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The GABA uptake inhibitor -alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis Keita Ishiwari, Susana Mingote, Merce Correa1 , Jennifer T. Trevitt2 , Brian B. Carlson, John D. Salamone∗ Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA Received 30 October 2003; accepted 29 March 2004
Abstract Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker -alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of -alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. -Alanine (250–500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of -alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms. © 2004 Elsevier B.V. All rights reserved. Keywords: Basal ganglia; Striatonigral; Acetylcholine; Parkinson’s disease; Muscarinic; Dialysis
1. Introduction Substantia nigra pars reticulata (SNr) is a mesencephalic nucleus that serves several important functions in the overall circuitry of the basal ganglia (Bevan et al., 1996; Bolam et al., 2000; Trevitt et al., 2001). Although substantia nigra pars compacta contains dopamine (DA) cell bodies that project to ∗
Corresponding author. Tel.: +1 860 486 4302; fax: +1 860 486 2760. E-mail address:
[email protected] (J.D. Salamone). 1 Present address: Area de Psicobiologia, Campus Riu Sec, Universitat Jaume I, 12079 Castell´o, Spain. 2 Present address: Department of Psychology, California State University, Fullerton, CA, USA. 0165-0270/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneumeth.2004.03.030
neostriatum, the SNr is ventral to the compacta, and receives GABAergic projections from both 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). GABAergic neurons that originate in SNr project to thalamic motor nuclei and various brainstem motor areas (Faull and Mehler, 1978; Fallon and Laughlin, 1995; Kha et al., 2001), and therefore SNr is thought to be one of the major relay nuclei through which basal ganglia output is conveyed to other motor regions of the brain. Several studies have focused upon the behavioral functions of forebrain DA systems (e.g., McCullough et al., 1993; Salamone, 1996; Salamone et al., 1994, 1997; Sokolowski et al., 1998), yet much less is known about the behavioral functions of
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SNr GABA. The SNr is very rich in GABA, and the predominant postsynaptic GABA receptor in SNr is the GABAA subtype (Bowery et al., 1987). Pharmacological modulation of GABAA receptor function in SNr can affect various aspects of behavioral function, including locomotor activity, startle, catalepsy and lever pressing (Di Chiara et al., 1998; Scheel-Kruger et al., 1981a, 1981b; Scheel-Kruger, 1983; Cools et al., 1983; Baumeister et al., 1988; Timmerman and Abercrombie, 1996; Koch et al., 2000; Correa et al., 2003). GABAA receptor blockade has been shown to reduce motor activity, while stimulation of GABAA function in SNr induced motor activity and produced effects consistent with antiparkinsonian actions in animal models (Trevitt et al., 2002; Wichmann et al., 2001). Moreover, it has been suggested that some of the behavioral effects of DA D1 agonists are mediated by GABA release in SNr (Starr and Starr, 1989; Matuszewich and Yamamoto, 1999; Trevitt et al., 2002). Local infusion of the D1 agonist SKF 82958 into SNr substantially elevated extracellular GABA as measured by microdialysis (Trevitt et al., 2002). The stimulation of locomotion and suppression of tremor induced by SKF 82958 were reversed by infusions of the GABAA receptor antagonist bicuculline directly into SNr (Mayorga et al., 1999; Trevitt et al., 2002). One of the animal procedures that is used to study motor functions of the basal ganglia is tremulous jaw movements. Tremulous jaw movements are rapid vertical deflections of the lower jaw that have many of the characteristics of Parkinsonian tremor (Salamone et al., 1998). The pharmacological induction and suppression of tremulous jaw movements is characterized by an acetylcholine/DA interaction that is similar to that seen in parkinsonism (for reviews see Salamone et al., 1998, 2001). These movements can be induced by striatal DA depletions (Jicha and Salamone, 1991; Finn et al., 1997a), pharmacological depletion of DA (Steinpreis and Salamone, 1993; Salamone and Baskin, 1996), and by acute or sub-chronic administration of DA antagonists (Steinpreis et al., 1993; Steinpreis and Salamone, 1993; Trevitt et al., 1999; Wisniecki et al., 2003; Correa et al., 2004). The jaw movements induced by DA antagonism and DA depletion can be reduced by antiparkinsonian anticholinergic drugs (Steinpreis and Salamone, 1993; Salamone and Baskin, 1996). Cholinomimetics, which are known to induce or exacerbate parkinsonian symptoms such as tremor in humans (Ott and Lannon, 1992; Salamone et al., 2001), also induce tremulous jaw movements in rats (Salamone et al., 1986, 1990, 1998, 2001). Because cholinomimetic-induced jaw movements in rats can be reduced by various antiparkinsonian drugs (Cousins et al., 1997; Salamone et al., 1998), this behavioral test has been used to study the role of basal ganglia circuitry in motor functions that may be related to parkinsonian tremor. Several studies have implicated SNr GABA in the regulation of tremulous jaw movements. The suppression of cholinomimetic-induced tremulous jaw movements that was produced by the D1 agonist SKF 82958 was completely reversed by infusion of the GABAA antagonist bicuculline
