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Amantadine increases l -DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats
Brain Research 972 (2003) 229–234 www.elsevier.com / locate / brainres
Short communication
Amantadine increases L-DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats Akira Arai a , Kazuya Kannari b , *, Huo Shen a , Tetsuya Maeda b , Toshihiro Suda b , Muneo Matsunaga a a
Department of Neurological Science, Institute of Brain Science, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036 -8216, Japan b Third Department of Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036 -8216, Japan Accepted 25 February 2003
Abstract We investigated the effect of amantadine on L-DOPA-derived extracellular dopamine (DA) levels and aromatic L-amino acid decarboxylase (AADC) activity in the striatum of rats with nigrostriatal dopaminergic denervation by 6-hydroxydopamine (6-OHDA). Pretreatment with 30 mg / kg amantadine increased the cumulative amount of extracellular DA in the striatum of 6-OHDA-lesioned rats treated with 10 mg / kg benserazide and 50 mg / kg L-DOPA to 250% of that without amantadine (P,0.01). Under pretreatment with 10 mg / kg benserazide, AADC activity after 30 mg / kg amantadine administration was reduced to 43% of controls (P,0.01). Amantadineinduced increase in L-DOPA-derived extracellular DA provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. However, the effect of amantadine on L-DOPA-derived extracellular DA may not be caused by changes in AADC activity. 2003 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Catecholamines Keywords: Amantadine; L-DOPA; Dopamine; Striatum; Parkinson’s disease; Aromatic L-amino acid decarboxylase
Although amantadine can reduce parkinsonian symptoms in any stages of patients with Parkinson’s disease (PD) [4,14,19,23,30], the antiparkinsonian effect is milder than that of L-3,4-dihydroxyphenylalanine ( L-DOPA) [17,30]. However, recent clinical studies have shown that amantadine can reduce dyskinesias and motor fluctuations induced by long-term L-DOPA therapy in advanced PD patients [31]. This distinctive action of amantadine is likely to be due to its antagonistic activity on N-methyl-Daspartate (NMDA) type of glutamate receptors [12,26]. In addition, several studies provide evidence that the NMDA receptor antagonism by amantadine induces an increase in aromatic L-amino acid decarboxylase (AADC) activity, one of the important enzymes for L-DOPA metabolism [5,7,13]. It is generally accepted that the mechanism underlying the antiparkinsonian properties of amantadine mainly *Corresponding author. Tel.: 181-172-39-5142; fax: 181-172-395143. E-mail address: [email protected] (K. Kannari).
stems from an increase of dopamine (DA) release [21,27,28,33] and an inhibition of DA reuptake [7,13] in the striatum. However, most of the data concerning the effects of amantadine on dopaminergic neurotransmission were obtained from intact animals. Moreover, the effects of amantadine were detected only when very high doses of amantadine were given. Since there are substantial differences between intact and dopaminergic denervated striatum with respect to DA metabolism, it is hard to speculate the mechanism of the antiparkinsonian properties of amantadine only from the data obtained from intact animals. To determine whether amantadine induces changes in DA metabolism in the striatum with dopaminergic denervation, we performed in vivo microdialysis experiments on rats with unilateral dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA), the rat model of PD, and measured L-DOPA-derived extracellular DA levels in the striatum. In addition, to assess the effect of amantadine on AADC activity, we measured AADC activity in the
0006-8993 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0006-8993(03)02531-9
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striatum of 6-OHDA-lesioned rats with and without amantadine administration. Male Wistar rats (250–300 g, Clea, Japan) were housed in a temperature-controlled room (around 25 8C) with a 12-h day-and-night cycle with free access to food and water. The animals were anesthetized with pentobarbital (50 mg / kg i.p.) and mounted in a stereotaxic apparatus (David Kopf, USA) with incisor bar at 3.3 mm below horizontal. They were pretreated with desipramine (25 mg / kg i.p.) 30 min before 6-OHDA injection to prevent denervation of noradrenergic neurons. The dopaminergic neurotoxin 6-OHDA (8 mg in 4 ml saline with 0.01% ascorbic acid) was injected into the right medial forebrain bundle (AP 24.5 mm and L 11.2 mm from the bregma, DV 27.8 mm from the dura surface) [20] through the stainless steel needle (0.4 mm O.D.) over a period of 8 min. The needle was kept at the same position for more than 2 min to prevent leakage. Two weeks later, the rats were placed in a stainless steel bowl 36 cm in diameter and apomorphine (0.05 mg / kg in saline with 0.1% ascorbic acid) was injected s.c. to verify the dopaminergic denervation. Complete 3608 rotations