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

Abstract

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...

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

“…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.…”

“…Additionally, it has been previously shown that GHB receptors are found mostly on nerve terminals (Maitre et al, 1983). A presynaptic mechanism of action of GHB has also been proposed in the hippocampus in experiments on paired pulse facilitation (Berton et al, 1999) or following exogenous application of GABA (Cammalleri et al, 2002). A presynaptic mechanism underlying the effect of GHB does not conflict with the observed reduction of sIPSCs amplitude.…”

“…GHB has been shown to reduce GABA-mediated synaptic transmission in different brain systems (Cammalleri et al, 2002;Xie and Smart, 1992b;Hu et al, 2000). However, regulation by GHB of GABA release in the SNc has not been investigated and could be important in shaping the pattern of activity of dopamine neurons.…”

A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex

“…The majority of GABA A receptors contain a ␥2 subunit, expressed throughout the brain except in the thalamus. It is well known that GHB administration in rats modifies GABA release in brain (9,10,28), leading to a pharmacological profile (sleep, anesthesia, anxiolysis) similar to those described for other GABA A agonists.…”

“…Interestingly, the ␥2 chain of GABA A receptor was downregulated by the drug. This could be due to a sustained hyperstimulation because GABA A receptors seem to play a pivotal role in the functional and pharmacological effects of GHB (1,5,10,16,23,63). The majority of GABA A receptors contain a ␥2 subunit, expressed throughout the brain except in the thalamus.…”