Journal of Neurochemistry, 2002, 83, 645–654
Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat Diego Bustamante,* Zhi-Bing You, Marie-Noe¨lle Castel,à Sara Johansson, Michel Goiny, Lars Terenius,§ Tomas Ho¨kfeltà and Mario Herrera-Marschitz*, *Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago, Chile Departments of Physiology & Pharmacology, àNeuroscience and §Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
Abstract The main purpose of this study was to characterize the initial neurotransmission cascade elicited by methamphetamine, analysing simultaneously with in vivo microdialysis monoamine, amino acid and neuropeptide release in substantia nigra and neostriatum of the rat. The main effect of a single systemic dose of methamphetamine (15 mg/kg, subcutaneously) was an increase in dopamine levels, both in substantia nigra ( 10-fold) and neostriatum ( 40-fold), accompanied by a significant, but lesser, increase in dynorphin B ( two-fold, in both regions), and a decrease in monoamine metabolites. A similar effect was also observed after local administration of methamphetamine (100 lM) via the microdialysis probes, but restricted to the treated region. In other experiments, rats were repeatedly treated with methamphetamine or saline, with
the last dose administered 12 h before microdialysis. Dopamine K+-stimulated release was decreased following repeated methamphetamine administration compared with that following saline, both in the substantia nigra (by 65%) and neostriatum (by 20%). In contrast, the effect of K+-depolarization on glutamate, aspartate and GABA levels was increased following repeated administration of methamphetamine. In conclusion, apart from an impairment of monoamine neurotransmission, repeated methamphetamine produces changes in amino acid homeostasis, probably leading to NMDA-receptor overstimulation. Keywords: amino acids, basal ganglia, dynorphin, methamphetamine, microdialysis, monoamines. J. Neurochem. (2002) 83, 645–654.
There is evidence that high or repeated doses of d-N, a-dimethylphenylethylamine (methamphetamine, Meth) induce long-term deficits in basal ganglia neurotransmission, both in rodents and humans, mainly affecting the monoamines dopamine (DA; Fibiger and McGeer 1971; Seiden et al. 1976; Ricaurte et al. 1980; Marek et al. 1990) and serotonin (5-hydroxytryptamine, 5-HT; Ricaurte et al. 1980; Haughey et al. 2000), but also amino acids (Sonsalla et al. 1989; Nash and Yamamoto 1992; Marshall et al. 1993; Abekawa et al. 1994; Burrows and Meshul 1997, 1999) and neuropeptides (Castel et al. 1994; Smith and McGinty 1994; Wang and McGinty 1995, 1996; Alburges et al. 2001a, 2001b). The long-term effects of Meth are largely restricted to the nigrostriatal DA system (Ricaurte et al. 1980; Marshall and Navarrete 1990; Marshall et al. 1993; Burrows and Meshul 1997). Short- and long-term effects have also been described in limbic and cortical systems, but these systems are less and differently affected than the neostriatum (Axt and Molliver
1991; Brunswick et al. 1992; Eisch et al. 1996). Furthermore, while, as measured by quantitative autoradiography, the neurotoxic effect of Meth is seen in widespread brain regions receiving monoamine terminals, the cell body regions are largely unaffected (Brunswick et al. 1992). It has been proposed that the long-term effects of Meth depend on the amount of overflow of DA induced by the drug
Received April 4, 2002; revised manuscript received July 4, 2002; accepted July 26, 2002. Address correspondence and reprint requests to Dr Mario HerreraMarschitz, Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago 7, Casilla 70.000, Chile. E-mail:
[email protected] Abbreviations used: Asp, aspartate; DA, dopamine; DOPAC, 3,4dihydroxyphenylacetic acid; Dyn B, dynorphin B; GABA, c-aminobutyric acid; Glu, glutamate; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; HVA, homovanillic; MAO, monoaminoxidase; Meth, methamphetamine.
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646 D. Bustamante et al.
