SUBSTANTIA NIGRA PARS RETICULATA GABA IS INVOLVED IN THE REGULATION OF OPERANT LEVER PRESSING: PHARMACOLOGICAL AND MICRODIALYSIS STUDIES M. CORREA, a,b S. MINGOTE, a A. BETZ, a A. WISNIECKI a AND J. D. SALAMONE a * a Department of Psychology, University of Connecticut, Storrs, CT, 06269-1020, USA b Area de Psicobiologia, Campus Riu Sec, Universitat Jaume I, 12071, Castello, Spain Abstract—Substantia nigra pars reticulata (SNr) is an impor- tant mesencephalic nucleus that functions as a relay area for basal ganglia output. SNr receives GABAergic inputs from the neostriatum and globus pallidus, and in turn sends pro- jections to a variety of motor areas. Although a large number of studies have focused upon the behavioral functions of basal ganglia dopamine, much less is known about the be- havioral functions of SNr GABA. The present studies were undertaken to investigate the role of SNr GABA in lever pressing behavior. In the first experiment, the GABA A antag- onist bicuculline was infused locally into SNr to determine if blockade of GABA receptors interfered with the performance of lever pressing on a fixed ratio 5 schedule. SNr injections of bicuculline produced a dose-related suppression of operant responding. Analysis of interresponse time bins showed that SNr bicuculline produced a response slowing characterized by a relative reduction in the number of fast interresponse times, and an increase in the relative number of pauses. In an additional experiment, microdialysis methods were used to determine if extracellular GABA is elevated during the per- formance of fixed ratio five lever pressing. During the 30 min lever pressing session, extracellular GABA showed a signif- icant and substantial increase relative to baseline levels. These data support the hypothesis that SNr GABA is in- volved in the regulation of motor output, and indicate that GABA release in this structure is increased during behavioral stimulation. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: basal ganglia, motor, Parkinson’s disease, dialysis, bicuculline, GABA A . Substantia nigra pars reticulata (SNr) is a mesencephalic nucleus that functions as a relay area for basal ganglia output (Bevan et al., 1996; Bolam et al., 2000). Although pars compacta contains dopamine (DA) cell bodies that project to neostriatum, the SNr is ventral to the compacta, and receives GABAergic projections from neostriatum and lateral globus pallidus (Parent et al., 1984; Loopjuit and Van der Kooy, 1985; Gerfen, 1992; Parent and Hazrati, 1993; Fallon and Laughlin, 1995). In turn, GABAergic neu- rons that originate in SNr project to thalamic motor nuclei, superior colliculus and brainstem motor areas (Faull and Mehler, 1978; Fallon and Laughlin, 1995; Kha et al., 2001). Although a large number of studies have focused upon the behavioral functions of forebrain DA systems, much less is known about the behavioral functions of SNr GABA. Phar- macological evidence indicates that GABA in SNr is in- volved in various aspects of motor function (Di Chiara et al., 1978; Scheel-Kruger et al., 1981a, 1981b; Scheel- Kruger, 1983; Cools et al., 1983; Baumeister et al., 1988; Finn et al., 1997; Kriem et al., 1998; Mayorga et al., 1999; Koch et al., 2000; Wichmann et al., 2001). Transplantation of engineered GABA-releasing cells into SNr was shown to reduce tremulous movements induced by cholinergic stim- ulation (Carlson et al., in press). Recent studies in rats indicated that local infusions of the GABA A agonist musci- mol into SNr increased locomotion and circling behavior, and that injections of the GABA A antagonist bicuculline decreased open field locomotion and motor activity in small test chambers (Trevitt et al., 2002). The present studies were undertaken to investigate the role of SNr GABA in lever pressing behavior. Lever press- ing was studied because this behavior is known to be sensitive to antagonism or depletion of DA in the basal ganglia (Nowend et al., 2001; Salamone et al., 1993, 1997, 1999, 2001; Trevitt et al., 2001), and also because lever pressing is associated with increases in extracellular DA activity in striatum and nucleus accumbens (Cousins and Salamone, 1996; Salamone et al., 1999; McCullough et al., 1993; Salamone et al., 1989, 1994; Sokolowski et al., 1998; see reviews by Salamone, 1996; Salamone et al., 1999). Two experiments were performed in the present investigation. In the first experiment, the GABA A antago- nist bicuculline was infused locally into SNr to determine if blockade of GABA receptors would interfere with the per- formance of lever pressing on a fixed ratio 5 schedule. A GABA A antagonist was used in this experiment because there are a greater number of GABA A receptors than GABA B receptors on cell bodies in the SNr (Bowery et al., 1987; Nicholson et al., 1992; Ng and Yung, 2000), and because most of the GABA B receptors in SNr are thought to be located on either presynaptic terminals as autorecep- tors, or on the dendrites of SNc DA neurons (Giralt et al., 1990; Nicholson et al., 1992; Shen and Johnson, 1997; Ng and Yung, 2000). In addition, previous studies have shown that drugs acting on GABA A receptors have very potent behavioral effects when injected into SNr (Di Chiara et al., *Corresponding author. Tel: +1-860-486-4302; fax: +1-860-486- 2760. E-mail address: salamone@psych.psy.uconn.edu (J. D. Salamone). Abbreviations: SNr, substantia nigra pars reticulata; DA, dopamine; FR5, fixed ratio 5; IRT, interresponse time; OPA, o-phthalidialdehyde; HPLC, high-performance liquid chromatography; aCSF, artificial cere- brospinal fluid; ANOVA, analysis of variance; TTX, tetrodotoxin. Neuroscience 119 (2003) 759 –766 0306-4522/03$30.00+0.00 © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-4522(03)00117-9 759