to the left (contralateral to the lesioned side) were counted and only rats turning more than 20 times per 5 min (between 15 and 20 min after apomorphine injection) were included in the study. Our previous study demonstrated that rats that met the above criteria for apomorphine-induced rotations show more than 99% DA depletion in the striatal tissue [29]. Moreover, other previous study demonstrated that rats with extensive dopaminergic denervation exhibit no compensatory sprouting in the striatum [6]. Microdialysis study was performed between 3 and 4 weeks after 6-OHDA lesioning. A stainless steel guide cannula (Eicom, Japan) was stereotaxically implanted in the denervated side of the striatum 2 days before the perfusion study (AP 10.5 mm and L 13.0 mm from the bregma, DV 13.0 mm from the dura surface) [20]. One day before the perfusion study, a microdialysis probe with 3 mm active membrane was implanted in the right striatum through the guide cannula. The probe was continuously perfused with an artificial Ringer’s solution (Na 1 147 mM, K 1 4 mM, Ca 21 2.3 mM, Cl 2 155.6 mM) at a constant flow rate of 2 ml / min. Dialysate was collected for every 20 min (40 ml) and automatically injected onto the column for high-performance liquid chromatography (HPLC). The mobile phase consisted of 0.1 M sodium phosphate buffer (pH 6.0) containing 50 mg / l L-octanesulfonic acid, 500 mg / l Na 2 EDTA, and 20% methanol. Flow rate was set at 230 ml / min. DA was separated on a reverse phase analytical column (Eikompak CA-5 ODS; Eicom, Japan; particle size 5 mm, 2.13150 mm) and detected by electrochemical detection system (Eicom, Japan), consisting of an electrochemical cell with a graphite working electrode set at 1450 mV versus an Ag /AgCl reference electrode. Chromatogram peaks were analyzed by means of PowerChrome data recording system (AD Instruments,
Australia) with a computer (iMac, Apple computer, USA). Detection limit of the HPLC assay for DA was about 0.1 pg (0.5 fmol) per sample. After DA levels became stable (about 3 h from the beginning of perfusion), all rats were injected with benserazide (10 mg / kg) and L-DOPA (50 mg / kg, 30 min after benserazide injection). They were divided into three groups and amantadine 10 or 30 mg / kg, or vehicle was administered 15 min prior to L-DOPA injection. At the end of microdialysis experiment, rats were decapitated and the brains were cut along with the trace of the dialysis probe. We verified that all the placement of dialysis probes ended in the striatum. Apart from the microdialysis study, AADC activity in the striatum of other rats lesioned with 6-OHDA for 3–4 weeks were assessed as previously described with some modifications [16]. Three groups received a single administration of amantadine 10 or 30 mg / kg, or vehicle, respectively. Other three groups received a first treatment with vehicle or 10 mg / kg benserazide, and 15 min after that a second treatment with vehicle or 30 mg / kg amantadine. One hour after amantadine or vehicle administration, rats were killed by decapitation and the brains were rapidly removed. The sagittal brain section with 2 mm thickness containing the striatum, during 20.4 mm and 11.6 mm from the bregma [20], was dissected and placed on ice. The striatum was punched out from the section as a cylinder with 3.0 mm diameter. The tissue was homogenized in 1 ml of 0.25 M sucrose solution and the homogenates were centrifuged 12 0003g for 20 min at 4 8C. An incubation mixture in a total volume of 400 ml contained: sodium phosphate buffer, pH 7.2 (50 mM); pyridoxal-5phosphate (0.01 mM); pargyline (0.1 mM); 2-mercaptoethanol (1 mM); Na 2 EDTA (0.1 mM); ascorbic acid (0.17 mM); L-DOPA (0.1 mM); and 50 ml of the supernatant. Blank values were determined by substituting water for the L-DOPA substrate. The incubation was performed for 20 min at 37 8C. The reaction was stopped by adding 300 ml of 0.4 mM perchloric acid containing 10 ml of 0.04 mM isoproterenol as an internal standard. This mixture was centrifuged for 10 min at 12 0003g. The supernatant was filtered and stored at 280 8C for a later assay. The amount of DA formed in the supernatant was determined by HPLC. AADC activity was expressed as pmol DA / mg striatum per 20 min at 37 8C. The mobile phase consisted of 0.1 M acetate–citrate buffer (pH 3.9) containing 160 mg / l L-octanesulfonic acid, 10 mg / l Na 2 EDTA, and 17% methanol. Flow-rate was set at 220 ml / min. DA was separated on a reversed-phase analytical column (Eicompak MA-5 ODS; Eicom, Japan; particle size 5 mm, 2.13150 mm) and detected by electrochemical detection system (Eicom, Japan), consisting of an electrochemical cell with a graphite working electrode set at 1650 mV versus an Ag /AgCl reference electrode. Chromatogram peaks were analyzed by means of PowerChrom data recording system (AD Instruments,
A. Arai et al. / Brain Research 972 (2003) 229–234