(O’Dell et al. 1991), and, in agreement, it has been shown that Meth-induced damage is prevented by inhibition of DA synthesis (Gibb and Kogan 1979; Hotchkiss and Gibb 1980; Schmidt et al. 1985), DA transport (Schmidt and Gibb 1985; Marek et al. 1990), or even by DA receptor antagonism (Sonsalla et al. 1986; O’Dell et al. 1993). It has been argued, however, that Meth may also increase glutamate (Glu) overflow (Sonsalla et al. 1989; Nash and Yamamoto 1992; Stephans and Yamamoto 1994), leading to the hypothesis that there is a synergism between both DA and Glu release, and that this is a requirement for Meth-induced neurotoxicity (Abekawa et al. 1994; Eisch et al. 1996). Microdialysis has been proposed as a method for monitoring in vivo neurotransmitter release, in brain and peripheral tissue (Ungerstedt et al. 1982; see Ungerstedt 1984, 1991), and it has been widely used for monitoring the effects of amphetamines (Zetterstro¨m et al. 1983, 1986; Westerink et al. 1987; Butcher et al. 1988; Hurd and Ungerstedt 1989a,b), including those of Meth (O’Dell et al. 1991; Nash and Yamamoto 1992; Holson et al. 1996; Sabol et al. 2001). In the present study, we have investigated the effect of Meth on several putative neurotransmitters monitored simultaneously with in vivo microdialysis in the rat, measuring the monoamine DA, the amino acids Glu, Aspartate (Asp) and c-aminobutyric acid (GABA), and the neuropeptide dynorphin B (Dyn B), as well as the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels, simultaneously, in substantia nigra and neostriatum. A high-dose regimen of Meth administration [1 · or 3 · 15 mg/kg subcutaneously (s.c.)], which has been shown to produce clear signs of neurotoxicity or long-term morphological changes (Pu and Vorhees 1993; Castel et al. 1994; Stephans and Yamamoto 1994; Eisch et al. 1996; Fleckenstein et al. 1997), without producing acute mortality (Fukumura et al. 1998) was chosen. A main purpose was to characterize the initial neurotransmission cascade elicited by Meth, hopefully revealing mechanisms triggering neurotoxicity. The experiments were performed under anaesthesia, in order to control several physiological variables, such as breathing rate, body temperature, heart frequency and spontaneous motility, while studying the interaction among several neurotransmitter systems in different brain regions. Some authors prefer an awake preparation based on the idea that anaesthesia may interfere with the pharmacological treatments (see Adachi et al. 2001). That can be true, as much as a chronic cannulation, chronic pain, inflammation and spontaneous behaviour can also interfere with releasing mechanisms. It is our experience, when not primarily interested in behaviour (e.g. Ungerstedt et al. 1982; Zetterstro¨m et al. 1986), that the presence or absence of anaesthesia is related to rather quantitative than qualitative pharmacological differences (see Herrera-Marschitz et al.
1992, 1996; You et al. 1999; Adachi et al. 2001). Thus, we have chosen a protocol controlling general physiological conditions, but concentrating on the interactions among several putative neurotransmitter systems.
Materials and methods In vivo microdialysis and drug treatment Male Sprague–Dawley rats (ALAB, Stockholm, Sweden), weighing 350–450 g, were anaesthetized with a mixture of air and halothane, placed in a Kopf stereotaxic frame and two microdialysis probes (CMA 12, CMA/Microdialysis AB, Stockholm, Sweden) were stereotaxically implanted, one into the left striatum (dialysing length, 4 mm; diameter, 0.5 mm; co-ordinates: A )0.5, L )3.5, V )8.0; according to Paxinos and Watson 1982) and the other into the left substantia nigra (dialysing length, 2 mm; diameter, 0.5 mm; coordinates: A )6.0, L )7.5, V )9.0, inserted with a 40 angle from the vertical in the coronal plane). The microdialysis probes were perfused with a modified cerebrospinal fluid (CSF) solution (148 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl2, 0.85 mM MgCl2) at a flow rate of 2 lL/min. After approximately 200 min following the implantation of the microdialysis probes, drugs were administered systemically [Meth hydrochloride (Sigma Chemical Co., St Louis, MD, USA) dissolved in saline and administered in a volume of 1 mL/kg body weight], or locally, via one of the microdialysis probe for a 40-min period (diluted in the CSF solution). In a series of experiments, Meth (15 mg/kg, s.c.), or saline was administered three times (1 · at 9, 15 and 21 h, respectively), the last dose given 12 h before the microdialysis experiment. K+-depolarization was produced by adding 100 mM KCl to the perfusion medium of the substantia nigra (200- to 240-min period after the beginning of the microdialysis experiment), or neostriatum (320- to 360-min period).The perfusion medium was adjusted to pH 7 when required. Changes in the perfusion medium were performed with a syringe selector coupled to a microfraction collector (CMA 111, CMA/Microdialysis AB). The rats were maintained under halothane anaesthesia throughout the experiment, by free breathing into a mask fitted over the nose (1% halothane in an air flow of 1.5 L/min), if not otherwise indicated. Body temperature was maintained at 37C by using a temperature control system (CMA 150, CMA/Microdialysis AB). Breathing, heart frequency and motility were permanently recorded. Samples were collected every 40 min (80 lL) and split for analysis of dynorphin B (50 lL), DA and monoamine metabolites (10 lL), and amino acids (10 lL). The experimental protocols were approved by a National Committee for Ethics of Experiment with Laboratory Animals (Norra Djurfo¨rso¨ksetiska Na¨mnd). Determination of monoamines DA and its metabolites DOPAC and HVA, and the 5-HT metabolite 5-HIAA were measured with high-performance liquid chromatography (HPLC) coupled to electrochemical detection. The detection limit was 0.2 nM for DA, DOPAC and 5-HIAA, and 1 nM for HVA (Herrera-Marschitz et al. 1992, 1996).
