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Gammahydroxybutyrate (GHB) receptor ligand effects on evoked synaptic field potentials in CA1 of the rat hippocampal slice

  • Basic Neurosciences and Genetics
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Summary

GHB produced a concentration-dependent depression of evoked synaptic field potentials (EFPs) recorded extracellularly in the CA1 region of the in vitro rat hippocampal slice. The concentration/response function revealed a threshold near ImM, with IC50 of 10.85 mM and a Hill coefficient of 1.29.

The gamma-aminobutyric acid B-receptor (GABA-B) agonist baclofen also depressed the EFP, but even maximally effective concentrations of the GABA-B antagonist 2-hydroxy-saclofen (800 μM) could not completely block the GHB-induced EFP depression. Nor was GHB-induced EFP depression blocked by the GHB receptor “antagonist” NCS-382, which does not displace GABA-B receptor ligands. However, NCS-382 produced a concentration-dependent increase in EFP slope. The threshold concentration was about 100 μM but the maximally effective concentration, and thus the IC50, could not be determined in the perfusion slice system. NCS-382 may be an inverse agonist at hippocampal GHB receptors, or else endogenous hippocampal GHB receptor ligands mediate a tonic inhibition in CA1.

At concentrations sufficient to induce EFP depression GHB did not alter pH. Although isosmotic sucrose did depress CA1 EFPs it was essentially ineffective at the IC50 for GHB. Gamma-butyrolactone, a prodrug of GHB, was only 1/20th as effective as GHB. This is consistent with previous data suggesting that GBL is freely permeable (does not substantially disturb tonicity) and that brain has very little capacity to either enzymatically convert the lactone to GHB or respond to the lactone itself.

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References

  • Banerjee PK, Snead OC (1995) Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB. J Pharmacol Exp Ther 273(3): 1534–1543

    Google Scholar 

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

    Google Scholar 

  • Benavides J, Rumigny JF, Bourguignon J, Wermuth CG, Mandel P, Maitre M (1982b) A high affinity, Na-dependent uptake system for γ-hydroxybutyrate in membrane vesicles prepared from rat brain. J Neurochem 38: 1570–1575

    Google Scholar 

  • Bernasconi R, Lauber J, Marescaux C, Vergnes M, Martin P, Rubio V, Leonhardt T, Reymann N, Bittiger H (1992) Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors. J Neural Transm [Suppl] 35: 155–177

    Google Scholar 

  • Berthier M, Bonneau D, Desbordes JM, Chevrel J, Oriot D, Jaeken J, Laborit H (1994) Possible involvement of a gamma-hydroxybutyric acid receptor in startle disease. Acta Paediatr 83(6): 678–680

    Google Scholar 

  • Biggio G, Cibin M, Diana M, Fadda F, Ferrara SD, Gallimberti L, Gessa GL, Mereu GP, Rossetti ZL, Serra M (1992) Suppression of voluntary alcohol intake in rats and alcoholics by gamma-hydroxybutyric acid: a non-GABAergic mechanism. Adv Biochem Psychopharmacol 47: 281–288

    Google Scholar 

  • Bowery NG, Hudson AL, Price GWSO (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20(2): 365–383

    Google Scholar 

  • Cash CD (1994) Gamma-hydroxybutyrate: an overview of the pros and cons for it being a neurotransmitter and/or a useful therapeutic agent. Neurosci Biobehav Rev 18(2): 291–304

    Google Scholar 

  • Centers for Disease Control (1991) Multistate outbreak of poisonings associated with illicit use of gamma hydroxy butyrate [see comments]. JAMA 265(4): 447–448

    Google Scholar 

  • Cheramy A, Nieoullon A, Glowinski J (1977) Stimulating effects of gammahydroxybutyrate on dopamine release from the caudate nucleus and the substantia nigra of the cat. J Pharmacol Exp Ther 203: 283–293

