Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum

Brain Research Bulletin 67 (2005) 176–181

Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum Yushi U. Adachi a,b,∗ , Shigeyuki Yamada b , Maiko Satomoto c , Hideyuki Higuchi d , Kazuhiko Watanabe e , Tomiei Kazama b a

Medical Clinic of Hamamatsu Base, Japan Air Self Defense Force, Nishiyama-cho-1, Hamamatsu City, Shizuoka 432-8551, Japan b Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan c Gifu Hospital, Japan Air Self Defense Force, Kagamihara, Japan d Department of Anesthesiology, Tokyo Women’s Medical University, Tokyo, Japan e Department of Anesthesia, Shiki Citizen Hospital, Shiki, Japan Received 1 June 2005; received in revised form 7 June 2005; accepted 7 June 2005 Available online 27 July 2005

Abstract The effect of isoflurane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) modulated by pargyline, monoamine oxidase inhibitor, was studied using in vivo microdialysis techniques. A microdialysis probe was implanted into the right striatum of male SD rats. Each rat (n = 5–6) was given saline or the same volume of 30 or 75 mg kg−1 pargyline intraperitoneally with or without 1 h isoflurane anesthesia (1 or 3%). Isoflurane anesthesia increased the extracellular concentration of DA in high dose (3%) and increased the metabolite concentrations in a dose-dependent manner. Pargyline administration increased the extracellular concentration of DA and 3-MT, and decreased that of other metabolites. After 30 mg kg−1 pargyline treatment, 1% isoflurane-induced DA release and increasing of 3-MT were preserved, whereas high dose isoflurane (3%) decreased the concentration of metabolites (DOPAC and HVA), despite of the increase by low dose isoflurane (DOPAC). When 75 mg kg−1 pargyline was administered, isoflurane anesthesia decreased the concentration of DA and DOPAC. The isoflurane-induced 3-MT increase was preserved in all experiments. Our results suggest that isoflurane anesthesia induced biphasic effect on DA regulation probably by the potentiation of DA release and the inhibition of DA synthesis. Isoflurane might modulate DA homeostasis presynaptically. © 2005 Elsevier Inc. All rights reserved. Keywords: Microdialysis; Isoflurane anesthesia; Dopamine; Monoamine oxidase inhibitor; Pargyline

1. Introduction Many investigations demonstrated the neuroprotective effect of volatile anesthetics as a result of antagonizing release of neurotransmitters in central nervous system after cytotoxic insult [3,9,23,26]. In the striatum, exaggerated dopamine (DA) release and subsequent DA metabolism induces neurotoxic effect, including neural death. Previously, we reported that halothane anesthesia itself increased the extracellular concentration of DA and its metabolites using in vivo micro∗ Corresponding author. Tel.: +81 53 472 1111x3288; fax: +81 53 472 1111x3789. E-mail address: [email protected] (Y.U. Adachi).

0361-9230/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2005.06.020

dialysis technique in the rat striatum [2]. Opacka-Juffry et al. [16] demonstrated that nomifensine-induced increase in extracellular striatal DA is enhanced by isoflurane anesthesia. In an in vitro model of cerebral ischemia, the antagonizing effect on increasing DA concentration with volatile anesthetics was unclear [24], whereas the ability of the anesthetics to reduce neuronal damage is well known [23,26]. Although the exact mechanism of anesthesia is still unclear, it is possible that volatile anesthetics modulate DA homeostasis including release and metabolism [25]. We hypothesized that the effect of anesthetics on DA release and metabolism might be dependent on the modification of DA regulation before induction of anesthesia. In another study, halothane attenuated haloperidol- and enhanced clozapine-

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induced DA release in the rat striatum [1]. The biphasic effect of halothane might be explained by the non-synaptic neural transmission of striatal interneurons. However, there are scarce investigation for the effect of volatile anesthesia on DA release and metabolism modified by pharmacological treatments in advance to the inhalation of anesthesia. Ischemia-induced DA release has been extensively studied [23] and the certain neuroprotective effect of volatile anesthetics was reported [25]. In the current investigation, we studied the effect of isoflurane anesthesia on pargyline (monoamine oxidase inhibitor)induced DA increase using in vivo microdialysis techniques in the rat striatum.