into SNr (Mayorga et al., 1999). Injections of bicuculline directly into the SNr were shown to induce tremulous jaw movements (Salamone et al., 1998). Local infusions of the GABAA agonist muscimol into SNr were able to completely block cholinomimetic-induced jaw movements, while infusions of muscimol into entopeduncular nucleus failed to affect jaw movement activity (Finn et al., 1997b). Implantations of engineered GABA-synthesizing cells into SNr also significantly reduced cholinomimetic-induced tremulous jaw movements, whereas implantations of these cells into a dorsal brainstem control site did not (Carlson et al., 2003). Thus, several lines of evidence indicate that SNr GABA is involved in the modulation of tremulous jaw movement activity. The present studies were undertaken to investigate the behavioral functions of GABA using a combination of behavioral pharmacology and microdialysis methods. As described above, previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements, suggesting that increasing GABAergic tone in SNr may alleviate parkinsonian symptoms. To examine this possibility, the present study tested the GABA uptake blocker -alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In addition, parallel neurochemical studies investigated the effect of systemic injections of a behaviourally active dose of -alanine on extracellular levels of GABA in SNr samples using microdialysis methods. SNr has been shown to be rich in GABA transporters, particularly of the GAT-1 and GAT-3 subtypes (Ikegaki et al., 1994; Wang and Ong, 1999). Moreover, research with SNr synaptosomes has shown that GABA transport in SNr can be inhibited by a variety of compounds, including -alanine (Bahena-Trujillo and Arias-Monta˜no, 1999). Thus, it was hypothesized that systemic administration of -alanine should reduce pilocarpineinduced tremulous jaw movements, and that a behaviourally active dose of -alanine should also elevate levels of GABA in SNr dialysate samples.
2. Materials and methods 2.1. Animals Male Sprague–Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) weighing 280–330 g were used (total n = 20). The rat colony was maintained at 23 ◦ C with a 12-h/12-h light/dark cycle (lights on at 07:00 h). Animal protocols were approved by the Institutional Animal Care Committee, and were in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council). 2.2. Observations of pilocarpine-induced tremulous jaw movements Observations of animals in the first experiment took place in a clear Plexiglas chamber (30 cm × 30 cm × 30 cm) with a wire mesh floor. The chamber was elevated 42 cm from the
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bottom of the table top, which allowed for the viewing of the animal from several angles. Tremulous jaw movements were defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus (Salamone et al., 1998). Each individual deflection of the jaw was recorded using a mechanical hand counter, by an observer who was blind to the experimental condition of the animal being observed. Separate studies with two observers demonstrated an interrater reliability of r = 0.96 (p < 0.05) using these methods. For assessment of tremulous jaw movements, rats received injections of 4.0 mg/kg pilocarpine, and were observed during a 5-min period beginning 10 min after pilocarpine injection.
ophile. GABA, OPA, and sulfite react to form a stable, electrochemically active GABA-isoindole sulfonate derivative. Fifty microliters of dialysate or a standard solution (10−7 M GABA), and 20 l derivatizing reagent (22.0 mg OPA dissolved in 0.5 ml ethanol, with 0.5 ml 0.0313 M sodium sulfite and 9.0 ml 0.1 M sodium tetraborate), were mixed and allowed to react for 15 min. The sample was then assayed using HPLC [mobile phase = 100 mM sodium phosphate buffer, 8% methanol, 10.0 l 4.0 M EDTA, set to pH 4.9; flow rate = 1.0 ml/min]. After the elution of GABA, an injection of 40 l ethanol was made to remove late-eluting peaks. Standards of GABA were assayed before and after the dialysis samples.