    Google Scholar 

  • Choi EY, Park SY, Jang SH, Song MS, Cho SW, Choi SYAD (1995) Production and characterization of monoclonal antibodies to bovine brain succinic semialdehyde reductase. J Neurochem 64(1): 371–377

    Google Scholar 

  • Colombo G, Agabio R, Bourguignon J, Fadda F, Lobina C, Maitre M, Reali R, Schmitt M, Gessa GL (1995) Blockade of the discriminative stimulus effects of gammahydroxybutyric acid (GHB) by the GHB receptor antagonist NCS-382. Physiol Behav 58(3): 587–590

    Google Scholar 

  • Doherty JD, Roth RH (1978) Metabolism of gamma-hydroxy-[l-14C] butyrate by rat brain: relationship to the Krebs cycle and metabolic compartmentation of amino acids. J Neurochem 30(6): 1305–1309

    Google Scholar 

  • Doherty JD, Hattox SE, Snead OC, Roth RH (1978) Identification of endogenous — hydroxybutyrate in human and bovine brain and its regional distribution in human, guinea-pig, and rhesus monkey brain. J Pharmacol Exp Ther 207: 130–139

    Google Scholar 

  • Fadda F, Colombo G, Mosca E, Gessa GL (1989) Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats. Alc Alcohol 24(5): 447–451

    Google Scholar 

  • Feigenbaum JJ, Simantov R (1996) Lack of effect of γ-hydroxybutyrate on μ, σ and σ opiate receptor binding. Neurosci Lett 212: 5–8

    Google Scholar 

  • Gallimberti L, Canton G, Gentile N, Ferri M, Cibin M, Ferrara SD, Fadda F, Gessa GL (1989) Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet ii(8666): 787–789

    Google Scholar 

  • Gallimberti L, Ferri M, Ferrara SD, Fadda F, Gessa GL (1992) Gamma-hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Alcohol Clin Exp Res 16(4): 673–676

    Google Scholar 

  • Gallimberti L, Cibin M, Pagnin P, Sabbion R, Pani PP, Pirastu R, Ferrara SD, Gessa GL (1993) Gamma-hydroxybutyric acid for treatment of opiate withdrawal syndrome. Neuropsychopharmacology 9(1): 77–81

    Google Scholar 

  • Gallimberti L, Schifano F, Forza G, Miconi L, Ferrara SD (1994) Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal. Eur Arch Psychiatry Clin Neurosci 244(3): 113–114

    Google Scholar 

  • Gessa GL, Gallimberti L (1992) Gamma-hydroxybutyric acid in the treatment of alcohol dependence. Clin Neuropharmacol 15[Suppl 1] Pt A: 303A-304A

    Google Scholar 

  • Gehlert DR, Yamamura HI, Wamsley JKSO (1985) gamma-Aminobutyric acidB receptors in the rat brain: quantitative autoradiographic localization using [3H](−)-baclofen. Neurosci Lett 56(2): 183–188

    Google Scholar 

  • Giarman NJ, Schmidt KF (1963) Some neurochemical aspects of the depressant action of y-hydroxybutyrolactone on the central nervous system. Br J Pharmacol 20: 563–568

    Google Scholar 

  • Godbout R, Jelenic P, Labrie C, Schmitt M, Bourguignon JJ (1995) Effect of gamma-hydroxybutyrate and its antagonist NCS-382 on spontaneous cell firing in the prefrontal cortex of the rat. Brain Res 673(1): 157–160

    Google Scholar 

  • Gerasimov VD, Artemenko DP (1990) The depressing effect of GABA on synaptic excitation in isolated rat hippocampal slices. Neirofiziologiia 22(5): 627–633

    Google Scholar 

  • Haller C, Mende M, Schuier F, Schuh R, Schrock H, Kuschinsky W (1990) Effect of gamma-hydroxybutyrate on local and global glucose metabolism in the anesthetized cat brain. J Cereb Blood Flow Metab 10(4): 493–498