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Determination of amino acids GABA was measured in 10 lL of the perfusates using an HPLC system with a 100 · 1 mm microbore column (SepStick, 3 lm C18, BAS, West Lafayette, IN, USA), a fluorescence detector, a refrigerated microsampler (CMA 200, CMA/Microdialysis AB), and an integrator (Spectra-Physics, San Jose, CA, USA). The precolumn derivatization of GABA was performed with o-pthaldialdehyde-mercaptoethanol reagent, as shown in You et al. (1996). The detection limit for GABA was 2 nM. Glu and Asp were measured using a procedure similar to that for GABA, but with a different column (ODS 5-lm particles) and elution procedure (Herrera-Marschitz et al. 1992, 1996). The detection limit for both Glu and Asp was 10 nM. Dynorphin B radioimmunoassay The determination of Dyn B was carried out as reported previously (You et al. 1994b). Briefly, samples (50 lL of perfusate) and standards diluted in the perfusion medium were incubated with the antiserum and the labelled peptide in Eppendorf polyethylene tubes for 24 h at 4C. Samples without antiserum (to determine nonspecific binding) and samples without unlabelled peptide (to determine maximal tracer binding) were simultaneously incubated. Dyn B (Bachem, Bubendorf, Switzerland) was labeled with 125I using a chloramine-T procedure, and purified by reverse-phase HPLC with a gradient of 15–40% acetonitrile containing 0.04% trifluoroacetic acid. The antiserum and the labelled peptide used in the assay were dissolved in 0.05 M phosphate buffer containing 0.15 M NaCl, 0.1% gelatine, 0.1% bovine serum albumin, 0.02% sodium azide and 0.1% Triton X-100. After incubation, the antibody-bound and free tracer were separated by addition of antirabbit immunoglobulin G coupled to Sepharose (Pharmacia Decanting Suspension 3, Pharmacia AB, Uppsala, Sweden), and centrifugation for 15 min in a Beckman Microfuge. The bound fraction was counted in a gamma counter. The detection limit was 0.1–0.2 fmol/tube (1 pM). The non-specific binding of the tracer in the absence of the antiserum was less than 2%.
In vitro recovery The 2 mm and 4 mm microdialysis probes used in this study showed 14% and 20% in vitro recovery for DA, DOPAC, HVA,
5-HIAA, GABA, Glu and Asp, and 6% and 9% for Dyn B, respectively. Histology After completion of the microdialysis experiments, the rats were killed with an overdose of halothane and the brain was dissected out. The probe location was examined at low magnification with a surgical microscope. Only animals with correctly implanted probes are included in the statistics. Statistics The levels of the assayed substances are expressed as the concentrations found in the perfusates (means and SEM). Basal values refer to the values obtained before drug or 100 mM KCl administration, and are set as 100%. The dose-effect was analysed with F-ANOVA and a post-hoc test (Fisher’s protected partial least square test) when required. A level of p < 0.05 for a two-tailed test was considered critical for statistical significance.