2.3. Implantations of dialysis cannulae and probes
2.5. Experiment 1: effects of -alanine on pilocarpine-induced jaw movements
For cannulae implantations in the dialysis experiment, rats were anesthetized with a solution (1.0 ml/kg, i.p.) that contained ketamine (100 mg/ml) and xylazine (20 mg/ml). The incisor bar on the stereotax was set to 5.0 mm above the interaural line. Rats received unilateral implantation (with side balanced across rats) of a 10-mm guide cannula purchased from Bioanalytical Systems, Inc. (BAS; West Lafayette, IN). All guide cannula were placed 2.0 mm above the rostral SNr at the following coordinates: AP −3.0 mm (from bregma), LM ±1.8 mm (from midline), DV −7.2 mm (ventral from skull surface). The guide cannulae were secured to the skull using stainless-steel screws and cranioplastic cement. A stainless-steel stylet was inserted through each cannula to ensure its patency throughout the experiment. Prior to insertion of the dialysis probe, rats were given an injection of 1.5 mg/kg acepromazine maleate to produce mild sedation. Each rat then had a concentric dialysis probe (2.0 mm active surface; BAS) inserted through the guide cannula. After insertion, the probe extended 2.0 mm beyond the guide cannula, with the active surface located in the SNr. At the time of implantation, the dialysis probe was attached via polyethylene tubing to a fluid swivel. Artificial cerebrospinal fluid (aCSF) was continuously perfused through the tubing at a rate of 2.0 l/min. 2.4. Neurochemical analysis of GABA GABA was assayed using high-performance liquid chromatography (HPLC) and electrochemical detection (ESA, New Bedford, MA). The HPLC methods used for the present study were originally developed by Trevitt et al. (1999), using a modification of the method published by Phillips and Cox (1997). The HPLC system comprised a Waters dualpiston pump, a precolumn filter, a reverse-phase column (Velosep, C-18, 3 mm × 100 mm), an electrochemical detector (Coulochem II model 5014A), and a data acquisition station (ESA). Detector parameters were as follows: detector 1 = +0.35 V, detector 2 = +0.60 V, guard cell = +0.65 V. Pre-injection derivatization of GABA was accomplished using o-phthalidialdehyde (OPA) with sulfite as the nucle-
A group of rats (n = 13) was used to assess the effects of acute -alanine injection on pilocarpine-induced jaw movements. Animals were tested once a week for 3 weeks. On test days each animal received an injection of 4.0 mg/kg pilocarpine (10 min before testing) to induce tremulous jaw movements, as well as a dose of -alanine or vehicle 20 min before testing. The following doses of -alanine were used: vehicle, 250.0 and 500.0 mg/kg; -alanine was dissolved in 0.3% tartaric acid, and this vehicle solution also was used as the vehicle control treatment. Each rat received all treatments in a randomly varied order, with one injection per week. All drugs were administered via i.p. injection. Rats were placed in the observation chamber after pilocarpine injection for a 10-min habituation, and were observed for 5 min during the period 10–15 min after pilocarpine injection. Pilocarpine injections generally produce jaw movements during a period ranging from 5 to 45 min after injection, and the 10–15 min time period was selected because this represents the period of maximal jaw movement activity. 2.6. Experiment 2: effects of -alanine on extracellular GABA As described above, a single unilateral guide cannula was surgically implanted above SNr. After recovery from this surgery (7–10 days), rats had dialysis probes inserted (BAS; West Lafayette, IN) through the guide cannulae. Dialysis samples were collected every 30 min on the day following probe implantation. Artificial cerebrospinal fluid (147.2 mM NaCl, 1.2 mM CaCl2 , 4.0 mM KCl) was pumped through the probe at a rate of 2.0 l/min. Three baseline samples were conducted prior to drug injection, and then four additional samples were collected after injection of 500.0 mg/kg -alanine. Samples were frozen and later analyzed for GABA content using reverse-phase HPLC with electrochemical detection as described above. After the last sample was collected, the probes were removed and the rats were anesthetized and perfused. Only rats with verified placements in
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SNr were used for statistical analysis of the neurochemistry data (n = 7). 2.7. Histology Several days after each dialysis session, each animal was anesthetized with CO2 and perfused with physiological saline followed by a 10% formalin solution. The brains were removed and stored in formalin, and then were cut with a cryostat in 50-m slices, which were mounted on glass microscope slides. Following mounting, slides were stained with Cresyl Violet, and cannulae placements were determined using a microscope. 2.8. Data analysis For the first experiment, tremulous jaw movement data were analyzed using repeated measures analysis of variance (ANOVA). Planned comparisons using the overall error term were used to assess the differences between each dose and the control condition, which kept the total number of comparisons to the number of conditions minus one (Keppel, 1982; pp. 106–124). For the dialysis experiment, repeated measures ANOVA was used to analyze the neurochemical data, and planned comparisons were conducted to compare each post-injection sample with the last baseline sample.
