γ-Hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices

Berton, Fulvia; Brancucci, Alfredo; Beghè, F.; Cammalleri, Maurizio; Demuro, Angelo; Francesconi, Walter; Gessa, G L

doi:10.1016/s0014-2999(99)00515-4

Cited by 36 publications

(35 citation statements)

References 35 publications

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“…In conclusion, the present and previous results (Berton et al 1999) indicate that GHB exerts an inhibitory control on GABA and glutamate release in the hippocampus by acting on presynaptic GHB receptors. These results raise a number of questions, such as whether endogenous GHB has a physiological role in modulating GABAergic and glutamatergic neurotransmission in the hippocampus and in other brain areas where GHB receptors are present, whether GHB and GABA B receptors are separate entities or whether GHB and some GABA B receptor subunits might be associated in brain areas where the two are co-expressed and might interact cooperatively or in a negative manner.…”

Section: Discussionsupporting

confidence: 75%

“…Current investigation on the mechanism of action of GHB are aimed at elucidating the role of endogenous GHB in sleep, anxiety, petit mal epilepsy, and alcohol and drug abuse, etc. Previous studies from our laboratory (Berton et al 1999) have shown that GHB reduces both NMDA and AMPA-mediated excitatory postsynaptic potentials (EPSP) elicited in hippocampal pyramidal neurons by the stimulation of Schaffer collateral/commissural fibers. These effects were seen in hippocampal slices superfused with GABA B receptor antagonists, ruling out an involvement of GABA B -receptors, but were antagonized by NCS-382, suggesting that they are mediated by GHB receptors.…”

Section: Gamma-hydroxybutyric Acid (Ghb) Is a Psychoactive Drug And Amentioning

confidence: 99%

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Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Cammalleri

Brancucci

Berton

et al. 2002

Neuropsychopharmacology

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Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter, derived from gammaaminobutyric acid (GABA). At micromolar concentrations GHB binds to specific high and low affinity binding sites present in discrete areas of the brain, while at millimolar concentrations GHB also binds to GABA B receptors. Previous studies indicated that GHB inhibits bothGamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter (Bernasconi et al. 1999;Maitre 1997). Administered peripherally, GHB penetrates freely into the brain and produces doserelated pharmacological effects including euphoria, antidepressant, and anxiolytic effects, sedation, sleep, anesthesia (Agabio and Gessa 2002;Colombo et al. 1998;De Couedic and Voisse 1964;Laborit et al. 1960;Rinaldi et al. 1967;Schmidt-Mutter et al. 1998). GHB has been used clinically as a general anesthetic and as a sleep inducer in the treatment of narcolepsy (Agabio and Gessa 2002;Broughton and Mamelak 1979). GHB is currently marketed in Italy and Austria for the treatment of alco- Gallimberti et al. 1989Gallimberti et al. , 2000. However, GHB has also gained popularity in the illicit market in the United States, being abused for its euphoriant action, which reportedly resembles that of alcohol and ecstasy (Boyce et al. 2000;Kam and Yoong 1998;Nicholson and Balster 2001). However, GHB is also synthesized and released by specific neurons in the brain and possesses most of the properties required to be classified as a neurotransmitter and/or neuromodulator. In fact, synthesis, release, uptake mechanisms, and specific binding sites for GHB have been identified in the mammalian brain (Benavides et al. 1982a,b;Hechler et al. 1985Hechler et al. , 1992Maitre et al. 1983;Rumigny et al. 1981;Snead and Liu 1984;Vayer et al. 1988). GHB binding sites exhibit high (Kd 30-580 nM) and low (about 20 M) affinity for GHB (Benavides et al. 1982a) and are sensitive to pertussis toxin, suggesting that these sites could represent G protein coupled receptors (Kemmel et al. 1998;Rotomponirina et al. 1995). GHB binding sites have a discrete brain distribution including the frontal cortex, nucleus accumbens, amygdala, hypothalamus, and, with highest density, the hippocampus (Hechler et al. 1992;Maitre et al. 2000;Snead et al. 1990). The synthetic structural analog of GHB, 6,7,8, (Maitre et al. 2000). In vivo, NCS-382 diminishes the sedative effect and the petit mal seizures induced by GHB (Hu et al. 2000;Schmidt et al. 1991;Schmidt-Mutter et al. 1998) and suppresses GHB-intravenous self-administration in mice (Martellotta et al. 1998). Moreover, NCS-382 inhibits GHB-induced increase in Guanosine 3 Ј ,5 Ј -cyclic monophosphate (cGMP) levels and inositol phosphate turnover in the hippocampus both in vivo and in vitro Snead 2000). At millimolar concentrations GHB displaces [ 3 H] baclofen from GABA B (gammaaminobutyric acid) receptors (Mathivet et al. 1997;Snead 1996). GHB action on GABA B receptors appears to mediate some of the pharmacological actions of GHB...

