GHB

Oral🕒 Plan

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🧬 Receptor activityPH

Mechanism of actionPH

GHB is present at much higher concentrations in the brain, where it activates GABA-B receptors to exert its sedative effects. With high affinity, GHB binds to excitatory GHB receptors that are densely expressed throughout the brain, including the cotex and hippocampus. There is some evidence in research that upon activation of GHB receptors in some brain areas, the excitatory neurotransmitter glutamate is released. GHB stimulates dopamin release at low concentrations by acting on the GHB receptor, and the release of dopamine occurs in a biphasic manner. At higher concentrations, GHB inhibits dopamine release by acting on the GABA-B receptors, which is followed by GHB receptor signaling and increased release of dopamine. This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. It is proposed that overtime, the level of GHB in the brain decreases below the threshold for significant GABA-B receptor activation, leading to preferential activation of GHB receptor over GABA-B receptors and enhanced wakefulness.
Oxybate (GHB) is a metabolite of gamma-aminobutyric acid (GABA) which is synthesised and accumulated by neurones in the brain. It is present at uM concentrations in all brain regions investigated as well as in several peripheral organs, particularly in the gastro-intestinal system. Neuronal depolarization releases GHB into the extracellular space in a Ca2+-dependent manner. A family of GHB receptors in rat brain have been identified and cloned and most probably belong to the G-protein-coupled receptors. High-affinity receptors for GHB are present only in neurones, with a restricted specific distribution in the hippocampus, cortex and dopaminergic structures of rat brain. In general, stimulation of these receptors with low (physiological) amounts of GHB induces hyperpolarization in dopaminergic structures with a reduction of dopamine release. However, in the hippocampus and frontal cortex, GHB seems to induce depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. However, at higher (therapeutic) exposures, GHB receptors are saturated and probably de-sensitized and down-regulated. Such GHBergic potentiations induce dopaminergic hyperactivity, strong sedation with anaesthesia and EEG changes that are consistent with normal sleep and/or epileptic spikes.
Gamma-hydroxybutyrate (GHB), a four-carbon fatty acid and anesthetic, is widely considered to be a relatively specific inhibitor of central dopamine (DA) release. The inhibitory effect of GHB on the latter is thought to occur as a consequence of its diminution of impulse flow in central dopaminergic neurons. However, a number of studies have recently reported that GHB primarily stimulates rather than inhibits central DA release, with any inhibitory effect produced of a modest and transitory nature. GHB has been and continues to be widely used as an important research tool largely because it is one of only a few drugs available that acts primarily on DA release. Consequently, it is important to determine whether GHB inhibits DA release as previously thought, or stimulates DA release, as more recently suggested. Following a critical review of the literature, the present report suggests that GHB does inhibit rather than stimulate presynaptic DA release in consonance with its behavioral and pharmacological activity. Recent in vivo studies indicating that GHB stimulates DA release were done under anesthesia or in the presence of a high concentration of calcium. Both conditions have been found to spuriously enhance striatal DA release in vivo, which may account for the failure of some studies to observe an inhibitory effect of GHB on DA release in vivo.
Sodium oxybate is an endogenous 4-carbon fatty acid that is thought to act as a neurotransmitter in the regulation of sleep cycles, blood flow, emotion, and memory. Its actions are thought to be mediated through brain receptors specific for GHB as well as through binding to GABA-B receptors. At low doses, the drug inhibits presynaptic dopamine release, while at high doses, dopamine release may be stimulated. It is believed that sodium oxybate decreases the symptoms of narcolepsy by inducing REM sleep and increasing delta sleep. The precise mechanism by which sodium oxybate produces anticataplectic activity in patients with narcolepsy is unknown. /Sodium oxybate/

PharmacodynamicsPH

GHB predominantly works at two distinct binding sites in the central nervous system: it works as an agonist at the newly-characterized excitatory GHB receptor, while acting as a weak agonist at the inhibitory GABAB receptor. Since it is a naturally occurring substance, its physiological action is similar to that of some endogenous neurotransmitters in mammalian brain. GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.

Pharmacokinetics

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