Australia) with a computer (Power Macintosh 8100; Apple Computer, USA). 6-OHDA hydrobromide, desipramine hydrochloride, apomorphine hydrochloride, L-DOPA methyl ester hydrochloride, benserazide hydrochloride, and amantadine hydrochloride were purchased from Sigma (USA). Desipramine, L-DOPA, benserazide, and amantadine were dissolved in saline and were immediately administered intraperitoneally. Dialysate DA levels in each 20-min sample (40 ml) were expressed as mean6S.E.M. fmol / sample. The overall effect of treatments on L-DOPA-derived DA levels was determined by two-way analysis of variance (ANOVA) with repeated measures over time. Changes in the cumulative amounts of L-DOPA-derived DA induced by drug treatments were analyzed by one-way ANOVA followed by Tukey’s post-hoc test. Changes in AADC activity were assessed by one-way ANOVA followed by Tukey’s posthoc test. A single administration of L-DOPA to 6-OHDA-lesioned rats increased extracellular DA levels with the peak value of 286634 fmol / sample at 80 min after L-DOPA administration (n55) (Fig. 1a). Pretreatment with amantadine increased L-DOPA-derived extracellular DA levels, with the highest value of 388671 fmol / sample at 100 min in amantadine 10 mg / kg group (n55), and 6706115 fmol / sample at 80 min in amantadine 30 mg / kg group (n55). Two-way ANOVA with repeated measures revealed a significant effect of time (P,0.01) and treatment (P, 0.001) and a significant interaction of both (P,0.001). The cumulative amounts of extracellular DA derived from L-DOPA combined with amantadine during 300 min were 1.5960.15 pmol in vehicle group (n55), 2.5560.40 pmol in amantadine 10 mg / kg group (n55), and 3.986059 pmol in amantadine 30 mg / kg group (n55) (Fig. 1b). Thus, in amantadine-treated groups, the cumulative amounts of extracellular DA were increased to 160% (10 mg / kg) and 250% (30 mg / kg) as compared with vehicle-treated group. Among these, the increase induced by 30 mg / kg amantadine was statistically significant (P, 0.01, one-way ANOVA followed by Tukey’s post-hoc test). The AADC activity in vehicle treatment group was 0.7260.06 nmol DA / mg striatum / 20 min (n55) (Fig. 2). A single administration of 10 mg / kg amantadine showed a slight increase of AADC activity to 0.8260.07 nmol DA / mg striatum per 20 min (n55). However, this was not a statistically significant increase. 30 mg / kg amantadine significantly increased AADC activity to 1.0260.09 nmol DA / mg striatum per 20 min (n55, 143% of vehicle group, P,0.05). A single administration of 10 mg / kg benserazide decreased AADC activity to 0.3160.02 nmol DA / mg striatum per 20 min in the striatum of 6-OHDA-lesioned rats (n55, 43% of vehicle group, P,0.01) (Fig. 3). Under pretreatment with 10 mg / kg benserazide, 30 mg / kg aman-
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Fig. 1. (a) Effect of amantadine on L-DOPA-derived extracellular DA levels in the striatum of 6-OHDA-lesioned rats. Data are mean6S.E.M. (n55). Rats were injected i.p. with either vehicle (s), or 10 mg / kg (d) or 30 mg / kg (m) of amantadine. Benserazide, amantadine, and L-DOPA were injected i.p. at 220, 25 and 10 min, respectively. (b) The cumulative amounts of L-DOPA-derived extracellular DA in the 6-OHDAlesioned striatum during 300 min following L-DOPA administration. Data are mean6S.E.M. (n55). Ten and 30 mg / kg amantadine induced increases in the cumulative amount of L-DOPA-derived extracellular DA compared with the vehicle treatment group, among which 30 mg / kg showed a significant increase (one-way ANOVA followed by Tukey’s post-hoc test, **P,0.01).
tadine did not elevate AADC activity in the striatum of 6-OHDA-lesioned rats and it remained reduced to 0.3160.02 nmol DA / mg striatum per 20 min (n55, 43% of vehicle group, P,0.01). In the present study, we have shown that administration of 30 mg / kg amantadine, relatively smaller dose than in earlier experiments, increased L-DOPA-derived extracellular DA levels in the striatum of 6-OHDA-lesioned rats. Although there were several studies indicating the effect of amantadine on dopaminergic neurotransmission in intact animals [5,7,13,19,23,28], this is the first experimental study that demonstrated the effect of amantadine on the metabolism of exogenous L-DOPA in rats with dopaminergic denervation. Clinical observations have revealed the ability of amantadine to potentiate antiparkinsonian actions of L-DOPA [4,22,23,25,30]. Similarly, previous studies using DA-de-
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Fig. 2. Effect of single administration of amantadine on AADC activity in the striatum of 6-OHDA-lesioned rats. One hour after amantadine administration, rats were killed and the striatum was dissected. The homogenized striatum was incubated with L-DOPA at 37 8C for 20 min. AADC activity was expressed as the amount of DA formed (pmol / mg striatum per 20 min at 37 8C). Data are mean6S.E.M. (n55). Administration of both 10 and 30 mg / kg amantadine increased AADC activity compared with vehicle treatment group, among which 30 mg / kg showed a significant increase (one-way ANOVA followed by Tukey’s post-hoc test, *P,0.05).
