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G-Hydroxybutyrate Inhibits Excitatory Postsynaptic Potentials in Rat

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G-Hydroxybutyrate Inhibits Excitatory Postsynaptic Potentials in Rat European Journal of Pharmacology 380Ž. 1999 109±116 www.elsevier.nlrlocaterejphar g-Hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices Fulvia Berton a, Alfredo Brancucci a, Franco BegheÁ b, Maurizio Cammalleri a, Angelo Demuro a, Walter Francesconi a,), GianLuigi Gessa c a Department of Physiology and Biochemistry ``G. Moruzzi'', UniÕersity of Pisa, Õia S. Zeno 31, Pisa 56127, Italy b CT Pharmaceutical Laboratory, Õia D. Alighieri 71, San Remo 18038, Italy c Department of Neuroscience ``B.B. Brodie'', UniÕersity of Cagliari, Õia Porcel 4, Cagliari 09124, Italy Received 25 May 1999; accepted 16 July 1999 Abstract g-HydroxybutyrateŽ. GHB has been shown to mimic different central actions of ethanol, to suppress alcohol withdrawal syndrome, and to reduce alcohol consumption both in rats and in humans. The aim of the present study was to determine if GHB shared with alcohol the ability to inhibit glutamate action at both NMDA and AMPArkainate receptors. The NMDA or the AMPArkainate receptors-media- ted postsynaptic potentials were evoked in CA1 pyramidal neurons by stimulation of Schaffer-collateral commissural fibers in the presence of CGP 35348, bicuculline to block the GABABA and GABA receptors, and 10 mM 6,7-dinitroquinoxaline-2,3-dioneŽ. DNQX or 30 mM DL-2-amino-5-phosphonovalerateŽ. d-APV to block AMPArkainate or NMDA receptors, respectively. GHB Ž 600 mM . produced a depression of both NMDA and AMPArkainate receptors-mediated excitatory postsynaptic potentials with recovery on washout. The GHB receptors antagonist, NCS-382, at the concentration of 500 mM had no effect per se on these responses but prevented the depressant effect of GHBŽ. 600 mM on the NMDA and AMPArkainate-mediated responses. In the paired-pulse experiments, GHB Ž.600 mM depressed the amplitude of the first and the second evoked AMPArkainate excitatory postsynaptic potentials, and significantly increased the paired-pulse facilitationŽ. PPF . These results suggest that GHB inhibits excitatory synaptic transmission at Schaffer-col- lateral commissural±pyramidal neurons synapses by decreasing the probability of release of glutamate. q 1999 Elsevier Science B.V. All rights reserved. r Keywords: GHB Ž.g-hydroxybutyrate ; GABAB receptor; NMDA receptor; AMPA kainate receptor; Excitatory postsynaptic potential; NCS-382; Paired-pulse facilitation; Hippocampal slice 1. Introduction distribution in the hippocampus, cortex and basal ganglia of the rat brainŽ Benavides et al., 1982b; Hechler et al., g-HydroxybutyrateŽ. GHB is a naturally occurring 1987; Hechler et al., 1991. Maximal high-affinity binding metabolite of g-aminobutyric acidŽ. GABA present in occurs in the CA1 field of the hippocampus where GHB micromolar quantities in the central nervous systemŽ Roth X X induces increase of guanosine cyclic 3 ,5 -phosphate and Giarman, 1970; Maitre, 1997. The highest concentra- Ž.cGMP levels Ž Vayer et al., 1987b; Vayer and Maitre, tion of GHB is found in the synaptosomal fractionŽ Maitre 1989; Hechler et al., 1992. This effect is blocked by the et al., 1983b; Snead, 1987. and in vitro, GHB is released q GHB receptors antagonist, NCS-382Ž. Maitre et al., 1990 . by neuronal depolarization in a Ca2 -dependent manner The central GHB receptors are of G protein-linked recep- Ž.Maitre and Mandel, 1982; Maitre et al., 1983a . A high- q tor type, and it has been suggested that the G proteins affinity, Na -dependent uptake system for GHB has also implicated in GHB receptor coupling are of the G or G been reportedŽ Benavides et al., 1982a; Hechler et al., io familyŽ. Ratomponirina et al., 1995 . 1985; Vayer et al., 1987a. GHB high-affinity binding sites Electrophysiological recordings of hippocampal or tha- are present only in neurons, with a restricted specific lamocortical neurons in vitro have revealed a hyperpolar- ization of the membrane potential after local application of ) Corresponding author. Tel.: q0039-50-553517; fax: q0039-50- GHBŽ Olpe and Koella, 1979; Kozhechkin, 1980; Xie and 552183 Smart, 1992a; Williams et al., 1995. In hippocampal CA1 0014-2999r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S0014-2999Ž. 99 00515-4 110 F. Berton et al.rEuropean Journal of Pharmacology 380() 1999 109±116 pyramidal neurons, a decrease in excitatory and inhibitory Ž.100±150 g were anaesthetized with halothane Ž. 3% in air postsynaptic potentials was also described. These actions and decapitated, and their brain rapidly removed and placed were blocked by GABAB receptor antagonists, CGP 36742 in ice-cold artificial cerebrospinal fluidŽ. aCSF gassed with or CGP 35348, suggesting that GHB can activate pre- and 95% O22 , 5% CO . The aCSF compositionŽ. in mM was: P postsynaptic GABAB receptorsŽ. Xie and Smart, 1992b . NaClŽ. 