Effects of gamma hydroxybutyric acid on inhibition and excitation in rat neocortex

doi:10.1016/j.neuroscience.2007.08.023

Neuroscience

Volume 150, Issue 1, 30 November 2007, Pages 82-92

https://doi.org/10.1016/j.neuroscience.2007.08.023 Get rights and content

Abstract

The mechanism by which the sedative and amnestic recreational drug gamma hydroxybutyric acid (GHB) acts is controversial. Some studies indicate that it acts at its unique receptor, while others demonstrate effects mediated through the GABA_B receptor. We examined the effect of GHB on evoked GABA_A receptor–mediated mono- and polysynaptic inhibitory postsynaptic currents (IPSCs) as well as on N-methyl-d-aspartate (NMDA) and AMPA-mediated excitatory postsynaptic currents (EPSCs) in layers II/III pyramidal cells of the frontal cortex of rat brain. One millimolar (mM) GHB suppressed monosynaptic IPSCs by 20%, whereas polysynaptic IPSCs were reduced by 56%. GHB (1 mM) also produced a significant suppression of NMDA-mediated EPSCs by 53% compared with 27% suppression of AMPA-mediated EPSCs. All effects of GHB on IPSCs and EPSCs were reversed by the specific GABA_B antagonist CGP 62349, but not by the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid. Consistent with a presynaptic site of action, GHB reduced the frequency but not the amplitude of AMPA receptor–mediated mEPSCs and had no effect on postsynaptic currents evoked by direct application of NMDA. Finally, even though GHB appeared to be acting at presynaptic GABA_B receptors, GHB and the GABA_B agonist baclofen appeared to have opposite potencies for depression of NMDA- vs. AMPA-mediated EPSCs. GHB showed a preference for depressing NMDA responses while baclofen more potently suppressed AMPA responses. The suppression of NMDA more than AMPA responses by GHB at intoxicating doses may make it attractive as a recreational drug and may explain why GHB is abused and baclofen is not.

Section snippets

Slice preparation

Frontal cortical slices were prepared from male, Sprague–Dawley rats (PD20–30, Charles River Laboratories, Raleigh, NC, USA). Animals were handled and housed according to the guidelines of the National Institutes of Health Committee on Laboratory Animal Resources. All experimental procedures or protocols were approved by Animal Care and Use Committee of Duke University and Durham VA Medical Center. The minimum number of animals needed to obtain statistically significant results was used. All

GHB effects on mono-synaptic IPSCs

Evoked mono-synaptic IPSCs were recorded from cortical pyramidal cells held at 0 mV in the presence of the excitatory amino acid antagonists APV (50 μM) and DNQX (20 μM). Bicuculline sensitive outward currents were continuously observed and the GHB effect was assessed. As shown in Fig. 1A, bath application of GHB (1 mM) for 20 min decreased the peak amplitude of IPSCs by 22% of control. The GHB effects were reversed after addition of the GABA_B receptor antagonist CGP 62349 (5 μM). The GHB

Discussion

In the rat neocortical slice we found that GHB reduced monosynaptic evoked GABA_A IPSCs in agreement with previously demonstrated reductions of spontaneous action potential–dependent IPSCs (Jensen and Mody, 2001) and reductions of GABA release as measured using microdialysis (Hu et al., 2000). The greater reduction of polysynaptic IPSCs is also expected if GHB is reducing synaptic excitation of interneurons and perhaps hyperpolarizing interneurons (Jensen and Mody, 2001). Thus GHB appears to act

Acknowledgments

The authors wish to acknowledge the generous support of the National Institute of Drug Abuse (DA 014931).

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Molecular neuroscienceEffects of gamma hydroxybutyric acid on inhibition and excitation in rat neocortex

Abstract

Section snippets

Slice preparation

GHB effects on mono-synaptic IPSCs

Discussion

Acknowledgments

Eur J Pharmacol

Eur J Pharmacol

Brain Res

Neuropsychopharmacology

Ann Emerg Med

Brain Res

Neuropharmacology

Prog Neurobiol

Drug Alcohol Depend

J Biol Chem

Pharmacol Biochem Behav

Trends Pharmacol Sci

Eur J Pharmacol

Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB)

FASEB J

Presynaptic modulation of spontaneous inhibitory postsynaptic currents by gamma-hydroxybutyrate in the substantia nigra pars compacta

Neuropsychopharmacology

The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies

J Pharmacol Exp Ther

Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system

Nat Neurosci

Gamma hydroxybutyrate (GHB): report of a mass intoxication and review of the literature

Prehosp Emerg Care

Molecular neuroscience
Effects of gamma hydroxybutyric acid on inhibition and excitation in rat neocortex