pleted animals have documented synergistic effects of combining amantadine with L-DOPA [8,9]. As shown in the present study, amantadine distinctly increased L-DOPA-
Fig. 3. Effect of amantadine on AADC activity in the striatum of 6-OHDA-lesioned rats under pretreatment with 10 mg / kg benserazide. Benserazide was injected 10 min prior to amantadine injection. Method for the measurement of AADC activity was the same as described in Fig. 2. Data are mean6S.E.M. (n55). Treatment with benserazide alone significantly decreased AADC activity. Under pretreatment with benserazide, AADC activity remained reduced to a significantly small value even after 30 mg / kg amantadine (one-way ANOVA followed by Tukey’s post-hoc test, **P,0.01).
derived DA in the denervated striatum. Elevation of LDOPA-derived extracellular DA could account for the synergistic antiparkinsonian effect of amantadine and LDOPA and it further provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. Interestingly, recent clinical studies have shown that amantadine restores L-DOPA effect in patients with LDOPA-tolerance (motor fluctuations) [22,24]. In line with these observations, amantadine prolonged the L-DOPAinduced contralateral turning in 6-OHDA-lesioned rats with repetitive L-DOPA treatment [11]. Furthermore, amantadine has been shown to reduce L-DOPA-induced dyskinesias in MPTP-treated monkeys and in PD patients [2,31]. Combined with these findings, amantadine could not only be used in early stages of PD patients but also be used in various stages of PD. Especially it would be beneficial in combination with L-DOPA in advanced PD patients suffering from motor fluctuations. It is believed that the major mechanisms of amantadine’s antiparkinsonian activity are the enhancement of DA release and inhibition of DA reuptake [8,15,21,28,33]. However, it is disputable whether these actions of amantadine are the cause of an increase in L-DOPA-derived extracellular DA in the denervated striatum, because the metabolism of exogenous L-DOPA in the denervated striatum is substantially different from that in the intact striatum. In the intact striatum, DA formed from exogenously administered L-DOPA exists in the dopaminergic nerve terminals in the same manner as endogenous DA. By contrast, in the lesioned striatum where dopaminergic neurons are almost lost, dopaminergic neurons can no longer serve as the main site of exogenous L-DOPA metabolism. The present microdialysis experiments were performed on rats with almost complete dopaminergic denervation. In these conditions, dopaminergic nerve terminals cannot be regarded as the site of amantadine activity. We did not examine the effect of a single amantadine administration on extracellular DA levels, because without L-DOPA, there would be no endogenous source for DA formation under dopaminergic denervation and changes in extracellular DA could not be detected. We have demonstrated previously that DA derived from exogenously administered L-DOPA is mainly stored in and released from serotonergic nerve terminals when dopaminergic neurons are denervated [29]. Thus, in the denervated striatum, amantadine might affect L-DOPA metabolism and / or release mechanisms of DA occurring in serotonergic nerve terminals, resulting in increases in LDOPA-derived extracellular DA. One of the intriguing hypotheses on the effect of amantadine is that an increase in AADC activity by amantadine results in an increase in L-DOPA-derived DA. AADC exists in serotonergic neurons as well as in dopaminergic neurons [1]. Indeed, we have demonstrated in the present study that single administration of amantadine to 6-OHDA-lesioned rats increased AADC activity
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in the denervated striatum, which is compatible with previous studies showing that amantadine increased AADC activity in the intact striatum [7,13]. However, we have also shown that AADC activity in the denervated striatum was reduced when benserazide was administered prior to amantadine. We have our own data that benserazide, originally considered a peripheral AADC inhibitor, reduces AADC activity in the central nerve system as well (unpublished data). It is important that we found amantadine-induced increase in L-DOPA-derived extracellular DA in spite of the fact that benserazide was always used before L-DOPA administration in the present microdialysis study. These results suggest that amantadine enhances L-DOPA-derived extracellular DA by a mechanism not related to changes in AADC activity. Another possible mechanism for amantadine-induced increase of extracellular DA in the dopaminergic denervated striatum is that amantadine might inhibit DA reuptake by affecting transporters for serotonin and / or noradrenaline (NA). For instance, it has been reported that amantadine inhibits uptake of both DA and NA at central [8] and peripheral nerve terminals [32]. Given that DA has high affinity for NA transporter [10,18], it is possible that amantadine might increase extracellular DA by inhibiting DA reuptake by influencing NA transporter functions. Indeed former anatomical studies revealed that there exist few NA nerve terminals in the striatum [3], but changes in the density of NA nerve terminals in the striatum with dopaminergic denervation remains to be determined. Although serotonergic hyperinnervation has been observed in the DA-depleted striatum [34], whether this phenomenon actually occurs is still controversial. More extensive studies should be made to elucidate the effects of amantadine on catecholamine transporters. In the present study, we used rats with almost complete DA depletion. As most PD patients have partial DA depletion, our present model does not accurately reproduce the clinical condition. Applying amantadine to partial lesioned rats might give much more clinical suggestions to amantadine therapy in PD. In conclusion, we have demonstrated that amantadine increases L-DOPA-derived extracellular DA in the striatum with dopaminergic denervation. We propose that amantadine would be beneficial when administered in combination with L-DOPA and it could be administered to patients with various stages of PD.