130 ; KCl Ž. 3.5 ; NaH24 PO Ž 1.25 . ; MgSO 47H 2 O P However, it has been shown that some neurophysiological Ž1.5 . ; CaCl222H O Ž. 2 ; NaHCO 3 Ž. 24 ; and glucose Ž. 10 . and neuropharmacological effects of GHB are mediated by To pharmacologically isolate the NMDA or the specific receptors. Indeed, NCS-382 has been reported to AMPArkainate synaptic components, we superfused the antagonize GHB-induced increase in guanosine cGMP lev- slices with 10 mM 6,7-dinitroquinoxaline-2,3-dione els in hippocampus and in vivo release of both dopamine Ž.DNQX or 30 mM DL-2-amino-5-phosphonovalerate Ž d- and opioid-like substancesŽ. Vayer et al., 1987b . In the APV.Ž. , respectively, together with bicuculline 30 mM and prefrontal cortex, two opposite effects on neuronal firing 0.5 mM CGP 35348 to block GABAAB and GABA recep- rate were observed with high and low doses of GHB where tors. only the increase of firing rate of neurons at low doses was Transverse hippocampal slices 400-mm thick were cut blocked by NCS-382Ž. Godbout et al., 1995 . on a brain slicer, incubated in an interface recording GHB has been shown to reduce voluntary alcohol in- chamber for 15 min, and then completely submerged and take in alcohol-preferring ratsŽ. Fadda et al., 1988 and continuously superfused with warmŽ. 338±348C gassed alcohol craving in humansŽ Gallimberti et al., 1992; Addo- aCSF at a constant flow rate of 2±4 mlrmin. lorato et al., 1998. In addition, GHB has been shown to suppress the severity of alcohol withdrawal symptoms in 2.2. Intracellular recordings both ethanol-dependent ratsŽ. Fadda et al., 1989 and alco- CA1 pyramidal neurons were recorded in the current- holicsŽ. Gallimberti et al., 1989 . The presence of symmet- clamp mode with 4 M K-acetate-filled electrodesŽ 80±120 rical generalization between the discriminative stimulus MV.. Current-clamp studies were performed with an Ax- effects of GHB and ethanol in ratsŽ. Colombo et al., 1995 oclamp-2B amplifierŽ. Axon Instruments . Selected traces could explain the pharmacotherapeutic use of GHB besides were stored on a PC for data analysis using a software supporting the hypothesis that GHB may have ethanol-like developed using LABVIEW of the National Instruments. action. Limited double-blind and more extended open stud- Several criteria were used to accept cells for experi- ies indicate that GHB is highly effective in reducing ments: stable resting membrane potentials of at least y60 craving, alcohol intake and relapses in alcoholic patients. mV and no spontaneous firing of action potentials; no GHB is self-administrated by rats, induces conditioned sudden drops in the input resistance, indicating cell dam- place preference, is voluntarily consumed by alcohol-pre- age; and constant amplitude of the spike Ž.)80 mV ferring rats and is potentially abused by humansŽ Gallim- obtained by direct activation of the cell. The postsynaptic berti et al., 1992; Addolorato et al., 1996. Although these excitatory and inhibitory potentials were evoked by ortho- studies reported no withdrawal symptoms when GHB was dromic stimulationŽ 80 ms stimulus duration, 0.05 Hz discontinued, it is worthy to mention that GHB has the frequency. of Schaffer-collateral commissural fibers with a potential to cause physical dependenceŽ Galloway et al., bipolar tungsten electrode placed in the stratum radiatum. 1997; Tunnicliff, 1997. Accumulating evidences suggest We averaged evoked responses from five sweeps and that neurophysiological and pathological effects of ethanol measured the peak amplitude. The usual testing protocol are mediated to considerable extent through the gluta- was: recording of excitatory or inhibitory postsynaptic matergic systemŽ. Tsai et al., 1995 . potentials for 10±15 min during superfusion of aCSF Ethanol inhibits both N-methyl-D-aspartateŽ. NMDA containing 10 mM DNQX or 30 mM d-APV, 30 mM and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic bicuculline and 0.5 mM CGP 35348Ž. ``control'' , followed acidŽ. AMPArkainate types of glutamatergic synaptic by switching to the same solution with GHBŽ 100±600 transmissionŽ Lovinger et al., 1989; Weight et al., 1991; mM. and repeating these measures after 5, 10, and 15 min Lovinger, 1993; Nie et al., 1994. of drug, followed by switching again to control solution The aim of the present study was to determine whether for 15±20 min with subsequent measuresŽ. ``washout'' . GHB shares with alcohol the ability to inhibit both NMDA For paired-pulse facilitationŽ. PPF experiments, low- and AMPArkainate-mediated excitatory postsynaptic po- strength paired responses were elicited by twin pulseŽ 60 tentials in the CA1 pyramidal cells in hippocampal slices. ms apart. in CA1 pyramidal neurons. The PPF is expressed as a ratio of the second to the first AMPArkainate-media- 2. Materials and methods ted excitatory postsynaptic potential amplitude. 2.1. Slice preparation 2.3. Data analysis We prepared hippocampal slices as described previ- Data are expressed as mean"standard error of the ouslyŽ. Berretta et al., 1990 . Briefly, male Wistar rats mean Ž."S.E.M. For statistical analysis, we used a one- F. Berton et al.rEuropean Journal of Pharmacology 380() 1999 109±116 111 factor ANOVAŽ.
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