maldonado E (1998) Tiapride-induced catalepsy is potentiated by gamma-hydroxybutyric acid administration. Prog Neuropsychopharmacol Biol Psychiatry 22:835–844

    Article  PubMed  CAS  Google Scholar 

  • Poldrugo F, Addolorato G (1999) The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies. Alcohol Alcohol 34:15–24

    PubMed  CAS  Google Scholar 

  • Rodgers J, Ashton CH, Gilvarry E, Young AH (2004) Liquid ecstasy: a new kid on the dance floor. Br J Psychiatry 184:104–106

    Article  PubMed  CAS  Google Scholar 

  • Seabrook GR, Howson W, Lacey MG (1990) Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices. Br J Pharmacol 101:949–957

    PubMed  CAS  Google Scholar 

  • Sevak RJ, France CP, Koek W (2004) Neuroleptic-like effects of gamma-hydroxybutyrate: interactions with haloperidol and dizocilpine. Eur J Pharmacol 483:289–293

    Article  PubMed  CAS  Google Scholar 

  • Snead OC III, Liu CC (1984) Gamma-hydroxybutyric acid binding sites in rat and human brain synaptosomal membranes. Biochem Pharmacol 33:2587–2590

    Article  PubMed  CAS  Google Scholar 

  • Tallarida RJ (2000) Drug synergism and dose–effect data analysis. CRC, Boca Raton

    Google Scholar 

  • Tunnicliff G, Raess BU (2002) Gamma-Hydroxybutyrate (orphan medical). Curr Opin Investig Drugs 3:278–283

    PubMed  CAS  Google Scholar 

  • Waldmeier PC (1991) The GABAB antagonist, CGP 35348, antagonizes the effects of baclofen, gamma-butyrolactone and HA 966 on rat striatal dopamine synthesis. Naunyn-Schmiedebergs Arch Pharmakol 343:173–178

    Article  CAS  Google Scholar 

  • Winter JC (1981) The stimulus properties of gamma-hydroxybutyrate. Psychopharmacology (Berl) 73:372–375

    Article  CAS  Google Scholar 

  • Wong CG, Gibson KM, Snead OC III (2004) From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid. Trends Pharmacol Sci 25:29–34

    Article  PubMed  CAS  Google Scholar 

  • Wullner U, Klockgether T, Schwarz M, Sontag KH (1987) Behavioral actions of baclofen in the rat ventromedial thalamic nucleus: antagonism by delta-aminovalerate. Brain Res 422:129–136

    Article  PubMed  CAS  Google Scholar 

  • Yamada K, Yu B, Gallagher JP (1999) Different subtypes of GABAB receptors are present at pre-and postsynaptic sites within the rat dorsolateral septal nucleus. J Neurophysiol 81:2875–2883

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The authors would like to thank Brittany Garcia, Adela Garza, and Aisa Mirelez for their excellent assistance. The work was supported by US Public Health Service Grants DA15692 (W.K.) and by Independent Scientist Award DA19634 (A.C.).

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Authors and Affiliations

  1. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Wouter Koek

  2. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Wouter Koek

  3. Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, USA

    Susan L. Mercer & Andrew Coop

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  1. Wouter Koek
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  2. Susan L. Mercer
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  3. Andrew Coop
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Correspondence to Wouter Koek.

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Koek, W., Mercer, S.L. & Coop, A. Cataleptic effects of γ-hydroxybutyrate (GHB), its precursor γ-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348. Psychopharmacology 192, 407–414 (2007). https://doi.org/10.1007/s00213-007-0718-y

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