2. Materials and methods 2.1. Animals Male Sprague–Dawley rats, weighing 280–320 g, were used in the experiments (CLEA Japan, Tokyo, Japan). The animals were housed in an animal room at 20–22 ◦ C and illuminated with a 12-h light:12-h dark cycle (light from 07:00 to 19:00 h). All animals had free access to food and drinking water. The experiments were approved by the Committee for Animal Research at the college. 2.2. Microdialysis Rats were anesthetized with sevoflurane and ventilated through an oro-tracheal tube. A unilateral guide cannula was implanted just above the striatum (AP +0.6 mm, ML +3.0 mm, DV −3.8 mm) following the atlas of Paxinos and Watson [18]. The rats were allowed to recover for at least 2 days before the experiment. After each experiment, the brain of rat was removed and the placement of the microdialysis probe was identified histologically. Microdialysis probes were obtained from EICOM (Kyoto Japan) (o.d. 0.22 mm, membrane length 3 mm, polycarbonate tubing, cutoff molecular weight 50,000). The probe was inserted carefully into the striatum through a guide cannula and fixed to the cannula with a screw at about 7:00 a.m. on the day of experimentation. The rat was placed in a clear open Plexiglas box (15 L capacity, 27 cm diameter × 26 cm high), and the probe was continuously perfused with modified Ringer solution (145.4 mEq L−1 Na+ , 2.8 mEq L−1 K+ , 2.3 mEq L−1 Ca2+ , 150.5 mEq L−1 Cl− ) at a flow rate of 2 ␮L min−1 using a micro-infusion pump (ESP-64, EICOM, Kyoto, Japan) to determine the baseline concentrations of DA and its metabolites. Samples were collected every 20 min and directly injected into an online analytical system with an auto-injector (EAS-20, EICOM), as described elsewhere [1,2]. The concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) in each dialysate (40 ␮L/20 min) were determined by HPLC with an electrochemical detector (ECD-300,

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EICOM). These compounds were separated by reverse-phase ion-pair chromatography with a 5 ␮m C-18 column (MA5ODS, 150 mm × 2.1 mm, EICOM) using an isocratic mobile phase (0.1 M sodium acetate, 0.1 M citric acid, 1.4 mM sodium 1-octanesulfonate, 5 ␮M EDTA-Na2 and 13–14% methanol, pH 3.9), delivered at a flow rate of 230 ␮L min−1 by a high-pressure pump (EP-300, EICOM). The compounds were quantified by electrochemical detection using a glassy carbon working electrode set at 650 mV against a Ag/AgCl reference electrode. The detection limit for each of the compounds was roughly 0.1 pg per sample. DA and its metabolites reached stable baseline concentrations within about 4.5 h after implantation of the microdialysis probe. Therefore, at least six dialysate samples were collected before starting the pharmacological experiment. The mean value obtained from the last three samples was used as the baseline concentration. The time at which the pharmacological manipulation started is hereafter called ‘fraction number 1’ (Fr. 1). 2.3. Experiments Each rat (n = 5–6) was intraperitoneally given saline or the same volume of 30 or 75 mg kg−1 pargyline preceding 3 h before inhalation. The rat was anesthetized in a semi-closed Plexiglas box, into which 5% isoflurane was initially introduced at a rate of 3 L min−1 for about 5 min until a steady state was achieved. Subsequently, 1 or 3% isoflurane was applied at a rate of 2 L min−1 , using air (23% oxygen) as the carrier. The rectal temperature of the rat was monitored and maintained at 37 ◦ C with an electrical heating pad. The concentrations of isoflurane and oxygen in the box were monitored using an infrared anesthetic gas analyzer (Capnomac Ultima, Datex, Helsinki, Finland) during each anesthesia. Immediately after the 1 h anesthesia, the gas in the box was exchanged with room air by forced ventilation. 2.4. Drugs Isoflurane was obtained from Abboot Japan Co. Ltd. (Tokyo, Japan). Pargyline were purchased from Sigma (Sigma Chemical Co., St. Louis, MO, USA). 2.5. Statistical analysis Data were analyzed by one-way analysis of variance with drugs as the between subjects variable for each fraction. For significant (p < 0.05) drug interactions, a subsequent Newman–Keuls post hoc multiple comparison test was performed (NCSS 2000, Number Cruncher Statistical Systems, Kaysville, UT, USA). 3. Results Isoflurane anesthesia increased the extracellular concentration of DA in high dose (3%) and increased the metabolite

