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Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter, derived from gamma-aminobutyric 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 GABAB receptors. Previous studies indicated that GHB inhibits both NMDA and AMPA receptor mediated excitatory postsynaptic potentials in hippocampal CA1 pyramidal neurons. This action of GHB occurs in the presence of GABAB blockade and is antagonized by NCS-382, a specific GHB receptor antagonist, suggesting that it is mediated by GHB receptors. In the present study, we have investigated the effect of GHB on GABAA mediated inhibitory postsynaptic potentials (GABAA-IPSP) elicited in CA1 hippocampal pyramidal neurons by stimulation of Schaffer collateral-commissural fibers. We observed that GHB inhibited GABAA-IPSPs by about 40% at concentrations of 300–600 μM. GHB inhibition was blocked by NCS-382 (500 μM), which per se failed to modify GABAA-IPSPs. Moreover, GHB failed to modify cell membrane depolarization induced by the brief pressure application of GABA in the presence of tetrodotoxin (TTX), indicating that GHB does not inhibit postsynaptic GABA responses. However, GHB reduced the amplitude of GABAA-IPSPs elicited in pyramidal neurons by paired pulse stimulation and enhanced paired pulse facilitation with respect to control condition, suggesting that GHB reduces GABA release from nerve terminals. Finally, GHB failed to reduce the amplitude of GABAA-IPSPs in the presence of BaCl2, suggesting that the effect of GHB is due to GHB receptor-mediated presynaptic inhibition of Ca2+ influx. [Copyright &y& Elsevier]

The effect of γ-hydroxybutyric acid on extracellular glutamate levels in the hippocampus was studied by microdialysis in freely moving rats and in isolated hippocampal synaptosomes. Intra-hippocampal (CA1) perfusion with γ-hydroxybutyric acid (10 nm–1 mm) concentration-dependently influenced glutamate levels: γ-hydroxybutyric acid (100 and 500 nm) increased glutamate levels; 100 and 300 µm concentrations were ineffective; whereas the highest 1 mm concentration reduced local glutamate levels. The stimulant effect of γ-hydroxybutyric acid (100 nm) was suppressed by the locally co-perfused γ-hydroxybutyric acid receptor antagonist NCS-382 (10 µm) but not by the GABA[sub B] receptor antagonist CGP-35348 (500 µm). Furthermore, the γ-hydroxybutyric acid (1 mm)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10 µm), and it was also reversed into an increase by CGP-35348. Given alone, neither NCS-382 nor CGP-35348 modified glutamate levels. In hippocampal synaptosomes, γ-hydroxybutyric acid (50 and 100 nm) enhanced both the spontaneous and K[sup +]-evoked glutamate efflux, respectively, both effects being counteracted by NCS-382 (100 nm), but not by CGP-35348 (100 µm). These findings indicate that γ-hydroxybutyric acid exerts a concentration-dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct γ-hydroxybutyric acid receptor mediated facilitation is observed at nanomolar γ-hydroxybutyric acid concentrations, and an indirect GABA[sub B] receptor mediated inhibition predominates at millimolar concentrations. [ABSTRACT FROM AUTHOR]

Experiment 1 in the present study investigated the time course and dose range of γ-hydroxybutyric acid (GHB) to reduce voluntary ethanol intake in selectively bred Sardinian ethanol-preferring (sP) rats. Ethanol (10%, v/v) and tap water were offered under the two-bottle free choice regimen with unlimited access. GHB (200, 300, AND 400 mg/kg, i.p.) was administered 15-20 min prior to the start of the dark phase of the light-dark cycle. Ethanol and water intakes were recorded at different time intervals during the dark phase. GHB significantly reduced ethanol intake at doses of 300 and 400 mg/kg; statistical significance occurred only at 15-min and 30-min observation times. The GHB dose of 300 mg/kg was devoid of any sedative effect, as demonstrated in Experiment 2 by the lack of any impairment of spontaneous locomotor activity. Finally, this dose of GHB was also found to exert a robust anxiolytic effect in sP rats tested on the elevated plus maze (Experiment 3). Collectively, the results of the present study demonstrate that a non-sedative and anxiolytic dose of GHB effectively reduced voluntary ethanol intake in sP rats. The rapid onset of the reducing effect of GHB on ethanol intake as well as its anxiolytic effect, are discussed in terms of adding further support to the hypothesis that GHB may control alcohol craving and consumption in humans by substituting for ethanol's reinforcing effects. [ABSTRACT FROM PUBLISHER]

Abstract: Palatability and variety of foods are major reasons for “hedonic” eating, and hence for overeating and obesity. Palatable food and drugs of abuse share a common reward mechanism, and compounds that block the reinforcing effect of drugs of abuse preferentially suppress the intake of palatable foods. This research was aimed at studying the influence of the gamma-hydroxybutyrate analogue N-(4-trifluoromethylbenzyl)-4-methoxybutanamide (GET73) – that inhibits alcohol consumption – on consumption and reinforcing effect of palatable food. Adult male rats were used. For place preference conditioning, sweetened corn flakes were used as the reinforcer, and GET73 (50, 100 and 200mgkg−1) or vehicle were orally (p.o.) administered either 30min before each training session and the test session, or only before the test session. To study the influence on consumption, GET73 was given p.o. at the same doses once daily for 12 days to rats given free access to both palatable and varied food (cafeteria diet) or to standard chow. Both acquisition and expression of palatable food-induced conditioned place preference were inhibited by GET73, either administered throughout the conditioning period or only before the test session. GET73 reduced also the consumption of cafeteria food, while that of standard chow was increased. At these doses, GET73 had no detrimental effect on open-field behaviour. GET73 seems to specifically attenuate the gratification produced by varied and palatable food, without affecting the consumption of not particularly palatable chow. Since, overweight and obesity are mostly due to the overeating of palatable and varied foods, drugs like GET73 could represent a somewhat ideal and rational approach to obesity treatment. [Copyright &y& Elsevier]