Effects Of Gamma-hydroxybutyric Acid Research Articles

Effects of gamma hydroxybutyric acid on inhibition and excitation in rat neocortex

The mechanism by which the sedative and amnestic recreational drug gamma hydroxybutyric acid (GHB) acts is controversial. Some studies indicate that it acts at its unique receptor, while others demonstrate effects mediated through the GABA B receptor. We examined the effect of GHB on evoked GABA A receptor–mediated mono- and polysynaptic inhibitory postsynaptic currents (IPSCs) as well as on N-methyl- d-aspartate (NMDA) and AMPA-mediated excitatory postsynaptic currents (EPSCs) in layers II/III pyramidal cells of the frontal cortex of rat brain. One millimolar (mM) GHB suppressed monosynaptic IPSCs by 20%, whereas polysynaptic IPSCs were reduced by 56%. GHB (1 mM) also produced a significant suppression of NMDA-mediated EPSCs by 53% compared with 27% suppression of AMPA-mediated EPSCs. All effects of GHB on IPSCs and EPSCs were reversed by the specific GABA B antagonist CGP 62349, but not by the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6 H-benzo[ a][7]annulen-6-ylidene ethanoic acid. Consistent with a presynaptic site of action, GHB reduced the frequency but not the amplitude of AMPA receptor–mediated mEPSCs and had no effect on postsynaptic currents evoked by direct application of NMDA. Finally, even though GHB appeared to be acting at presynaptic GABA B receptors, GHB and the GABA B agonist baclofen appeared to have opposite potencies for depression of NMDA- vs. AMPA-mediated EPSCs. GHB showed a preference for depressing NMDA responses while baclofen more potently suppressed AMPA responses. The suppression of NMDA more than AMPA responses by GHB at intoxicating doses may make it attractive as a recreational drug and may explain why GHB is abused and baclofen is not.

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.

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.

The effects of gammahydroxybutyric acid on canine cerebral blood flow and metabolism.

Gammahydroxybutyric acid has been proposed as an alternative to high-dose barbiturate therapy for protecting the brain after ischemic or traumatic insult. The cerebral and systemic metabolic and vascular effects of gammahydroxybutyrate and its lactone analogue, gammabutyrolactone, are addressed in this paper. In anesthetized normal dogs, gammahydroxybutyrate or gammabutyrolactone was infused intravenously at a rate of 1 gm/kg/hr. Cerebral blood flow (CBF) decreased progressively with increasing doses of either agent. Cerebral metabolic rate of oxygen (CMRO2) increased initially with gammahydroxybutyrate, but not following gammabutyrolactone. Reduction in CBF exceeded that of CMRO2 at all doses in both series. The primary systemic effect noted was a severe, lethal metabolic acidosis resulting from infusion of gammabutyrolactone. Gammahydroxybutyrate did not cause a similar acidosis. The imbalance of the CBG-CMRO2 reduction following gammahydroxybutyrate administration suggests that it has no advantage over barbiturates in the management of patients with cerebral vascular insufficiency or intracranial hypertension.

Respiratory effects of gamma-hydroxybutyric acid in anesthetized rats

Rats lightly anesthetized with halothane were treated with graded intraperitoneal doses of gamma-hydroxybutyric acid (GHBA), a GABA analogue. The drug induced a dose dependent decrease in minute ventilation, mainly due to reduced respiratory frequency. A reduced pH in arterial blood was recorded. GHBA also blunted or abolished the respiratory response to CO2 exposure in a dose-related way. Picrotoxin (0.25, 0.5 or 1.0 mg/kg intravenously), a presumed GABA antagonist did not significantly change the respiratory pattern when given alone but clearly antagonized the GHBA-induced respiratory depression. It is concluded that GABA-ergic mechanisms are involved in central respiratory control.

Gammahydroxy butyric acid: cardiovascular effects in the rat.

Gammahydroxybutyric acid (GHBA) 1 g/kg i.p. induced a marked and sustained increase in heart frequency and blood pressure in the rats. These effects of GHBA were abolished by a high spinal transection. In biochemical experiments GHBA in the same dose increased the turnover of brain noradrenaline but decreased the turnover of dopamine. The cardiovascular effects of GHBA are suggested to be of central origin, and possibly involve central noradrenergic mechanisms.