Effects of the GABA-uptake inhibitor tiagabine in rat globus pallidus.
To elucidate the cellular action of tiagabine, an inhibitor of GAT-1 GABA transporter, in the globus pallidus, whole-cell patch-clamp recordings were made from rat globus pallidus neurons in the acutely prepared brain slice. Superfusion of tiagabine significantly prolonged the decay kinetics of both action potential-dependent and -independent (tetrodotoxin-resistant) inhibitory postsynaptic currents (IPSCs) that were mediated by GABA(A) receptors. Furthermore, it decreased the frequency of these IPSCs. The latter effect was reversed by the GABA(B) receptor antagonist CGP55845, which alone had no effect, suggesting the involvement of presynaptic GABA(B) receptors. Thus, tiagabine could inhibit or disinhibit globus pallidus neurons by increasing the activation of the GABA(A) receptors and presynaptic GABA(B) receptors, respectively. In the behaving animal, tiagabine when injected unilaterally into the globus pallidus caused consistent ipsilateral rotation of the rats indicative of increased inhibition of globus pallidus activity. This finding could be explained by the proposition that in the presence of tiagabine, prolonged action of GABA on GABA receptors would dominate over the inhibitory effect of tiagabine on GABA release. Our findings on the electrophysiological and behavioral effects of tiagabine in globus pallidus suggest that this basal ganglia nucleus is one of the sites of action of tiagabine and provides a rationale for investigating its involvement in epilepsy.
Chen
Lei
L
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Yung
Wing-Ho
WH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004553:Electric Conductivity; D018756:GABA Antagonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000187:drug effects*; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D013569:Synapses / Q000502:physiology; D000078308:Tiagabine
D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010721:Phosphinic Acids; D011412:Propanolamines; D011963:Receptors, GABA-A; C085075:CGP 55845A; D000078308:Tiagabine