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Short communication
Amantadine increases L-DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats Akira Arai a , Kazuya Kannari b , *, Huo Shen a , Tetsuya Maeda b , Toshihiro Suda b , Muneo Matsunaga a a
Department of Neurological Science, Institute of Brain Science, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036 -8216, Japan b Third Department of Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036 -8216, Japan Accepted 25 February 2003
Abstract We investigated the effect of amantadine on L-DOPA-derived extracellular dopamine (DA) levels and aromatic L-amino acid decarboxylase (AADC) activity in the striatum of rats with nigrostriatal dopaminergic denervation by 6-hydroxydopamine (6-OHDA). Pretreatment with 30 mg / kg amantadine increased the cumulative amount of extracellular DA in the striatum of 6-OHDA-lesioned rats treated with 10 mg / kg benserazide and 50 mg / kg L-DOPA to 250% of that without amantadine (P,0.01). Under pretreatment with 10 mg / kg benserazide, AADC activity after 30 mg / kg amantadine administration was reduced to 43% of controls (P,0.01). Amantadineinduced increase in L-DOPA-derived extracellular DA provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. However, the effect of amantadine on L-DOPA-derived extracellular DA may not be caused by changes in AADC activity. 2003 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Catecholamines Keywords: Amantadine; L-DOPA; Dopamine; Striatum; Parkinson’s disease; Aromatic L-amino acid decarboxylase
Although amantadine can reduce parkinsonian symptoms in any stages of patients with Parkinson’s disease (PD) [4,14,19,23,30], the antiparkinsonian effect is milder than that of L-3,4-dihydroxyphenylalanine ( L-DOPA) [17,30]. However, recent clinical studies have shown that amantadine can reduce dyskinesias and motor fluctuations induced by long-term L-DOPA therapy in advanced PD patients [31]. This distinctive action of amantadine is likely to be due to its antagonistic activity on N-methyl-Daspartate (NMDA) type of glutamate receptors [12,26]. In addition, several studies provide evidence that the NMDA receptor antagonism by amantadine induces an increase in aromatic L-amino acid decarboxylase (AADC) activity, one of the important enzymes for L-DOPA metabolism [5,7,13]. It is generally accepted that the mechanism underlying the antiparkinsonian properties of amantadine mainly *Corresponding author. Tel.: 181-172-39-5142; fax: 181-172-395143. E-mail address: [email protected] (K. Kannari).
stems from an increase of dopamine (DA) release [21,27,28,33] and an inhibition of DA reuptake [7,13] in the striatum. However, most of the data concerning the effects of amantadine on dopaminergic neurotransmission were obtained from intact animals. Moreover, the effects of amantadine were detected only when very high doses of amantadine were given. Since there are substantial differences between intact and dopaminergic denervated striatum with respect to DA metabolism, it is hard to speculate the mechanism of the antiparkinsonian properties of amantadine only from the data obtained from intact animals. To determine whether amantadine induces changes in DA metabolism in the striatum with dopaminergic denervation, we performed in vivo microdialysis experiments on rats with unilateral dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA), the rat model of PD, and measured L-DOPA-derived extracellular DA levels in the striatum. In addition, to assess the effect of amantadine on AADC activity, we measured AADC activity in the
0006-8993 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0006-8993(03)02531-9
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striatum of 6-OHDA-lesioned rats with and without amantadine administration. Male Wistar rats (250–300 g, Clea, Japan) were housed in a temperature-controlled room (around 25 8C) with a 12-h day-and-night cycle with free access to food and water. The animals were anesthetized with pentobarbital (50 mg / kg i.p.) and mounted in a stereotaxic apparatus (David Kopf, USA) with incisor bar at 3.3 mm below horizontal. They were pretreated with desipramine (25 mg / kg i.p.) 30 min before 6-OHDA injection to prevent denervation of noradrenergic neurons. The dopaminergic neurotoxin 6-OHDA (8 mg in 4 ml saline with 0.01% ascorbic acid) was injected into the right medial forebrain bundle (AP 24.5 mm and L 11.2 mm from the bregma, DV 27.8 mm from the dura surface) [20] through the stainless steel needle (0.4 mm O.D.) over a period of 8 min. The needle was kept at the same position for more than 2 min to prevent leakage. Two weeks later, the rats were placed in a stainless steel bowl 36 cm in diameter and apomorphine (0.05 mg / kg in saline with 0.1% ascorbic acid) was injected s.c. to verify the dopaminergic denervation. Complete 3608 rotations to the left (contralateral to the lesioned side) were counted and only rats turning more than 20 