    Google Scholar 

  • Harris NC, Webb C, Greenfield SA (1989) The effects of gamma-hydroxybutyrate on the membrane properties of guinea-pig pars compacta neurons in the substantia nigra in vitro. Neuroscience 31(2): 363–370

    Google Scholar 

  • Hechler V, Bourguignon JJ, Wermuth CG, Mandel P, Maitre M (1985) γ-Hydroxybutyrate uptake by rat brain striatal slices. Neurochem Res 10: 387–396

    Google Scholar 

  • Hechler V, Weissmann D, Mach E, Pujol JF, Maitre M (1987) Regional distribution of high-affinity gamma-[3H]hydroxybutyrate binding sites as determined by quantitative autoradiography. J Neurochem 49(4): 1025–1032

    Google Scholar 

  • Hechler V, Gobaille S, Maitre M (1989) Localization studies of γ-hydroxybutyrate receptors in rat striatum and hippocampus. Brain Res Bull 23: 129–135

    Google Scholar 

  • Hechler V, Gobaille S, Maitre M (1992) Selective distribution of γ-hydroxybutyrate receptors in the rat forebrain and midbrain as revealed by quantitative autoradiography. Brain Res 572: 345–348

    Google Scholar 

  • Hechler V, Peter P, Gobaille S, Bourguignon JJ, Schmitt M, Ehrhardt JD, Mark J, Maitre M (1993) Gamma-hydroxybutyrate ligands possess antidopaminergic and neuroleptic-like activities. J Pharmacol Exp Ther 264(3): 1406–1414

    Google Scholar 

  • Hechler V, Ratomponirina C, Maitre M (1997) Gamma-Hydroxybutyrate conversion into GABA induces displacement of GABAB binding that is blocked by valproate and ethosuximide. J Pharmacol Exp Ther 281(2): 753–760

    Google Scholar 

  • Hedner T, Lundborg P (1983) Effects of gamma-hydroxybutyric acid on serotonin synthesis, concentration, and metabolism in developing rat brain. J Neural Transm 57: 39–48

    Google Scholar 

  • Huang R, Aitken PG, Somjen GG (1996) Hypertonie environment prevents depolarization and improves functional recovery from hypoxia in hippocampal slices. J Cereb Blood Flow Metab 16(3): 462–467

    Google Scholar 

  • Hutchins DA, Rayevsky KS, Sharman DF (1972) The effect of sodium γ-hydroxybutyrate on the metabolism of dopamine in the brain. Br J Pharmacol 46: 409–415

    Google Scholar 

  • Kalra MA, Hart LL (1992) Gammahydroxybutyrate in narcolepsy. Ann Pharmacother 26(5): 647–648

    Google Scholar 

  • Kaufman EE, Nelson T (1987) Evidence for the participation of a cytosolic NADP+dependent oxidoreductase in the catabolism of gamma-hydroxybutyrate in vivo. J Neurochem 48(6): 1935–1941

    Google Scholar 

  • Kaufman EE, Nelson T (1991) An overview of gamma-hydroxybutyrate catabolism: the role of the cytosolic NADP(+)-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway. Neurochem Res 16(9): 965–974

    Google Scholar 

  • Kerr DIB, Ong J, Johnston GAR, Abbenante J, Prager RH (1988) 2-hydroxy-saclofen: an improved antagonist at central and peripheral GABAB receptors. Neurosci Lett 92: 92–96

    Google Scholar 

  • Laborit H (1964) Sodium 4-hydroxybutyrate. Int J Neuropharmacol 3: 433–452

    Google Scholar 

  • Ladinsky H, Console S, Zatta A, Vezzani A (1983) Mode of action of gammabutyrolactone on the central cholinergic system. Naunyn Schmiedebergs Arch Pharmacol 322: 42–48

