ã-Hydroxybutyrate (GHB) is a central nervous system depressant17, inducing a sleep-like state in experimental animals in doses ranging from 0.1 to 1.5g/kg10, 5, 16. Although many neurotransmitter systems are affected by treatment with GHB17, the dopaminergic system is consistently altered by GHB1, 18. Treatment with GHB has been mainly shown to inhibit dopamine release1, 18, 17. Although some studies have shown that GHB initially inhibits dopamine release and then causes a time-dependent release6, this has subsequently been found to have been a result of experimental errors, such as ignoring the effects of anaesthetics, or having unusually high levels of Ca2+ in the growth medium6.
The mechanism of how GHB affects dopamine and the CNS in general is unclear, but it is almost certainly mediated by either the GABAB receptor or the putative GHB receptor. The evidence that GHB affects the GABAB receptor is threefold. On a behavioral level, antagonizing the GABAB receptor stops animals from identifying GHB in drug-discrimination tests3. On a cellular level, GHB causes a pronounced hyperpolarization of nerve cells and this effect is blocked by GABAB antagonists but not by GHB receptor antagonists19. Finally, on a molecular level GHB binds (although weakly, KD 100µM14) to the GABAB receptor, showing its own innate agonistic properties11. It is possible that GHB could also be metabolized to GABA8 (although this seems unlikely14) or releases GABA in pathways expressing the GABAB receptor7, 9.
The putative GHB receptor is a novel binding site, showing its own properties, as far as agonists, antagonists and binding profiles are concerned15 and is now widely believed to be a molecularly distinct receptor, although its sequence has not been identified. Importantly, the putative GHB receptor exhibits an extremely high affinity to GHB2, 17. Certain frontal lobe neurons become hyperactive in animals treated with GHB, presumably because the cells are normally inhibited by dopamine, but due GHB's lowering the release of dopamine, this inhibition is partially ablated.8 This hyper activity can be attributed GHB receptor activation, because when the animal is then treated with the selective GHB-receptor antagonist NCS-382, the cells dose-dependantly revert to their normal firing rate. 8.
Both the GHB and GABAB receptor systems have been shown to be inhibitory in nature17 (meaning that increasing activation of these receptors reduces the activity of associated systems), explaining many of GHBs actions (catalepsy, inhibition of breathing, coma). It also explains why GHB can be so dangerous in combination with alcohol, benzodiazepines, barbiturates and other sedatives17. Although the exact nature of the putative GHB receptor has not been identified, it is known to be distributed in the hippocampus, cortex and dopaminergic structures12 and hence would be consistent with areas implicated by the known effects of GHB. Even though the GHB receptor may be responsible for GHB's ability to induce seizures13, it seems that the GHB receptor is not the main mediator of GHB's subjective effects. A recent report showed that most behavioral effects of GHB were not significantly affected by GHB receptor antagonists4. Interestingly, it has been shown that GHB receptor antagonists inhibit GHB's effect on dopamine13, and hence, GHB's effect on dopamine is not considered important in mediating GHB's behavioral effects.
Although the scientific community isn't in agreement, in light of the evidence available to date, it seems that GHB's subjective "high" and behavioral effect is due mainly to its effect on the GABAB receptor and not the GHB receptor or dopamine blockade and release. Although the GHB receptor appears to be responsible for many physiological changes seen during treatment with GHB, the ultimate mediator of the response is the GABAB receptor. How GHB affects the GABAB receptor is unclear: It may be through metabolism of GHB to GABA, or more likely, via release of GABA. It is possible that there may be sub-groups of GHB receptors, or that GHB is an allosteric modulator of the GABAB receptor. It is likely that the question of GHB's exact mechanism will remain unanswered until the GHB receptor is isolated and sequenced, and its properties are better understood.