Results
Acute effect of a single systemic Meth treatment Table 1 shows basal levels of DA and metabolites, amino acids and Dyn B, in substantia nigra and ipsilateral neostriatum. A single systemic Meth treatment (15 mg/kg s.c.) produced a strong increase of DA levels, in substantia nigra ( 10-fold) and neostriatum (> 36-fold), followed by a decrease in metabolites, including 5-HIAA. Dyn B levels were also significantly increased, both in substantia nigra and neostriatum ( two-fold). Figure 1 shows the time-course of the effect produced by Meth on DA (Figs 1a and b), DOPAC, HVA and 5-HIAA (Figs 1c and d) levels, in substantia nigra (Figs 1a and c) and neostriatum (Figs 1b and d), respectively, compared with that following saline administration. The effect of Meth on DA levels was long-lasting (> 240 min), with a peak observed immediately after drug administration in the neostriatum (maximum effect observed
Table 1 Effect of a single systemic Meth treatment (15 mg/kg, s.c.) on extracellular, dopamine, DOPAC, HVA, glutamate aspartate and dynorphin B levels (means ± SEM, n ¼ 6) measured in substantia nigra and neostriatum with microdialysis in halothane-anaesthetized rats Substantia nigra Basal Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dynorphin B, pM
0.62 ± 0.09 12 ± 3 11 ± 2 196 ± 15 1839 ± 548 99 ± 11 14 ± 2 9±2
Neostriatum Meth 4.6 ± 0.8 5±2 5±1 127 ± 26 2254 ± 532 119 ± 26 16 ± 7 16 ± 0.3
% of basal a
970 ± 143 39 ± 4a 52 ± 8a 64 ± 13a 135 ± 24 117 ± 17 117 ± 42 197 ± 46a
Basal 5.1 ± 1136 ± 525 ± 413 ± 1287 ± 111 ± 20 ± 11 ±
Meth 0.9 64 40 18 409 11 4 5
166 229 357 321 1624 148 30 19
% of basal ± ± ± ± ± ± ± ±
23 18 21 10 476 43 8 8
3608 20 69 78 134 129 130 204
± ± ± ± ± ± ± ±
620a 2a 6a 3a 25 25 14 39a
The maximum effect observed among successive samples taken after drug administration is expressed as the percentage of the respective basal value; ap < 0.05.
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Fig. 1 (a–d) Effect of systemic Meth (1 · 15 mg/kg s.c.) on nigral (a and c) and striatal (b and d) DA (a and b) and metabolite (c and d) levels measured with in vivo microdialysis. The arrow indicates the time of drug administration. Levels are expressed as the percentage of the respective basal values (n ¼ 6 for each group). In (a and b), black circles refer to dopamine levels following methamphetamine; grey
circles, saline. In (c and d), black circles, DOPAC; grey circles, HVA; grey triangles, 5-HIAA. The 100% level is indicated by the opentriangle-labelled curve, denoting a 10% variance, the averaged variance observed when DA and metabolite levels are measured with microdialysis. *p < 0.05, compared with basal levels.
during the 0- to 40-min period), but the effect in the substantia nigra was delayed (maximum effect observed during the 40- to 80-min period after drug administration; cf. Fig. 1a vs. Fig. 1b). The effect of Meth on metabolites increased with the time after drug administration. The maximum effect was observed 160 min after drug administration, but a significant effect on DOPAC levels was already observed at the 0- to 40-min period (Figs 1c and d).
experiments were performed and samples collected from substantia nigra and neostriatum for analysing DA and metabolites, amino acids and Dyn B levels, under basal and K+-depolarizing conditions. As shown in Table 3, K+-depolarization produced a strong increase in DA, GABA and Dyn B levels following saline treatment. DA and GABA levels were increased 10- and 40-fold, in substantia nigra and neostriatum, respectively, while Dyn B levels were increased by four-fold in both regions. Glu and Asp levels were also increased, but the effect of K+-depolarization was minor ( two-fold). The effect of K+-depolarization was largely restricted to the stimulated region, with the exception of Dyn B levels, which were also increased in the substantia nigra when the ipsilateral neostriatum was depolarized. Table 4 shows basal and K+-stimulated monoamine, amino acid and neuropeptide levels in substantia nigra and neostriatum after repeated Meth treatment. Although still strong, the effect of K+-depolarization on DA levels was diminished compared with that observed after saline, in substantia nigra and neostriatum ( six-fold vs. 10-fold, in substantia nigra, and 37-fold vs. 44-fold in neostriatum of Meth- vs. saline-treated rats, respectively; Figs 2a and b). In contrast, the effect of K+-depolarization on GABA levels was increased by Meth ( 14-fold vs. 10-fold, in substantia nigra, and 49-fold vs. 41-fold in neostriatum of Meth- vs. saline-treated rats, respectively; Figs 3a and b).
