Effect Of Gamma-hydroxybutyric Acid Research Articles

Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid.

Two gamma-hydroxybutyric acid (GHB) analogues, trans-gamma-hydroxycrotonic acid (t-HCA) and gamma-(p-methoxybenzyl)-gamma-hydroxybutyric acid (NCS-435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABAB receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5'-O-(3-[35S]thiotriphospate) [35S]GTPgammaS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mm concentration. GHB and baclofen effect was suppressed by the GABAB antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 nm and 1 mm GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348. t-HCA and NCS-435 (0.1-1000 microm) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 microm) but not by CGP 35348 (500 microm). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABAB-mediated effects, while the increase of glutamate levels is a GHB-mediated effect. Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABAB-mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.

Effect of Gamma-Hydroxybutyric Acid on Human Platelet Aggregation In Vitro

Endogenous formation of gamma-hydroxybutyric acid (GHB) (Fig. 1) has been described in humans [1]. It is considered to be a neurotransmitter and/or neuromodulator although its precise physiological role remains unclear [1]. This molecule is used in the treatment of alcoholism and alcohol withdrawal [2–4].

Characterization of the discriminative stimulus effects of gamma-hydroxybutyric acid as a means for unraveling the neurochemical basis of gamma-hydroxybutyric acid actions and its similarities to those of ethanol

The present paper reviews the drug discrimination studies, both from the literature and from this laboratory, conducted to investigate the pharmacological profile of the discriminative stimulus effects of gamma-hydroxybutyric acid. Collectively, the results of these studies suggest that: (1) the discriminative stimulus effects of gamma-hydroxybutyric acid are composed of different cues, each one being the effect of gamma-hydroxybutyric acid on a specific receptor system; (2) the proportion of each component cue varies as the training dose of gamma-hydroxybutyric acid is increased; (3) the gamma-aminobutyric acid B-mediated cue is a major ingredient of the mixed stimulus of gamma-hydroxybutyric acid, but it is more prominent at high training doses than at low training doses of gamma-hydroxybutyric acid; and (4) positive modulation of the gamma-aminobutyric acid A receptor is a relevant part of the discriminative stimulus effects of low gamma-hydroxybutyric acid doses. Finally, data indicating symmetrical generalization between the discriminative stimulus effects of a specific range of doses of gamma-hydroxybutyric acid and those of ethanol are discussed in regard to their further support of the hypothesis that gamma-hydroxybutyric acid may exert its antialcohol effects through a substitution mechanism.

Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence

We briefly review two double-blind, placebo-controlled surveys conducted in this laboratory with the aim of evaluating the efficacy of gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome as well as alcohol craving and consumption in alcoholics. In the first study, acute administration of 50 mg/kg gamma-hydroxybutyric acid, a nonhypnotic dose in alcoholic patients, resulted in a rapid and significant reduction of the severity score of alcohol withdrawal signs and symptoms that lasted as long as 7 hours. In the second study, treatment with 50 mg/kg/day gamma-hydroxybutyric acid for 3 consecutive months (1) reduced the number of daily drinks by approximately 50%, (2) increased the days of abstinence approximately threefold, and (3) reduced the alcohol craving score by up to 60%. These results feature gamma-hydroxybutyric acid as an effective agent for the treatment of alcohol dependence. Data on the effect of gamma-hydroxybutyric acid on opiate withdrawal syndrome also are reviewed. Administration of 25 mg/kg induced a marked reduction of opiate withdrawal score in both heroin- and methadone-dependent subjects. Finally, we report the cases of adverse reactions to and abuse of gamma-hydroxybutyric acid revealed in a retrospective analysis of patients recruited in this laboratory over a 10-year period.

Failure of gammahydroxy butyric acid to stimulate growth hormone secretion in cocaine addicts

This study discusses the effect of gammahydroxy butyric acid (GHB) on growth hormone (GH) secretion changes in cocaine addicts. Ten male cocaine users and 10 normal controls were tested with a single oral administration of GHB at a dose of 25 mg/kg body weight. Cocaine addicts were tested before and after 30 days of abstinence. All subjects underwent a control with a placebo. Basal GH levels were similar in normal controls and cocaine users and remained unmodified during the control test. In the normal control subjects, plasma GH levels rose significantly after the administration of GHB; in contrast, plasma GH concentrations failed to increase after GHB treatment in cocaine addicts. These data show that a chronic abuse of cocaine induces alterations of the GABAergic system which were unmasked by the absent GH response to GHB.

Gamma-hydroxybutyric acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors

The effect of gamma-hydroxybutyric acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.

Gamma-hydroxybutyric acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABA B receptors

The effect of gamma-hydroxybutyric acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.