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Section: Discussionsupporting

confidence: 75%

Section: Gamma-hydroxybutyric Acid (Ghb) Is a Psychoactive Drug And Amentioning

confidence: 99%

Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Cammalleri

Brancucci

Berton

et al. 2002

Neuropsychopharmacology

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“…Moreover, the dose-response relationship (Figure 1g) and previous reports showed maximal and specific action of GHB at the concentration of 600 mM (Berton et al, 1999;Cammalleri et al, 2002). It should be noted that previous studies (Madden and Johnson, 1998;Erhardt et al, 1998;Shepard and Connelly, 1999) reported an inhibitory effect of GHB on nigral dopamine neurons.…”

Section: Discussionsupporting

confidence: 75%

Presynaptic Modulation of Spontaneous Inhibitory Postsynaptic Currents by Gamma-hydroxybutyrate in the Substantia Nigra Pars Compacta

Brancucci

Berretta

Mercuri

et al. 2003

Neuropsychopharmacol

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The regulation of GABA release from the inhibitory input to dopamine cells in the substantia nigra pars compacta (SNc) plays a key role in different reward-related behaviors. Gamma-hydroxybutyrate (GHB) has therapeutical properties in various psychiatric disorders, especially in alcohol abuse. GHB is also used as a drug of abuse, which induces sedation and euphoria. Using whole-cell patch-clamp recordings, we studied the effects of GHB on GABA release in the SNc by recording spontaneous inhibitory postsynaptic currents (sIPSCs) in brain slices of 21-to 25-day-old rats. We found that GHB depressed the frequency and amplitude of sIPSCs, while the frequency and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of TTX, were not affected. However, in the presence of high extracellular potassium (15 mM), which increases the contribution of voltage-dependent calcium channels, GHB induced a reduction in the frequency of the mIPSCs without any effect on their amplitude. All of these effects were GABA B -independent and they were blocked by the GHB receptor antagonist NCS-382. The present results indicate that GHB inhibits spontaneous inhibitory synaptic transmission recorded from dopaminergic neurons in the SNc likely by reducing voltage-dependent calcium influx involved in presynaptic GABA release.

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“…Previously we have demonstrated that GHB, at millimolar concentration in vitro, reduces neuronal excitability and synaptic activity in both neocortical and hippocampal neurons mediated via GABA B receptors (31). In our current experiments, we chose a high of dose of GHB (500 mg/kg), because the concentration of GHB in cerebrospinal fluid or brain in animals and in humans, after an exogenous administration at this dose, reached millimolar levels (14, 40 -42), compatible with the affinity of GABA B receptors for GHB (43). Acute administration of GHB (500 mg/kg) in vivo caused a rapid and long lasting inhibition on MAP kinase phosphorylation in both frontal cortex and hippocampus (Fig.…”

Section: Discussionmentioning

confidence: 99%

γ-Hydroxybutyrate Reduces Mitogen-activated Protein Kinase Phosphorylation via GABAB Receptor Activation in Mouse Frontal Cortex and Hippocampus

Ren

Módy

2003

Journal of Biological Chemistry

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␥-Hydroxybutyrate (GHB) naturally occurs in the brain, but its exogenous administration induces profound effects on the central nervous system in animals and humans. The intracellular signaling mechanisms underlying its actions remain unclear. In the present study, the effects of GHB on the activation (phosphorylation) of mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase 1 and 2 (ERK1/2), were investigated. Acute administration of GHB (500 mg/kg, intraperitoneal) induced a fast and long lasting inhibition of MAP kinase phosphorylation in both frontal cortex and hippocampus. The reduced MAP kinase phosphorylation was observed in the CA1 and CA3 areas but not in the dentate gyrus. Pretreatment with the specific ␥-aminobutyric acid, type B (GABA B ), receptor antagonist CGP56999A (20 mg/kg, intraperitoneal) prevented the action of GHB, and the effect of GHB was mimicked by baclofen, a selective GABA B receptor agonist, whereas the high affinity GHB receptor antagonist NCS-382 (200 mg/kg, intraperitoneal) had no effect on GHB-inhibited MAP kinase phosphorylation. Moreover, the GHB dehydrogenase inhibitor valproate (500 mg/kg, intraperitoneal), which inhibits the conversion of GHB into GABA, failed to block the effect of GHB on MAP kinase phosphorylation. Altogether, these data suggest that GHB, administered in vivo, reduces MAP kinase phosphorylation via a direct activation of GABA B receptors by GHB. In contrast, GHB (10 mM for 15 min) was found ineffective on MAP kinase phosphorylation in brain slices, indicating important differences in the conditions required for the second messenger activating action of GHB.␥-Hydroxybutyrate (GHB) 1 is a natural constituent of the mammalian brain derived from the metabolism of ␥-aminobutyric acid (GABA) (1). Peripherally administered GHB can readily cross the blood-brain barrier and produces significant behavioral, electrophysiological, and biochemical effects. Clinically, GHB has been used as an anesthetic agent (2), in the treatment of alcohol withdrawal and dependence (3), opiate withdrawal (4), and in sleep disorders (5). Recently GHB has emerged as a major recreational drug of abuse, and its abuse or intoxication has been associated with a mild euphoria, respiratory depression, headache, vomiting, agitation, seizures, and even death (6 -8).GHB has been suggested to play a role as a neurotransmitter or neuromodulator in brain (9 -11) and was shown to modulate neuronal excitability and the release of some neurotransmitters in the different brain regions (12)(13)(14)(15)(16). Although the precise mechanisms underlying GHB actions have not been established, accumulating evidence supports that GHB acts via GABA B receptors. For instance, the sedative/hypnotic effect of GHB is entirely mediated by the stimulation of GABA B receptors (17), and GHB can increase the concentrations of neurosteroids in the brain via a GABA B receptor-mediated mechanism (18). Despite these findings, little is known about intracellular signaling pathways possibly re...

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γ-Hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices

Cited by 36 publications

References 35 publications

Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Presynaptic Modulation of Spontaneous Inhibitory Postsynaptic Currents by Gamma-hydroxybutyrate in the Substantia Nigra Pars Compacta

γ-Hydroxybutyrate Reduces Mitogen-activated Protein Kinase Phosphorylation via GABAB Receptor Activation in Mouse Frontal Cortex and Hippocampus

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