    Google Scholar 

  • Liu Z, Snead OC III, Vergnes M, Depaulis A, Marescaux C (1991) Intrathalamic injections of gamma-hydroxybutyric acid increase genetic absence seizures in rats. Neurosci Lett 125(1): 19–21

    Google Scholar 

  • Maitre M, Cash CD, Weissmann-Nanopoulos D, Mandel P (1983) Depolarizationevoked release of γ-hydroxybutyrate from rat brain slices. J Neurochem 41: 287–290

    Google Scholar 

  • Maitre M, Hechler V, Vayer P, Gobaille S, Cash CD, Schmitt M, Bourguignon JJ (1990) A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties. J Pharmacol Exp Ther 255(2): 657–663

    Google Scholar 

  • Mamelak M (1989) Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neurosci Biobehav Rev 13: 187–198

    Google Scholar 

  • Mathivet P, Bernasconi R, De Barry J, Marescaux C, Bittiger H (1997) Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist. Eur J Pharmacol 321(1): 67–75

    Google Scholar 

  • Morgenroth H, Walters JR, Roth RH (1976) Dopaminergic neurons. Alterations in the kinetic properties of tyrosine hydroxylase after cessation of impulse flow. Biochem Pharmacol 25: 655–661

    Google Scholar 

  • Olsen RW (1981) GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 37: 1–13

    Google Scholar 

  • Roth RH, Giarman J (1966) γ-Butyrolactone and γ-hydroxybutyric acid. I. Distribution and metabolism. Biochem Pharmacol 15: 1333–1348

    Google Scholar 

  • Roth RH, Giarman NJ (1969) Conversion in vivo of γ-aminobutyric acid to γ-hydroxybu-tyric acid in mammallian brain. Biochem Pharmacol 18: 247–250

    Google Scholar 

  • Rumigny JF, Cash CD, Mandel P, Maitre M (1981) Evidence that a specific succinic semialdehyde reductase is responsible for γ-hydroxybuytyrate synthesis in brain slices. FEES Lett 134: 96–98

    Google Scholar 

  • Schmidt C, Gobaille S, Hechler V, Schmitt M, Bourguignon JJ, Maitre M (1991) Anti-sedative and anti-cataleptic properties of NCS-382, a gamma-hydroxybutyrate receptor antagonist. Eur J Pharmacol 22, 203(3): 393–397

    Google Scholar 

  • Serra M, Sanna E, Foddi C, Concas A, Biggio G (1991) Failure of gammahydroxybutyrate to alter function of the GABAA receptor complex in the rat cerebral cortex. Psychopharmacol 104(3): 351–355

    Google Scholar 

  • Snead OC 3d (1991) The gamma-hydroxybutyrate model of absence seizures: correlation of regional brain levels of gamma-hydroxybutyric acid and gamma-butyrolactone with spike wave discharges. Neuropharmacology 30(2): 161–167

    Google Scholar 

  • Snead OC (1994) The ontogeny of [3H]gamma-hydroxybutyrate and [3H]GABAB binding sites: relation to the development of experimental absence seizures. Brain Res 659(1–2): 147–156

    Google Scholar 

  • Snead OC 3d, Morley BJ (1981) Ontogeny of gamma-hydroxybutyric acid. I. Regional concentration in developing rat, monkey and human brain. Brain Res 227(4): 579–589

    Google Scholar 

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

    Google Scholar 

  • Snead OC, Nichols AC (1987) γ-hydroxybutyric acid binding sites: evidence for coupling to a chloride ion channel. Neuropharmacol 26: 1519–1523

    Google Scholar 

  • Snead OC, Nichols AC, Liu CC (1992) γ-hydroxybutyric acid binding sites: interaction with the GABA-benzodiazepine-picrotoxin receptor complex. Neurochem Res 17: 201–204

    Google Scholar 

  • Spano PF, Tagliamonte A, Tagliamonte P, Gessa GL (1971) Stimulation of brain dopamine synthesis by gamma-hydroxybutyrate. J Neurochem 18: 1831–1836