Effect of intracerebral (local) administration of Meth (100 lM; Table 2) In a series of experiments, Meth was administered directly into the substantia nigra or neostriatum via the microdialysis probe for a 40-min period. The effect of local Meth (100 lM) was largely localized to the treated region, increasing DA levels to a similar magnitude to that observed following systemic administration, both in substantia nigra and neostriatum. Dyn B levels were also significantly increased. Only minor effects could be observed on metabolites and other substances. Effect of repeated systemic saline or Meth administration (Tables 3 and 4; Figs 2–5) In a series of experiments, saline (3 · 1 mL/kg, s.c.; Table 3) or Meth (3 · 15 mg/kg, s.c.; Table 4) was repeatedly administered during the day before the microdialysis experiment. Twelve hours after the last dose of Meth, microdialysis
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Table 2 Effect of nigral (A) or striatal (B) Meth (100 lM) perfusion on extracellular, dopamine, DOPAC, HVA, glutamate aspartate and dynorphin B levels (means ± SEM; n ¼ 6) measured with microdialysis in rats Substantia nigra Basal A Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dynorphin B, pM
0.66 16 19 180 271 61 4.5 15
± ± ± ± ± ± ± ±
0.07 1.4 4 42 40 10 0.7 1
B Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dynorphin B, pM
0.56 13 21 178 379 64 4 21
± ± ± ± ± ± ± ±
0.08 2 6 41 53 11 0.4 1
Neostriatum Meth 100 lM
% of basal
5.3 14 20.1 169 379 67 4.4 23
779 82 94 94 134 110 105 156
± ± ± ± ± ± ± ±
95 86 94 92 112 107 94 121
± ± ± ± ± ± ± ±
± ± ± ± ± ± ± ±
1.7 1.7 3.8 39 80 11 1 2
0.6 ± 0.12 14 ± 2 20 ± 6 170 ± 40 426 ± 67 64 ± 11 4 ± 0.6 25 ± 2
Basal
Meth 100 lM
135a 9 12 3 11 2 22 9a
4.02 ± 0.37 927 ± 110 697 ± 113 418 ± 102 1199 ± 706 95 ± 30 10 ± 3 14 ± 2
4.34 919 719 416.2 1233 109 10 14
0.28 106 117 103 678 32 3 4
111 93 99 99 112 131 108 95
± ± ± ± ± ± ± ±
9 4 2 3 6 27 11 11
18 4 12 6 4 5 12 5a
4.17 ± 0.64 878 ± 98 715 ± 115 400 ± 96 1443 ± 866 111 ± 39 13 ± 4 15 ± 0.3
165 ± 21 764 ± 68 675 ± 95 376 ± 93 1494 ± 808 110 ± 49 10 ± 3.9 21 ± 3
4353 84 94 91 116 105 99 149
± ± ± ± ± ± ± ±
665a 3 3 3.4 9 13 27 14a
± ± ± ± ± ± ± ±
% of basal
The maximum effect observed among successive samples taken immediately after drug administration is expressed as the percentage of the respective basal value; ap < 0.05.
Table 3 Effect of nigral (A) or striatal (B) KCl (100 mM) on extracellular levels of dopamine, DOPAC, HVA, glutamate aspartate and dynorphin B (means ± SEM) measured with microdialysis in rats, 12 h after systemic saline (3 · 1 mL/kg s.c.; every 6 h; n ¼ 6) treatment Substantia nigra Basal
Neostriatum 100 mM KCl
% of basal
Basal
100 mM KCl
% of basal
A Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dyn B, pM
0.5 36 17 407 1023 111 10 11
0.07 9 2 101 157 17 2 2
4.5 ± 0.99 28 ± 9 14 ± 2 308 ± 72 1720 ± 437 148 ± 25 105 ± 40 36 ± 8
1001 76 86 77 177 136 1043 406
± ± ± ± ± ± ± ±
275a 8a 9a 2a 51a 18a 146a 52a
2.9 ± 0.18 1468 ± 58 728 ± 88 719 ± 75 1113 ± 180 123 ± 18 19 ± 4 14 ± 3
3.07 ± 0.4 1297 ± 95 691 ± 98 673 ± 69 1578 ± 375 142 ± 40 18 ± 4 15 ± 2
108 ± 9 88 ± 4 94 ± 3 94 ± 3 147 ± 40 117 ± 22 97 ± 13 126 ± 18
B Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dyn B, pM
0.48 ± 0.07 35 ± 8 17 ± 2 425 ± 98 1161 ± 253 81 ± 19 14 ± 6 9±2
0.45 ± 0.05 34 ± 9 17 ± 3 412 ± 94 1157 ± 108 108 ± 37 13 ± 5 13 ± 3
99 96 100 104 117 139 113 154
± ± ± ± ± ± ± ±
14 3 10 3 20 56 15 28a
2.9 ± 0.42 1524 ± 30 758 ± 105 696 ± 66 988 ± 175 162 ± 55 22 ± 4 19 ± 4
112 ± 22 901 ± 55 556 ± 79 555 ± 55 2381 ± 1219 294 ± 134 826 ± 192 45 ± 0.9
4426 ± 502a 59 ± 3a 73 ± 2a 80 ± 2a 217 ± 43a 170 ± 36a 4153 ± 540a 388 ± 113a
± ± ± ± ± ± ± ±
The maximum effect observed among successive samples taken immediately after drug administration is expressed as the percentage of the respective basal value; ap < 0.05.