The effect of gamma-hydroxybutyric acid on naloxone-precipitated opiate withdrawal

Because gamma-hydroxybutyric acid (GHB), a GABA metabolite, attenuated spontaneous opiate withdrawal in a prior study, we studied GHB's effect on naloxone-precipitated opiate withdrawal. Eight opiate-dependent inpatients were stabilized on the opioid levorphanol, 18 mg daily. After an initial acclimatization challenge, subjects underwent three double-blind challenges on consecutive days. Pretreatment in a balanced randomization was with either placebo, GHB, 15 mg/kg, or GHB, 30 mg/kg, followed an hour later by intravenous naloxone, 0.4 mg/70 kg. GHB produced no significant attenuation of multiple withdrawal measures except for hot-cold feelings. GHB pretreatment slightly accelerated respiration prior to naloxone. Differences with prior studies may be due to (1) timing of GHB administration (giving postwithdrawal in prior studies), (2) direct reversal of GHB's anti-withdrawal effects by naloxone, or (3) differences between naloxone-precipitated and spontaneous opiate withdrawal.

?-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors

In the present study the actions of gamma-hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (< 200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularized firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularization but, in contrast to low doses, an inhibition of firing rate. Administration of the GABAB-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABAB-receptors.

GAMMA-HYDROXYBUTYRIC ACID FOR TREATMENT OF ALCOHOL WITHDRAWAL SYNDROME

The effect of gamma-hydroxybutyric acid (GHB) on ethanol withdrawal syndrome in alcoholics was investigated in a randomised double-blind study. Patients with withdrawal symptoms were treated either with GHB (orally in a syrup preparation) (11 patients) or with the syrup alone (12). GHB treatment (50 mg/kg) led to a prompt reduction in withdrawal symptoms, such as tremors, sweating, nausea, depression, anxiety, and restlessness. The only side-effect was dizziness. GHB may be useful in the management of alcohol withdrawal syndrome in man.

Effect of gammahydroxybutyric acid on serotonin synthesis, concentration and metabolism in the developing rat brain.

5-HT synthesis, levels and degradation were investigated in the whole brain and regional brain areas in 4, 14, and 28 days old rats after administration of gammahydroxybutyric acid (GHBA). 5-HT synthesis was investigated by means of 5-HTP accumulation after decarboxylase inhibition by NSD 1015. 5-HTP accumulation increased in the 14 and 28 days old rats but decreased in the 4 days old animals 90 min after GHBA, 750 mg/kg. In the 28 days old rats a corresponding increase was also noted in the precursor amino acid tryptophan. Regional and whole brain 5-HT levels were not altered by GHBA treatment. Regional as well as whole brain levels of 5-HIAA increased in the 14 and 28 days old rats after GHBA administration. In conclusion, the present data indicate that GHBA increases the synthesis and degradation of 5-HT in adolescent rats. These effects of GHBA were not seen in the neonatal animals.

Effect of gammahydroxybutyric acid on catecholamine synthesis and utilization in the developing rat brain

Gammahydroxybutyric acid (GHBA) was administered subcutaneously, 750 mg/kg, to 1, 4, 14 and 28 days old rats 30 or 90 min before sacrifice. Whole brain and regional brain levels of tyrosine, dopamine (DA) and noradrenaline (NA) were measured. In some experiments the tyrosine hydroxylase activity was studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) after inhibition of aromatic L-aminoacid decarboxylase. GHBA induced an increase in tyrosine and DA levels at the various ages except at 1 day of postnatal age. The effect of GHBA on the accumulation of DOPA after inhibition of aromatic L-aminoacid decarboxylase varied with age. Thus, tyrosine hydroxylase activity seemed to be enhanced in the 4 days old rats after 90 min and after 30 min in the 28 days old rats. Ninety minutes after GHBA administration to the 28 days old animals, DOPA accumulation reached or was slightly below control levels. Brain NA levels were not affected by GHBA administration. Regional analysis of DA and NA after inhibition of tyrosine hydroxylase with alpha-methyltyrosine demonstrated a reduced disappearance of DA after GHBA in the striatum region already from 4 days of postnatal age. GHBA administration did not affect the nerve impulse release of NA in any of the brain regions studied. It may be concluded that GHBA acts inhibitory on brain DA neurons during early postnatal development.

Evaluation of the protective effect of gamma-hydroxybutyric acid in stress

Administration of GHBA during emotional stress reduces the stress syndrome that manifests in the lesser increase of the corticosterone content in blood plasma, while the noradrenaline level in the heart remains unchanged. GHBA prevents necrosis and contracture injuries of heart muscle cells during the stress. Quantitative evaluation of GHBA protective effect on the organism exposed to stress helped determine that the preliminary administration of GHBA reduces twofold the time necessary for the appearance of eosinophilia after eosinopenia. This indicates that GHBA a powerful antistress action.

Microiontophoretic study of the mechanism of action of gamma-hydroxybutyric acid

The effect of gamma-hydroxybutyric acid (GHBA) on extracellularly recorded spontaneous unit activity in the sensomotor cortex was studied by microiontophoresis in rabbits. GHBA reduced the discharge frequency of most neurons. Bicuculline, a specific blocker of gamma-aminobutyric acid (GABA), prevented the inhibitory effect of GHBA. This indicates that competitive relations may arise between GHBA and GABA while they interact with the common receptor. The conditions for the appearance of such relations are discussed.