ABSTRACT
In a number of clinical conditions hypoactivity of the inhibitory GABA system has been hypothesised as the underlying mechanism of the pathology in question. These conditions include epilepsy, anxiety, stress, sleep disorders and pain. In contrast, schizophrenia has been suggested to be related to a hyperactivity of the GABAergic system (Theobald et al., 1968; Tamminga et al., 1978). However, although positive modulators of the GABAA receptor complex such as benzodiazepines are very effective in a number of circumstances, there is a general consensus that unselective benzodiazepines produce so many side effects that compounds substituting for presently used drugs are needed (Costa and Guidotto, 1996). In addition to allosteric modulators of the GABAA receptor complex (e.g., benzodiazepines, barbiturates and steroids) alternative strategies for enhancing GABAergic functioning includes direct GABA agonism and inhibitors of GABA’s re-uptake or metabolism. Elevation of the synaptic concentration of GABA will activate both the ionotropic GABAA receptors and the metabotropic GABAB receptors. For a review of the therapeutic aspects of GABAB receptor intervention the reader is referred to recent reviews (Bowery and Enna, 2000; Malcangio and Bowery, 1995). Inactivation of the inhibitory neurotransmitter GABA in synapses of the central nervous system (CNS) is primarily mediated by re-uptake into presynaptic terminals of neurons and into glial cells via high affinity sodium-dependent GABA uptake carriers (Nelson, 1998).