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Table 4 Effect of nigral (A) or striatal (B) KCl (100 mM) on extracellular levels of dopamine, DOPAC, HVA, glutamate aspartate and dynorphin B (means ± SEM) measured with microdialysis in rats, 12 h after systemic Meth (3 · 15 mg/kg s.c.; every 6 h; n ¼ 6) treatment Substantia nigra
Neostriatum
Basal
100 mM KCl
% of basal
A Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dynorphin B, pM
0.63 ± 0.1 16 ± 4.4 17 ± 2.3 342 ± 36 792 ± 186 85 ± 4 20 ± 2 20 ± 3
4.1 9 14 252 1028 126 281 58
± ± ± ± ± ± ± ±
0.8 3 2.2 28 269 10 64 10
652 ± 85a,b 56 ± 9a 80 ± 8a 74 ± 6a 145 ± 19a 149 ± 22a 1446 ± 171a,b 353 ± 92a
B Dopamine, nM DOPAC, nM HVA, nM 5-HIAA, nM Glutamate, nM Aspartate, nM GABA, nM Dynorphin B, pM
0.43 ± 0.04 18 ± 3.3 18 ± 3 318 ± 37 896 ± 183 71 ± 14 21 ± 3 19 ± 3
0.46 16 18 307 846 79 18 30
± ± ± ± ± ± ± ±
0.07 3.3 2.9 34 203 17 4 6
110 ± 9 88 ± 11 99 ± 3 97 ± 1 92 ± 14 119 ± 23 91 ± 21 153 ± 17a
Basal
100 mM KCl
% of basal
2.61 ± 0.24 866 ± 111 630 ± 57 543 ± 71.3 798 ± 242 174 ± 85 27 ± 7 26 ± 6
3.08 ± 0.57 847 ± 98 612 ± 56 535 ± 68 849 ± 277 173 ± 81 26 ± 7 33 ± 9.5
123 ± 27 99 ± 2 98 ± 3 99 ± 2 105 ± 4 110 ± 20 103 ± 5 127 ± 14
3.4 ± 0.6 827 ± 63 591 ± 46 487 ± 57 832 ± 254 154 ± 70 34 ± 7 26 ± 6
123 ± 25 531 ± 66 399 ± 48 398 ± 50 3612 ± 1562 310 ± 69 1248 ± 178 76 ± 12
3723 ± 334a,b 64 ± 5a 67 ± 4a 82 ± 4a 405 ± 52a,b 307 ± 48a,b 4890 ± 710a,b 356 ± 67a
The maximum effect observed among successive samples taken immediately after drug administration is expressed as the percentage of the respective basal value; ap < 0.05; bp < 0.05 compared with the effect observed following repeated saline treatment (Table 3).