3. Results
Fig. 1. Dose–response curve for the effect of i.p. injections of -alanine on pilocarpine-induced tremulous jaw movements. Pilocarpine (4.0 mg/kg) and -alanine were administered 10 and 20 min before observation, respectively. Mean (±S.E.M.) number of jaw movements during the 5-min observation period are shown. (*) Different from control by planned comparison, p < 0.05.
3.1. Experiment 1: effects of -alanine on pilocarpine-induced jaw movements In the first group of studies, the GABA transport inhibitor -alanine (250.0–500.0 mg/kg) reduced pilocarpine-induced tremulous jaw movements (Fig. 1). ANOVA demonstrated that injections of -alanine produced a significant overall effect on jaw movement activity (F(2,12) = 15.4, p < 0.01). Planned comparisons indicated that there were significant differences between vehicle and each dose of -alanine (p < 0.05). 3.2. Experiment 2: effects of -alanine on extracellular GABA in SNr As seen in Fig. 2, i.p. injection of 500.0 mg/kg -alanine, a behaviourally relevant dose that was shown in experiment 1 to reduce pilocarpine-induced jaw movements, also increased dialysate levels of GABA in SNr samples relative to the preinjection baseline. ANOVA indicated that there was a significant overall difference between samples in terms of GABA levels (F(6,36) = 5.21, p < 0.005). Planned comparisons indicated that the first two samples after drug injection differed significantly from the last baseline sample (p < 0.05, planned comparison). Fig. 3 is a photomicrograph, showing placement of a representative dialysis probe in SNr.
Fig. 2. Mean (±S.E.M.) levels of GABA in successive 30 min dialysis samples obtained during the baseline period (BL1–3), and after i.p. injection of 500.0 mg/kg -alanine. (*) Different from last baseline sample, p < 0.05; samples 0–30 min and 30–60 min after injection.
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Fig. 3. Photomicrograph of Nissl-stained coronal section through midbrain showing placements of dialysis probe in SNr of a representative rat. SNc (substantia nigra pars compacta), SNr (substantia nigra pars reticulata), cp (cerebral peduncle). Calibration bar = 0.5 mm.
4. Discussion The results of the first experiment demonstrated that i.p. injection of the GAT inhibitor -alanine reduced pilocarpineinduced tremulous jaw movements. Both doses of -alanine (i.e., 250.0 and 500.0 mg/kg) produced a significant reduction of jaw movement activity relative to injection of pilocarpine plus vehicle. Although -alanine has several pharmacological effects, including actions on other transmitters such as glycine (Mori et al., 2002), additional lines of evidence suggest that -alanine is acting on GABA systems to suppress jaw movement activity. Another GAT inhibitor, NO-711, also was shown recently to suppress pilocarpineinduced tremulous jaw movements (Ishiwari et al., 2003). NO-711 was much more potent than -alanine (i.e., NO711 suppressed jaw movements at doses of 2.5–5.0 mg/kg), which is consistent with an action of these drugs on GAT1 transporters. Also, -alanine was shown in experiment 2 to elevate extracellular GABA at one of the same doses (i.e., 500 mg/kg) that also suppressed jaw movement activity (see discussion below). These observations are consistent with previous studies showing that elevation of GABA transmission within the SNr can reduce cholinomimeticinduced tremulous jaw movements. Intranigral injections of the GABAA agonist muscimol, in doses as low as 6 ng, were shown to block pilocarpine-induced jaw movements (Finn et al., 1997b). Moreover, GABAA receptor stimulation in other brain areas, such as entopeduncular nucleus, or brainstem areas dorsal to SNr, was ineffective at reducing jaw movements (Finn et al., 1997b). More recently, work with engineered conditionally immortalized cell lines showed that transplantations of GABA-synthesizing cells