    Google Scholar 

  • Steele MT, Watson WA (1995) Acute poisoning from gamma hydroxybutyrate (GHB). Mol Med 92(7): 354–357

    Google Scholar 

  • Takahara J, Yunoki S, Yakushiji W, Wamauchi J, Yamane Y, Ofuji T (1977) Stimulatory effects of γ-hydroxybutyric acid on growth hormone and prolactin release in humans. J Clin Endocrinol Metab 44: 1014–1017

    Google Scholar 

  • Tremwell MF, Hunter BE (1994) Effects of chronic ethanol ingestion on long-term potentiation remain even after a prolonged recovery from ethanol exposure. Synapse 17: 141–148

    Google Scholar 

  • Tunnicliff G (1992) Significance of gamma-hydroxybutyric acid in the brain. Gen Pharmacol 23(6): 1027–1034

    Google Scholar 

  • Tunnicliff G (1994) Stimulation of mouse brain gamma-hydroxybutyric acid transport by pyridoxal 5′-phosphate. Pharmacol 49(5): 271–277

    Google Scholar 

  • Vargiu L, Crabai F, Camba R, Gessa GL (1966) Effect of gamma-butyrolactone on the cerebral content of monamine. Boll Soc Ital Biol Sper 42(22): 1633–1634

    Google Scholar 

  • Vayer P, Maitre M (1989) γ-Hydroxybuytyrate stimulation of the formation of cyclic GMP and inositol phosphates in rat hippocampal slices. J Neurochem 52: 1382–1387

    Google Scholar 

  • Vayer P, Mandel P, Maitre M (1987) Gamma-hydroxybutyrate, a possible neurotransmitter. Life Sci 41: 1547–1557

    Google Scholar 

  • Vayer P, Gobaille S, Mandel P, Maitre M (1987) 3′-5′ Cyclic guanosine monophosphate increase in rat brain hippocampus after gamma-hydroxybutyrate administration. Prevention by valproate and naloxone. Life Sci 41: 605–610

    Google Scholar 

  • Vayer P, Ehrhardt JL, GobaiUe S, Mandel P, Maitre M (1988) Gamma-hydroxybutyrate distribution and turnover rates in discrete brain regions of the rat. Neurochem Int 12: 53–59

    Google Scholar 

  • Waldmeier PC, Fehr B (1978) Effects of baclofen and γ-hydroxybutyrate on rat striatal and mesolimbic 5-HT metabolism. Eur J Pharmacol 49: 177–184

    Google Scholar 

  • Walters JR, Roth RH (1972) Effect of gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum. Biochem Pharmacol 21: 2111–2121

    Google Scholar 

  • Williams SR, Turner JP, Crunelli V (1995) Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GAB AB receptor-mediated hyperpolarization. Neuroscience 66: 133–141

    Google Scholar 

  • Xie X, Smart TG (1992) Gamma-hydroxybutyrate hyperpolarizes hippocampal neurones by activating GABAB receptors. Eur J Pharmacol 212(2–3): 291–294

    Google Scholar 

  • Xie X, Smart TG (1992) Gamma-hydroxybutyrate depresses monosynaptic excitatory and inhibitory postsynaptic potentials in rat hippocampal slices. Eur J Pharmacol 223(2–3): 193–196

    Google Scholar 

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  1. M. A. King

    Present address: Department of Neuroscience and Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA

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  1. VA Medical Center, University of Florida College of Medicine, Gainesville, FL, USA

    M. A. King & D. W. Walker

  2. Department of Neuroscience and Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA

    J. S. Thinschmidt & D. W. Walker

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King, M.A., Thinschmidt, J.S. & Walker, D.W. Gammahydroxybutyrate (GHB) receptor ligand effects on evoked synaptic field potentials in CA1 of the rat hippocampal slice. J. Neural Transmission 104, 1177–1193 (1997). https://doi.org/10.1007/BF01294719

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