times per 5 min (between 15 and 20 min after apomorphine injection) were included in the study. Our previous study demonstrated that rats that met the above criteria for apomorphine-induced rotations show more than 99% DA depletion in the striatal tissue [29]. Moreover, other previous study demonstrated that rats with extensive dopaminergic denervation exhibit no compensatory sprouting in the striatum [6]. Microdialysis study was performed between 3 and 4 weeks after 6-OHDA lesioning. A stainless steel guide cannula (Eicom, Japan) was stereotaxically implanted in the denervated side of the striatum 2 days before the perfusion study (AP 10.5 mm and L 13.0 mm from the bregma, DV 13.0 mm from the dura surface) [20]. One day before the perfusion study, a microdialysis probe with 3 mm active membrane was implanted in the right striatum through the guide cannula. The probe was continuously perfused with an artificial Ringer’s solution (Na 1 147 mM, K 1 4 mM, Ca 21 2.3 mM, Cl 2 155.6 mM) at a constant flow rate of 2 ml / min. Dialysate was collected for every 20 min (40 ml) and automatically injected onto the column for high-performance liquid chromatography (HPLC). The mobile phase consisted of 0.1 M sodium phosphate buffer (pH 6.0) containing 50 mg / l L-octanesulfonic acid, 500 mg / l Na 2 EDTA, and 20% methanol. Flow rate was set at 230 ml / min. DA was separated on a reverse phase analytical column (Eikompak CA-5 ODS; Eicom, Japan; particle size 5 mm, 2.13150 mm) and detected by electrochemical detection system (Eicom, Japan), consisting of an electrochemical cell with a graphite working electrode set at 1450 mV versus an Ag /AgCl reference electrode. Chromatogram peaks were analyzed by means of PowerChrome data recording system (AD Instruments,
Australia) with a computer (iMac, Apple computer, USA). Detection limit of the HPLC assay for DA was about 0.1 pg (0.5 fmol) per sample. After DA levels became stable (about 3 h from the beginning of perfusion), all rats were injected with benserazide (10 mg / kg) and L-DOPA (50 mg / kg, 30 min after benserazide injection). They were divided into three groups and amantadine 10 or 30 mg / kg, or vehicle was administered 15 min prior to L-DOPA injection. At the end of microdialysis experiment, rats were decapitated and the brains were cut along with the trace of the dialysis probe. We verified that all the placement of dialysis probes ended in the striatum. Apart from the microdialysis study, AADC activity in the striatum of other rats lesioned with 6-OHDA for 3–4 weeks were assessed as previously described with some modifications [16]. Three groups received a single administration of amantadine 10 or 30 mg / kg, or vehicle, respectively. Other three groups received a first treatment with vehicle or 10 mg / kg benserazide, and 15 min after that a second treatment with vehicle or 30 mg / kg amantadine. One hour after amantadine or vehicle administration, rats were killed by decapitation and the brains were rapidly removed. The sagittal brain section with 2 mm thickness containing the striatum, during 20.4 mm and 11.6 mm from the bregma [20], was dissected and placed on ice. The striatum was punched out from the section as a cylinder with 3.0 mm diameter. The tissue was homogenized in 1 ml of 0.25 M sucrose solution and the homogenates were centrifuged 12 0003g for 20 min at 4 8C. An incubation mixture in a total volume of 400 ml contained: sodium phosphate buffer, pH 7.2 (50 mM); pyridoxal-5phosphate (0.01 mM); pargyline (0.1 mM); 2-mercaptoethanol (1 mM); Na 2 EDTA (0.1 mM); ascorbic acid (0.17 mM); L-DOPA (0.1 mM); and 50 ml of the supernatant. Blank values were determined by substituting water for the L-DOPA substrate. The incubation was performed for 20 min at 37 8C. The reaction was stopped by adding 300 ml of 0.4 mM perchloric acid containing 10 ml of 0.04 mM isoproterenol as an internal standard. This mixture was centrifuged for 10 min at 12 0003g. The supernatant was filtered and stored at 280 8C for a later assay. The amount of DA formed in the supernatant was determined by HPLC. AADC activity was expressed as pmol DA / mg striatum per 20 min at 37 8C. The mobile phase consisted of 0.1 M acetate–citrate buffer (pH 3.9) containing 160 mg / l L-octanesulfonic acid, 10 mg / l Na 2 EDTA, and 17% methanol. Flow-rate was set at 220 ml / min. DA was separated on a reversed-phase analytical column (Eicompak MA-5 ODS; Eicom, Japan; particle size 5 mm, 2.13150 mm) and detected by electrochemical detection system (Eicom, Japan), consisting of an electrochemical cell with a graphite working electrode set at 1650 mV versus an Ag /AgCl reference electrode. Chromatogram peaks were analyzed by means of PowerChrom data recording system (AD Instruments,