into SNr also could reduce pilocarpine-induced jaw movements (Carlson et al., 2003). Of course, in the present study -alanine was injected systemically, so it is not clear that the SNr is the locus of action for the behavioral effects of this drug. For that reason, additional research should investigate the effects of intracranial injections of GAT inhibitors directly into SNr, and should characterize a wider range of compounds. The microdialysis experiment demonstrated that injection of 500.0 mg/kg -alanine, a dose which reduced jaw movement activity in the first experiment, produced a significant elevation of GABA in SNr dialysis samples. The drug-induced increase in dialysate GABA peaked within the first sample after injection, resulting in a mean percentage increase of more than 66% relative to the last baseline sample. GABA levels remained significantly elevated during the second postinjection sample, and thereafter declined back to baseline. These results demonstrate that a behaviorally relevant dose of -alanine is capable of elevating dialysate levels of GABA in SNr in vivo. A previous microdialysis experiment showed that GAT inhibitors, including tiagabine (30 M) and NNC 05-2045 (100 M), increased dialysate levels of GABA in hippocampus when perfused through the microdialysis probe in halothane anesthetized rats (Dalby, 2000). That experiment focused upon the hippocampal actions of these drugs because of their possible utility as anticonvulsant agents. The present study demonstrates that GAT inhibition also can elevate GABA levels in SNr, and suggests a potential role for GAT inhibitors as tremorolytic agents. It is not clear which GAT subtype is involved in the behavioral and neurochemical effects reported in the present study. Anatomical research has indicated that SNr has a dense expression of the GAT-
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1 and GAT-3 GABA transporter subtypes (Ikegaki et al., 1994; Wang and Ong, 1999). Although -alanine is more selective for the GAT-3 subtype (Clark and Amara, 1994), it does act on GAT-1 as well, and in vitro work indicates that -alanine can inhibit GAT-1 transport on SNr synaptosomes (Bahena-Trujillo and Arias-Monta˜no, 1999). Although the higher potency of NO-711 for suppressing tremulous jaw movements relative to -alanine (Ishiwari et al., 2003) suggests that GAT-1 inhibition may be involved in this effect, future studies with a wider range of compounds would be necessary to reach a definitive conclusion about the particular GAT subtype that mediates the behavioral and neurochemical effects of -alanine observed in the present experiments. Moreover, additional studies will be necessary to determine whether neurons or glia are the source of the increase in dialysate GABA levels that is induced by administration of various GAT inhibitors. The present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. The use of microdialysis methods for studying extracellular GABA may lead to a better understanding of how diverse motor processes such as tremor, locomotion and skilled voluntary movements are modulated by SNr GABA mechanisms (Timmerman and Westerink, 1995; Biggs et al., 1995; Morari et al., 1996; O’Connor, 1998; Bianchi et al., 1998; Matuszewich and Yamamoto, 1999; Trevitt et al., 2002; Correa et al., 2003). Research on the motor functions of SNr GABA is particularly important in view of the various models of basal ganglia circuitry that emphasize the role of GABAergic transmission in output structures such as medial globus pallidus and SNr (Delong, 1990; Gerfen, 1992; Vila et al., 1996; Wichmann and DeLong, 1996; Ferre et al., 1996; Hauber, 1998; Wichmann et al., 1999; Obeso et al., 2000). Additional research will be necessary to study the effects of conditions that induce parkinsonian symptoms, such as DA antagonists, DA depletions and cholinomimetic drugs, on extracellular GABA in SNr. Moreover, it will be important to evaluate the actions of antiparkinsonian agents from various classes for their potential actions on nigral GABA. Ultimately, this line of research may help to elucidate how parkinsonian symptoms are modulated by SNr GABA transmission. Acknowledgements This work was supported by grants to J.S. from the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health. References Bahena-Trujillo R, Arias-Monta˜no JA. [3 H] gamma-aminobutyric acid transport in rat substantia nigra pars reticulata synaptosomes: pharmacological characterization and phorbol ester-induced inhibition. Neurosci Lett 1999;274:119–22.
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