Unravelling the brain targets of gamma-hydroxybutyric acid

Abstract

Gamma-hydroxybutyric acid (GHB) is a naturally occurring gamma-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).

Figure 1

GHB synthesis and metabolism. Schematic diagram of the pathways responsible for the synthesis and metabolism of GHB (the enzymes involved are indicated by numbers, see below). GHB activates GHB receptors, but also GABA_B receptors as a weak agonist. Because GHB can be converted to GABA, some of the GABA_B receptor-mediated actions of GHB could be elicited by the GHB-derived GABA pool interacting with GABA_B receptors. 1: alcohol dehydrogenase and acetaldehyde dehydrogenase; 2: $\tilde{\beta }$-oxidation pathway; 3: NADPH-dependent cytoplasmic aldehyde reductase, ALR-1; 4: mitochondrial pyridine nucleotide-independent oxido-reductase; 5: NADPH-dependent cytoplasmic aldehyde reductase, ALR-2; 6: specific succinic semialdehyde reductase; 7: γ-aminobutyric acid transaminase; 8, succinic semialdehyde dehydrogenase; TCA: tricarboxylic acid.

Figure 2

GABA_B receptor-mediated cellular actions of GHB in the VTA. The lower EC₅₀ (0.9 mM) for the coupling of postsynaptic GABA_B receptors to GIRK channels in GABAergic compared to that of dopaminergic neurons (27 mM) is determined by the different GIRK subunit compositions (GIRK1, 2 and 3) in the two neuronal types [28]. At concentrations seen in its recreational use (<1 mM), GHB preferentially activates postsynaptic GABA_B receptors on GABAergic neurons, hyperpolarizing them and decreasing their firing rate (middle panel). This effect would in turn disinhibit the dopaminergic neurons, increasing their firing rate and thus leading to enhanced dopamine output from the VTA, which is typical of drugs of abuse (middle panel). Higher GHB concentrations, however, would also decrease the firing rate of dopaminergic neurons by directly hyperpolarizing these neurons, thus giving rise to an overall reduction in dopamine output from the VTA (right panel), which explains the anti-craving properties of GHB that are exploited therapeutically in the treatment of alcohol dependence/withdrawal [11]. No information is available on the action of GHB on presynaptic GABA_B receptors of GABAergic neurons (dashed line) and other nerve terminals of extrinsic origin to the VTA. Schematic representation of changes in firing under different conditions is represented on the right hand side of each neuronal type.

Figure 3

GABA_B receptor-mediated cellular effects of GHB in the thalamus. Increasing GHB concentrations (left to right in the figure) progressively affect a greater number of presynaptic GABA_B receptors on GABAergic terminals of the nucleus reticularis (NRT) neurons, whereas all presynaptic GABA_B receptors on the glutamatergic cortical and sensory afferents are activated, even by 250 μM GHB [38]. The intensity of this effect (i.e. depression of synaptic potentials), as well as the amplitude of the hyperpolarization resulting from the activation of postsynaptic GABA_B receptors on thalamocortical neurons, becomes stronger with increasing GHB concentrations (indicated by an increased thickness of curved arrows). The enhanced inhibition of thalamocortical neurons arising from the imbalance between excitatory and inhibitory synaptic drive with 250 μM GHB increases the number of active neurons, their bursting characteristics and synchronization (as shown by the left-hand electrical records), as it occurs during absence seizure paroxysms. Importantly, 240 μM GHB is the threshold brain concentration for the EEG appearance of EEG spike and wave discharge [7], the hallmark of absence seizures [8]. At higher GHB concentrations, the GIRK-mediated hyperpolarization [38,43] and the increased depression of synaptic inputs [38,44] hyperpolarize thalamocortical neurons (middle electrical record) into the membrane potential region where delta oscillations (enlarged section) might occur. At much higher GHB concentrations (right-hand electrical record), delta oscillations will only momentarily occur as the membrane potential crosses their voltage region of existence; eventually, a very hyperpolarized membrane potential will be instated, as is likely to occur during overdose/coma.