In a recently developed mouse model, both the GABAB receptor antagonist CPG 35348 and taurine, modify the neurotoxic effects of elevated gamma-hydroxybutyrate (GHB). This finding provides new scope for therapies for GHB drug abuse and succinic semialdehyde dehydrogenase deficiency (SSADH).
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). It is formed from L-glutamate by glutamic acid decarboxylation. GABA exerts its affect via three major classes of GABA receptors. These include the ligand gated GABAA and GABAC receptors and the metabotropic GABAB receptors.1 Significant resources have gone into understanding and identifying specific agonists and antagonists for each of these GABA receptors. GABA transaminase and succinic semialdehyde dehydrogenase metabolise GABA to succinic acid prior to entry into the Krebs cycle for energy production. Succinic semialdehyde may also be metabolised to gamma-hydroxybutyrate (GHB). Whilst GHB is a naturally occurring substance in the brain, its exact role is still being determined. Elevations in the levels of GHB, several orders of magnitude greater than normal, result in neurotoxicity and can occur with: (a) ingestion of GHB; or (b) the inborn error of metabolism SSADH (also known as 4-hydroxybutyric aciduria) (Figure 1).
Interest in GHB has increased due to its use as a recreational drug. GHB was first manufactured in the 1960s for use as an anaesthetic agent in children and was subsequently used clinically in the treatment of alcoholism and narcolepsy. Whilst it was an effective anaesthetic agent it failed to provide analgesia and had the unwanted side-affect of seizures leading to it being withdrawn from clinical use. It found its way into 'health food' stores for use by body builders. GHB in low doses (10 mg kg-1) results in euphoria, relaxation and sedation. Because of these affects it has become an increasingly popular 'recreational' drug of abuse particularly in the dance culture of raves and as a date rape drug. It can be produced relatively easily from its precursor gamma butyrolactone, which is found in solvents. Many home made 'brews' can have variable concentration. Overdose results in agitation, myoclonus, seizures and severe depression of consciousness, with fatalities reported. Recent data support evidence that chronic intake can lead to dependence and a withdrawal syndrome. Treatment has primarily been supportive with most overdoses recovering quickly with no long-term sequelae.
Similarities can be drawn between the clinical picture of GHB ingestion and SSADH. SSADH is a rare autosomal recessively inherited deficiency of the enzyme succinic semialdehyde dehydrogenase, in which both GABA and GHB accumulate. Over 150 patients have been reported in the literature to date, giving a clue as to its frequency. It is the elevated GHB that is postulated to result in the observed pathology. The clinical picture is heterogeneous even within families. Affected individuals typically present with variable psychomotor delay particularly affecting speech and language, somnolence, hypotonia, ataxia, and convulsion.2 There is evidence to suggest that these features modify with age. Older individuals have more significant problems with behavioural disturbance and aggressive, agitated behaviour. This change may correlate with the reduction in GHB levels observed in the CSF of patients with age. The irreversible GABA transaminase inhibitor, vigabatrin has been used in the treatment of this disorder as it inhibits GABA breakdown thereby limiting accumulation of GHB. In clinical use, vigabatrin is not affective in all patients and there are concerns surrounding its use following reports of visual field loss.3,4
Hogema et al recently described a knockout mouse model in which the SSADH gene (Aldh5a.1) had been targeted resulting in no detectable enzyme.5 These mice have elevated levels of GABA and GHB in urine and homogenates of liver and brain. Gliosis was observed in the hippocampus. They develop ataxia and seizures at around postnatal day 16 with death by postnatal day 22. It appears this model is an accurate model for the human disease SSADH and GHB ingestion. To date studies of the affects/action of GHB have relied on the intermittent administration of GHB to rats/mice. Based on these there is accumulating evidence to support GHB as a neurotransmitter. Numerous studies have confirmed GHB is a weak agonist at native and recombinant GABABR1/2 receptors and that it has high affinity binding to a GHB receptor, the nature of which is not currently clear.6,7
Hogema et al demonstrated that their mice could be maximally rescued with vigabatrin treatment thus confirming that the observed pathology is primarily due to the elevated GHB levels. They provide evidence to confirm high levels of GHB act upon GABAB receptors, as mice could also be rescued to a lesser extent with the GABAB antagonist CPG 35348. The correlation of the onset of clinical disease with weaning, in conjunction with previous studies identifying taurine as having effects on neurotransmission, led to the development of the hypothesis that taurine may play a role in disease protection. Administration of taurine alone to these mice resulted in rescue, although the exact mechanism remains unclear. The authors postulate that affected mice may be taurine depleted which is rectified by dietary supplement.
This unique mouse model represents a more physiologically accurate model, which should enable a better understanding of the neurophysiological effects of elevated GHB. It provides the opportunity to further clarify the role of GHB and its receptors in the mammalian central nervous system. The facilitation of the development of pharmacological agents for the treatment of GHB abuse, SSADH and potentially other neurological disorders is evident.
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