Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist.

Abstract

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specific GABA receptor agonist which does not influence the GABA uptake system or GABA metabolizing enzymes. The specificity for the GABA receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors. Since in recent years GABA receptor stimulants-among others THIP--have become available many have speculated as to what clinical indication GABA-ergic stimulation might be an important element. The first suggestion was that GABA-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in the GABA system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increase GABA receptor activity. Furthermore, recent results in humans have shown that GABA agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest that GABA-ergic stimulation may reduce pain perception and muscle tone.