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Australia) with a computer (Power Macintosh 8100; Apple Computer, USA). 6-OHDA hydrobromide, desipramine hydrochloride, apomorphine hydrochloride, L-DOPA methyl ester hydrochloride, benserazide hydrochloride, and amantadine hydrochloride were purchased from Sigma (USA). Desipramine, L-DOPA, benserazide, and amantadine were dissolved in saline and were immediately administered intraperitoneally. Dialysate DA levels in each 20-min sample (40 ml) were expressed as mean6S.E.M. fmol / sample. The overall effect of treatments on L-DOPA-derived DA levels was determined by two-way analysis of variance (ANOVA) with repeated measures over time. Changes in the cumulative amounts of L-DOPA-derived DA induced by drug treatments were analyzed by one-way ANOVA followed by Tukey’s post-hoc test. Changes in AADC activity were assessed by one-way ANOVA followed by Tukey’s posthoc test. A single administration of L-DOPA to 6-OHDA-lesioned rats increased extracellular DA levels with the peak value of 286634 fmol / sample at 80 min after L-DOPA administration (n55) (Fig. 1a). Pretreatment with amantadine increased L-DOPA-derived extracellular DA levels, with the highest value of 388671 fmol / sample at 100 min in amantadine 10 mg / kg group (n55), and 6706115 fmol / sample at 80 min in amantadine 30 mg / kg group (n55). Two-way ANOVA with repeated measures revealed a significant effect of time (P,0.01) and treatment (P, 0.001) and a significant interaction of both (P,0.001). The cumulative amounts of extracellular DA derived from L-DOPA combined with amantadine during 300 min were 1.5960.15 pmol in vehicle group (n55), 2.5560.40 pmol in amantadine 10 mg / kg group (n55), and 3.986059 pmol in amantadine 30 mg / kg group (n55) (Fig. 1b). Thus, in amantadine-treated groups, the cumulative amounts of extracellular DA were increased to 160% (10 mg / kg) and 250% (30 mg / kg) as compared with vehicle-treated group. Among these, the increase induced by 30 mg / kg amantadine was statistically significant (P, 0.01, one-way ANOVA followed by Tukey’s post-hoc test). The AADC activity in vehicle treatment group was 0.7260.06 nmol DA / mg striatum / 20 min (n55) (Fig. 2). A single administration of 10 mg / kg amantadine showed a slight increase of AADC activity to 0.8260.07 nmol DA / mg striatum per 20 min (n55). However, this was not a statistically significant increase. 30 mg / kg amantadine significantly increased AADC activity to 1.0260.09 nmol DA / mg striatum per 20 min (n55, 143% of vehicle group, P,0.05). A single administration of 10 mg / kg benserazide decreased AADC activity to 0.3160.02 nmol DA / mg striatum per 20 min in the striatum of 6-OHDA-lesioned rats (n55, 43% of vehicle group, P,0.01) (Fig. 3). Under pretreatment with 10 mg / kg benserazide, 30 mg / kg aman-
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Fig. 1. (a) Effect of amantadine on L-DOPA-derived extracellular DA levels in the striatum of 6-OHDA-lesioned rats. Data are mean6S.E.M. (n55). Rats were injected i.p. with either vehicle (s), or 10 mg / kg (d) or 30 mg / kg (m) of amantadine. Benserazide, amantadine, and L-DOPA were injected i.p. at 220, 25 and 10 min, respectively. (b) The cumulative amounts of L-DOPA-derived extracellular DA in the 6-OHDAlesioned striatum during 300 min following L-DOPA administration. Data are mean6S.E.M. (n55). Ten and 30 mg / kg amantadine induced increases in the cumulative amount of L-DOPA-derived extracellular DA compared with the vehicle treatment group, among which 30 mg / kg showed a significant increase (one-way ANOVA followed by Tukey’s post-hoc test, **P,0.01).
tadine did not elevate AADC activity in the striatum of 6-OHDA-lesioned rats and it remained reduced to 0.3160.02 nmol DA / mg striatum per 20 min (n55, 43% of vehicle group, P,0.01). In the present study, we have shown that administration of 30 mg / kg amantadine, relatively smaller dose than in earlier experiments, increased L-DOPA-derived extracellular DA levels in the striatum of 6-OHDA-lesioned rats. Although there were several studies indicating the effect of amantadine on dopaminergic neurotransmission in intact animals [5,7,13,19,23,28], this is the first experimental study that demonstrated the effect of amantadine on the metabolism of exogenous L-DOPA in rats with dopaminergic denervation. Clinical observations have revealed the ability of amantadine to potentiate antiparkinsonian actions of L-DOPA [4,22,23,25,30]. Similarly, previous studies using DA-de-
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Fig. 2. Effect of single administration of amantadine on AADC activity in the striatum of 6-OHDA-lesioned rats. One hour after amantadine administration, rats were killed and the striatum was dissected. The homogenized striatum was incubated with L-DOPA at 37 8C for 20 min. AADC activity was expressed as the amount of DA formed (pmol / mg striatum per 20 min at 37 8C). Data are mean6S.E.M. (n55). Administration of both 10 and 30 mg / kg amantadine increased AADC activity compared with vehicle treatment group, among which 30 mg / kg showed a significant increase (one-way ANOVA followed by Tukey’s post-hoc test, *P,0.05).
