Figure 2. Pharmacological strategies for altering the tonic conductance.

A number of clinically relevant drugs are available that are known to alter the tonic conductance via a variety of direct and indirect targets. Here we illustrate a number of these targets situated within the principal neuronal and non-neuronal compartments of the brain. Although it was originally thought to be a GABA mimetic, the mechanism of action for Gabapentin is currently unclear, but the drugs ability to increase ambient GABA levels in the brain could reflect an alteration in GABA synthesis or release. Gabapentin is currently prescribed for the treatment of partial-onset seizures in adults and the elderly as well as a combination therapy for alcohol withdrawal and for sleep disorders. Tiagabine is a GABA transporter blocker acting predominantly on GAT-1 in nerve terminals leading to raised ambient GABA levels. This drug is prescribed for the treatment of partial seizures as well as generalized anxiety disorders/panic disorders. Other GABA transporter blockers such as SNAP-5114 are more selective blockers of GABA uptake in astrocytes, but these also lead to enhanced ambient GABA levels. Although bestrophin-1 channels could be an alternative nonvesicular source of GABA release, blockade of these channels by NPPB (5-nitro-2-(3-phenylpropylamino) benzoic acid) has been reported to both increase(Rossi et al., 2003) and decrease tonic inhibition(Lee et al., 2010) onto cerebellar granule cells. Irreversible block of GABA transaminase with the prescription drug Vigabatrin represents another strategy for raising ambient GABA levels. Vigabatrin has been used for the treatment of refractory complex partial seizures and infantile spasms but is currently not favoured due to visual field loss in some adults and children. More direct mechanisms for altering tonic inhibition involve orthosteric and allosteric interactions with extrasynaptic GABA_ARs. For example, the orthosteric agonist THIP or gaboxadol will selectively activate δ-GABA_ARs and, therefore, promote non-REM sleep. DS-1 is a newly developed agonist that has greater selectivity for δ-GABA_ARs than THIP, but its clinical benefit has yet to be established. Inverse agonists such as L-655,508 are currently being used to block the current generated by α5-GABA_ARs with the general objective to being used as cognitive enhancers. Allosteric modulators such as neurosteroids also offer a mechanism for more directly enhancing tonic inhibition. One such drug, Ganaxolone, is currently being developed for the treatment of drug resistant forms of catamenial epilepsy. It may also be possible to enhance or reduce tonic inhibition with Finasteride that blocks neurosteroid synthesis and XBD173 that enhances neurosteroid synthesis via the mitochondrial 18 kD translocator protein TSPO. It is also possible that the β subunit isoform identity may provide a means for selectively modulating tonic inhibition as the preferred β partner is the β2 subunit (Belelli and Lambert, 2005; Belelli et al., 2005; Herd et al., 2008) for α4βδ subunit-containing GABARs in the thalamus and dentate gyrus of the hippocampus. Any future development of β-subunit-dependent phosphorylation drugs could be useful in this regard.