The effect of K+-depolarization on Glu and Asp levels was also increased, but only in neostriatum [for Glu: 1.5-fold vs. 1.8-fold in substantia nigra, and four-fold vs. twofold in neostriatum of Meth- vs. saline-treated rats, respectively (Figs 4a and b); for Asp: 1.5-fold vs. 1.4-fold in substantia nigra, and three-fold vs. 1.7-fold in neostriatum of Meth- vs. saline-treated rats, respectively (Figs 5a and b)]. Discussion
The present paper investigated the effect of single or repeated doses of Meth on neurotransmitter release and related molecules, analysed with in vivo microdialysis in substantia nigra and neostriatum of the rat. Whether systemically or locally administered, the main effect produced by a single dose of Meth is an increase of DA release, both in substantia nigra and neostriatum, the cell body and terminal regions of the nigrostriatal dopamine system, respectively (Dahlstro¨m and Fuxe 1964; Ungerstedt 1971). The increase of DA release was followed by a long-lasting decrease of the metabolites DOPAC and HVA, probably produced by a decrease in pre-synaptic DA, the substrate for intracellular monoaminoxidase (MAO)dependent metabolism (Zetterstro¨m et al. 1983; Hurd and Ungerstedt 1989a, 1989b), indicating a sustained inhibition of DA uptake and/or MAO inhibition (Sharp et al. 1986). 5-HIAA levels were also decreased, suggesting as well, even if
not measured, a sustained inhibition of 5-HT uptake and/or MAO inhibition. Dyn B levels were increased, probably as a secondary effect of an increased DA release. It has been shown earlier that the striatonigral Dyn pathway (Vincent et al. 1982; Christensson-Nylander et al. 1986) is modulated by inputs from D1 DA receptor expressing neurones (You et al. 1994a). As shown in Tables 3 and 4, K+-depolarization in neostriatum produced a significant increase of striatal, but also of nigral Dyn B levels, indicating a monosynaptic interaction. While the effect of high doses of Meth on DA release has been extensively demonstrated (O’Dell et al. 1991; Kuczenski and Segal 1992; Nash and Yamamoto 1992; Abekawa et al. 1994), this is the first time that the effect of Meth on monoamines, amino acids and neuropeptides is simultaneously analysed in substantia nigra and neostriatum, which is relevant, as the neurotoxic effect of Meth has been observed in terminals, but not in cell body regions (Brunswick et al. 1992). It has been proposed that not only DA, but also Glu levels have to be increased for Meth to produce neurotoxicity (Abekawa et al. 1994; Eisch et al. 1996), and that a repetitive regimen of Meth administration is required for producing long-term changes in basal ganglia function (Chapman et al. 2001; Wallace et al. 2001). Thus, we investigated the effect of repeated Meth doses on neurotransmitter release, evaluated under basal and K+-depolarizing conditions. It was found, as reported previously for
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Effect of methamphetamine on basal ganglia neurotransmission 651
Fig. 2 (a and b) Effect of repeated systemic Meth (3 · 15 mg/kg s.c.) or saline administration (last dose, 12 h before the microdialysis experiments were performed) on nigral (a) and striatal (b) DA levels measured under basal and K+-depolarization, induced by adding (during 40 min) 100 mM of KCl into the nigral or striatal perfusion medium, as indicated by the arrows. Levels are expressed as the percentage of the respective basal values (n ¼ 6 for each group). Black circles, dopamine levels following repeated methamphetamine treatment. Grey triangles, following saline. The 100% level is indicated by the grey-square-labelled curve, denoting a 10% variance, the averaged value observed when DA levels are measured with microdialysis. *p < 0.05, Meth versus saline group.
terminal regions (Nash and Yamamoto 1992; Abekawa et al. 1994), that the effect of K+-depolarization on DA release was diminished compared with that found in saline-treated rats, both in substantia nigra and neostriatum. This effect is perhaps due to a decrease in DA transport (Eisch et al. 1996; Fleckenstein et al. 1997), required for Meth to be taken up to elicit its effect on DA terminals (Marek et al. 1990). The most striking effect of repeated Meth was, however, on K+-evoked inhibitory (GABA) and excitatory (Glu, Asp) amino acid levels, which were increased. The effect of repeated Meth treatment on GABA release was even observed under basal conditions, as GABA levels were increased two- and 1.5-fold, in substantia nigra and neostriatum, respectively (cf. Table 4 vs. Table 3). It is suggested that this increase in GABA release is reflecting a compensatory effect to cope with a condition of increased neuronal activity produced by increased Glu and Asp levels. The effect of K+-depolarization on both Glu and Asp was augmented, indicating an increased Ca2+-inflow via N-methyl-D-aspartate (NMDA) receptor activation (see Dingledine et al. 1999), a mechanism of excitotoxicity according to the hypothesis originally proposed by Olney
Fig. 3 (a and b) Effect of repeated systemic Meth (3 · 15 mg/kg s.c.) or saline administration (last dose, 12 h before the microdialysis experiments were performed) on nigral (a) and striatal (b) GABA levels measured under basal and K+-depolarization, induced by adding (during 40 min) 100 mM of KCl into the nigral or striatal perfusion medium, as indicated by the arrows. Levels are expressed as the percentage of the respective basal values (n ¼ 6 for each group). Black circles, GABA levels following repeated methamphetamine treatment. Grey triangles, following saline. The 100% level is indicated by the grey-square-labelled curve, denoting a 20% variance, the averaged value observed when GABA levels are measured with microdialysis. *p < 0.05, Meth versus saline group.