pleted animals have documented synergistic effects of combining amantadine with L-DOPA [8,9]. As shown in the present study, amantadine distinctly increased L-DOPA-
Fig. 3. Effect of amantadine on AADC activity in the striatum of 6-OHDA-lesioned rats under pretreatment with 10 mg / kg benserazide. Benserazide was injected 10 min prior to amantadine injection. Method for the measurement of AADC activity was the same as described in Fig. 2. Data are mean6S.E.M. (n55). Treatment with benserazide alone significantly decreased AADC activity. Under pretreatment with benserazide, AADC activity remained reduced to a significantly small value even after 30 mg / kg amantadine (one-way ANOVA followed by Tukey’s post-hoc test, **P,0.01).
derived DA in the denervated striatum. Elevation of LDOPA-derived extracellular DA could account for the synergistic antiparkinsonian effect of amantadine and LDOPA and it further provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. Interestingly, recent clinical studies have shown that amantadine restores L-DOPA effect in patients with LDOPA-tolerance (motor fluctuations) [22,24]. In line with these observations, amantadine prolonged the L-DOPAinduced contralateral turning in 6-OHDA-lesioned rats with repetitive L-DOPA treatment [11]. Furthermore, amantadine has been shown to reduce L-DOPA-induced dyskinesias in MPTP-treated monkeys and in PD patients [2,31]. Combined with these findings, amantadine could not only be used in early stages of PD patients but also be used in various stages of PD. Especially it would be beneficial in combination with L-DOPA in advanced PD patients suffering from motor fluctuations. It is believed that the major mechanisms of amantadine’s antiparkinsonian activity are the enhancement of DA release and inhibition of DA reuptake [8,15,21,28,33]. However, it is disputable whether these actions of amantadine are the cause of an increase in L-DOPA-derived extracellular DA in the denervated striatum, because the metabolism of exogenous L-DOPA in the denervated striatum is substantially different from that in the intact striatum. In the intact striatum, DA formed from exogenously administered L-DOPA exists in the dopaminergic nerve terminals in the same manner as endogenous DA. By contrast, in the lesioned striatum where dopaminergic neurons are almost lost, dopaminergic neurons can no longer serve as the main site of exogenous L-DOPA metabolism. The present microdialysis experiments were performed on rats with almost complete dopaminergic denervation. In these conditions, dopaminergic nerve terminals cannot be regarded as the site of amantadine activity. We did not examine the effect of a single amantadine administration on extracellular DA levels, because without L-DOPA, there would be no endogenous source for DA formation under dopaminergic denervation and changes in extracellular DA could not be detected. We have demonstrated previously that DA derived from exogenously administered L-DOPA is mainly stored in and released from serotonergic nerve terminals when dopaminergic neurons are denervated [29]. Thus, in the denervated striatum, amantadine might affect L-DOPA metabolism and / or release mechanisms of DA occurring in serotonergic nerve terminals, resulting in increases in LDOPA-derived extracellular DA. One of the intriguing hypotheses on the effect of amantadine is that an increase in AADC activity by amantadine results in an increase in L-DOPA-derived DA. AADC exists in serotonergic neurons as well as in dopaminergic neurons [1]. Indeed, we have demonstrated in the present study that single administration of amantadine to 6-OHDA-lesioned rats increased AADC activity
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in the denervated striatum, which is compatible with previous studies showing that amantadine increased AADC activity in the intact striatum [7,13]. However, we have also shown that AADC activity in the denervated striatum was reduced when benserazide was administered prior to amantadine. We have our own data that benserazide, originally considered a peripheral AADC inhibitor, reduces AADC activity in the central nerve system as well (unpublished data). It is important that we found amantadine-induced increase in L-DOPA-derived extracellular DA in spite of the fact that benserazide was always used before L-DOPA administration in the present microdialysis study. These results suggest that amantadine enhances L-DOPA-derived extracellular DA by a mechanism not related to changes in AADC activity. Another possible mechanism for amantadine-induced increase of extracellular DA in the dopaminergic denervated striatum is that amantadine might inhibit DA reuptake by affecting transporters for serotonin and / or noradrenaline (NA). For instance, it has been reported that amantadine inhibits uptake of both DA and NA at central [8] and peripheral nerve terminals [32]. Given that DA has high affinity for NA transporter [10,18], it is possible that amantadine might increase extracellular DA by inhibiting DA reuptake by influencing NA transporter functions. Indeed former anatomical studies revealed that there exist few NA nerve terminals in the striatum [3], but changes in the density of NA nerve terminals in the striatum with dopaminergic denervation remains to be determined. Although serotonergic hyperinnervation has been observed in the DA-depleted striatum [34], whether this phenomenon actually occurs is still controversial. More extensive studies should be made to elucidate the effects of amantadine on catecholamine transporters. In the present study, we used rats with almost complete DA depletion. As most PD patients have partial DA depletion, our present model does not accurately reproduce the clinical condition. Applying amantadine to partial lesioned rats might give much more clinical suggestions to amantadine therapy in PD. In conclusion, we have demonstrated that amantadine increases L-DOPA-derived extracellular DA in the striatum with dopaminergic denervation. We propose that amantadine would be beneficial when administered in combination with L-DOPA and it could be administered to patients with various stages of PD.
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