D‐Tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons

D-Tubocurarine (d-TC) is a nicotinic cholinergic (nAch)-antagonist, which has been also reported to be a specific blocker of small calcium-activated potassium channels (SK-channels) (Brodie et al., 1999; Ishii et al., 1997; Wolfart et al., 2001). These channels are differently distributed in the central nervous system, with a very high density localized in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) (Bosch et al., 2002; Kohler et al., 1996; Stocker and Pedarzani, 2000; Wolfart et al., 2001). In fact, mRNA for the SK channel is highly expressed in dopamine (DA) cells and a dense labeling with antibodies against SK3 has been demonstrated in this structure (Bosch et al., 2002; Wolfart et al., 2001). In DA neurons SK channels generate a large afterhyperpolarization (AHP) (Bosch et al., 2002; Sah, 1996; Shepard and Bunney, 1991), control the frequency and precision of pacemaker spiking (Wolfart et al., 2001) and regulate a slow oscillatory potential (SOP) (Amini et al., 1999). The inhibition of SK channels by d-TC has been shown to reduce the AHP, increase firing discharge, and induce spontaneous and/or facilitate NMDAand DHPGmediated burst firing in DA neurons (Brodie et al., 1999; Ping and Shepard, 1996; Prisco et al., 2002; Seutin et al., 1993; Shepard and Bunney, 1991). Apart from the blockade of SK channels by d-TC in DA neurons, it has also been reported that d-TC clearly reduces GABAand/or glycine responses in other cells of the central and peripheral nervous systems (Tauck et al., 1988; Wotring and Yoon, 1995; Zhang and Berg, 1995). In DA neurons of the substantia nigra, both GABA and glycine evoke inhibitory responses mediated by GABAA and GABAB and by strychnine sensitive receptors (Rs), respectively (Hausser et al., 1994; Mercuri et al., 1990; Zheng and Johnson, 2001). Furthermore, intense barrages of inhibitory spontaneous PSPs mediated by GABAA receptors have been observed in DA cells both in vivo and in vitro (Berretta et al., 2001; Grace and Bunney, 1985; Grillner et al., 2000). Thus, the excitatory effects of d-TC on DA cells could be partially mediated by an interference with ongoing inhibitory GABA or glycine transmission. This study used whole-cell patch-clamp techniques to examine the effects of d-TC on the spontaneous GABAergic activity and on the postsynaptic responses evoked by GABA and glycine receptor stimulation in SNc neurons. We conclude that d-TC is an antagonist of GABAA responses.