Intensity of GABA-Evoked Responses Is Modified by Nitric Oxide-Active Compounds in the Subthalamic Nucleus of the Rat: A Microiontophoretic Study Pierangelo Sardo, * Fabio Carletti, Stefania D’Agostino, Valerio Rizzo, Vittorio La Grutta, and Giuseppe Ferraro Dipartimento di Medicina Sperimentale—Sezione di Fisiologia umana, Universita ` degli Studi di Palermo, Palermo, Italy We have previously described modulatory effects of nitric oxide (NO)–active drugs on subthalamic nucleus (STN) neurons. In this study, the effects of micro- iontophoretically applied NO-active compounds on GABA-evoked responses were investigated in sub- thalamic neurons extracellularly recorded from anes- thetized rats: 45 of 62 cells were excited by S-nitroso- glutathione (SNOG), an NO donor, whereas 28 of 43 neurons were inhibited by No-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. Nearly all neurons responding to SNOG and/or L-NAME showed sig- nificant inhibitory responses to the administration of iontophoretic GABA. In these cells, the changes induced by NO-active drugs in the magnitude of GABA-evoked responses were used as indicators of NO modulation. In fact, when an NO-active drug was co-iontophoresed with GABA, significant changes in GABA-induced responses were observed: generally, decreased magnitudes of GABA-evoked responses were observed during continuous SNOG ejection, whereas the administration of L-NAME enhanced GABA responses. In contrast, glutamate-evoked res- ponses were enhanced by SNOG and dampened by L-NAME co-iontophoresis. Furthermore, the iontopho- retic administration of bicuculline (a GABA A receptor antagonist) completely abolished the GABA-evoked inhibitory responses and reduced the magnitude of both the SNOG- and L-NAME-induced effects. The results suggest that the NO-mediated modulation of subthalamic neurons could also be a result of an inter- action between NO and GABA A neurotransmission. Increased NOS activity has been shown in the hyper- active STN neurons of parkinsonian patients; on the basis of our observations about the influence of NO- active drugs on the baseline and GABA-evoked activ- ity of subthalamic cells, such hyperactivity suggests the involvement of increased NO levels and reduced sensitivity to GABA. V V C 2009 Wiley-Liss, Inc. Key words: subthalamic nucleus; GABA; SNOG L-NAME The subthalamic nucleus (STN) receives inputs from cortical and subcortical structures and influences activity throughout basal ganglia (BG) circuits (Parent and Hazrati, 1995; Chesselet and Delfs, 1996; Levy et al., 1997). Direct glutamatergic afferents to the STN (Kitai and Deniau, 1981; Canteras et al., 1990) arise from motor cortical areas (Afsharpour, 1985; Nambu et al., 1996) and the parafascicular thalamic nucleus (Bevan et al., 1995; Deschenes et al., 1996), suggesting that the STN is an additional BG input structure (Levy et al., 1997). Moreover, the STN receives GABAergic afferents from the globus pallidus (GP), which in turn receives glutamatergic fibers from the STN (Plenz and Kitai, 1999; Bevan et al., 2002). The GP projection is predominantly directed to the somata and proximal den- drites of STN neurons (Smith et al., 1990), but 30% of the GABAergic inputs from the GP are directed to distal dendrites and are coaligned with cortical and thalamic inputs (Smith et al., 1990; Bevan et al., 1995). Finally, both GABAergic and glutamate-immunoreactive projec- tions to the STN arise from the mesopontine tegmen- tum (Bevan and Bolam, 1995). Importantly, previous studies showed that STN cells are under tonic GABAer- gic control either in anaesthetized rats or across the entire sleep–wake cycle, predominantly mediated via GABA A receptors (Rouzaire-Dubois et al., 1980; Fe ´ger et al., 1991; Urbain et al., 2002). In addition to classic neurotransmitters, a diffuse distribution of both the neu- Contract grant sponsor: Italian Ministry for University, Scientific, and Technological Research. *Correspondence to: Professor Pierangelo Sardo, Dipartimento di Medic- ina Sperimentale—Sezione di Fisiologia umana, Universita ` degli Studi di Palermo, Corso Tukory 129, 90134 Palermo, Italy. E-mail: pierangelo.sardo@unipa.it Received 2 October 2008; Revised 1 December 2008; Accepted 11 January 2009 Published online 6 March 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.22043 Journal of Neuroscience Research 87:2340–2350 (2009) ' 2009 Wiley-Liss, Inc.