(1969). An involvement of NMDA receptors has already been suggested by Sonsalla et al. (1989), as Meth toxicity is decreased by treatments with the non-competitive NMDA antagonist MK-801. Involvement of NMDA receptors is supported by the present observation that not only Glu, but also Asp levels were increased. Indeed, while Glu has high affinity for all types of Glu receptors, Asp is selective for the NMDA receptor subtype (Watkins and Evans 1981; Patneau and Mayer 1990). In a recent paper (Battaglia et al. 2002), it has been shown that not only NMDA, but also mGlu5 receptor stimulation may be necessary for Meth to produce neurotoxicity, suggesting a protective action by both NMDA and mGlu5 receptor antagonists. Moreover, it has been proposed that Meth toxicity is due to increased metabolism and free radical formation, enhanced by MAO inhibition (De Vito and Wagner 1989; Cadet et al. 1994, 1997), leading to an increase in cytosolic DA pools (Marek et al. 1990). In agreement, it has been reported that reserpine, but not a-methyl-p-tyrosine, enhances the longlasting DA depletion induced by Meth (Wagner et al. 1983), and that Meth produces a redistribution from vesicular to cytosolic DA pools (Sulzer et al. 1995; Frey et al. 1997;
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Fig. 4 (a and b) Effect of repeated systemic Meth (3 · 15 mg/kg s.c.) or saline administration (last dose, 12 h before the microdialysis experiments were performed) on nigral (a) and striatal (b) glutamate levels measured under basal and K+-depolarization, induced by adding (during 40 min) 100 mM of KCl into the nigral or striatal perfusion medium, as indicated by the arrows. Levels are expressed as the percentage of the respective basal values (n ¼ 6 for each group). Black circles, dopamine levels following repeated methamphetamine treatment. Grey triangles, following saline. The 100% level is indicated by the grey-square-labelled curve, denoting a 30% variance, the averaged value observed when glutamate levels are measured with microdialysis. *p < 0.05, Meth versus saline group.
Brown et al. 2000). This results in an increase of cytosolic DA metabolism, which has been suggested to be neurotoxic via formation of free-radicals (see Sulzer and Zecca 2000), and/or o-semiquinone-radical species from aminochrome (Segura-Aguilar et al. 2001). Under normal conditions DT-diaphorase, an enzyme present in DA neurones (Schultzberg et al. 1988), prevents the auto-oxidation and the redox cycling process produced during aminochrome metabolism (see Segura-Aguilar et al. 2001). Thus, it is tempting to hypothesize that Meth might not only inhibit MAO, but also DT-diaphorase, supporting the hypothesis of increased formation of DA-derived reactive species in Meth toxicity (Cadet et al. 1994; Culbells et al. 1994). In conclusion, the present study investigates the initial neurotransmission events elicited by acute or repeated Meth treatments, at concentrations earlier shown to produce neurotoxicity. The most prominent and immediate effect produced by Meth is an increase of DA release, which however, is followed by an increase of amino acid release when the drug is repeatedly administered. The release of both excitatory (Glu and Asp), and inhibitory (GABA) amino acids is increased following repeated Meth treatments. The
Fig. 5 (a and b) Effect of repeated systemic methamphetamine (3 · 15 mg/kg s.c.) or saline administration (last dose, 12 h before the microdialysis experiments were performed) on nigral (a) and striatal (b) aspartate levels measured under basal and K+-depolarization induced by adding (during 40 min) 100 mM of KCl into the nigral or striatal perfusion medium, as indicated by the arrows. Levels are expressed as the percentage of the respective basal values (n ¼ 6 for each group). Black circles, aspartate levels following repeated methamphetamine treatment. Grey triangles, following saline. The 100% level is indicated by the grey-square-labelled curve, indicating a 30% variance, the averaged variance observed when aspartate levels are measured with microdialysis. *p < 0.05, Meth versus saline group.
increased Glu and Asp release may lead to NMDA-receptor overstimulation, increase of Ca2+-conductance and a subsequent excitotoxic cascade. The increase of GABA levels probably implies a compensatory response to cope with an insult elicited by NMDA overstimulation. Acknowledgements This study was supported by grants from FONDECYT-Chile (grant n. 1000626), the Swedish Medical Research Council (8669, 10797, 2887, 3766, 3096), and the National Institute on Drug Abuse, Rockville, MD. We would like to acknowledge the excellent secretarial and technical assistance of Ms Rosa Ross and Mr Juan Santiban˜ez, Medical Faculty, University of Chile.
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