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Fig. 1. Effect of isoflurane anesthesia on the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)). In this and following figures, the ordinate of each graph shows the concentration of DA or its metabolites expressed as the percentage of the baseline concentration, which is the mean of three consecutive values immediately before the inhalation. * p < 0.05 against control value at each fraction. Each point is the mean (SEM) (n = 5–6 per each group). Dialysate fractions were obtained every 20 min. Isoflurane anesthesia increased the extracellular concentration of DA at high dose, and significantly increased those of metabolites (3-MT, DOPAC and HVA) in a concentration-dependent manner compared to control.

concentrations in a dose-dependent manner (Fig. 1). Pargyline administration increased the extracellular concentration of DA and 3-MT, and decreased that of other metabolites (Table 1). After 30 mg kg−1 pargyline treatment, 1% isoflurane-induced DA release and increase of 3-MT were preserved, whereas high dose isoflurane (3%) decreased the

concentration of metabolites (DOPAC and HVA), despite of the increase by low dose isoflurane (DOPAC) (Fig. 2). When 75 mg kg−1 pargyline was administered, isoflurane anesthesia decreased the concentration of DA and DOPAC (Fig. 3). Isoflurane-induced increase was found only in the concentration of 3-MT.

Table 1 The control values of extracellular concentration of DA said metabolites (ng 40 ␮L−1 )

4. Discussion

Control

Pargyline 30 mg kg−1

DA 3-MT DOPAC HVA

11.4 (4.94) 10.8 (5.78) 7922 (1191) 2884 (533)

(8.91)*

33.0 236.1 (107.2)* 3443 (1997)* 1131 (694)*

75 mg kg−1 40.3 (2.94)* 316.2 (94.1)* 428 (208)** 123 (54)**

Data are expressed as mean (SD). DA: dopamine; 3-MT: 3methoxytyramine; DOPAC: 3,4-dihydroxyphenylacetic acid; HVA: homovanillic acid. * p < 0.05 to control group. ** p < 0.05 to control and 30 mg kg−1 groups.

This study demonstrated that isoflurane anesthesia modified DA release induced by pargyline in different ways. Isoflurane itself increased the extracellular concentration of DA and its metabolites, whereas decreased it from the base line values induced by administration of pargyline. It was believed that classical volatile anesthetics, halothane, activates nigro-striatal DA neurons or the nigral neuron firing rate [4,14]. Spampinato and co-workers [13,22] reported that basal extracellular levels of DA in the striatum of halothane-anesthetized rats roughly doubled compared to those observed in freely moving animals. Halothane and

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Fig. 2. Effects of 30 mg kg−1 pargyline treatment on the extracellular concentrations of DA and its metabolites with or without isoflurane anesthesia. DA and 3-MT were significantly increased by isoflurane anesthesia. DOPAC was increased with low dose isoflurane and decreased with high dose one. * p < 0.05 against control value.

isoflurane, the latter is a more commonly used anesthetic, increase spontaneous but reduce the N-methyl-d-aspartateevoked DA release in rat striatal slices [8]. Both anesthetics had limited depressant effects on the KCl-stimulated DA release and showed no action on the KCl-induced gammaaminobutyric acid release in vitro [20]. Halothane increased the peak of the extracellular concentration of DA evoked by vanoxerine [5], and comparable observations were reported for isoflurane and nomifensine in vivo [16]. The increase in the extracellular concentration of DA might concomitantly induce the formation of reactive free oxygen radicals in metabolism and contribute to the neurons cell death [15]. Whereas isoflurane was reported to inhibit increasing of the neurotransmitter during cerebral ischemia [11], and the ability of volatile anesthetics to reduce neuronal injury in the setting of cerebral ischemia is well established [23,26]. The severe cerebral ischemia-induced lactacidosis and increased DA concentration [10,19]. Anesthetics have a possibility to suppress excitotoxicity both in vitro and in vivo experiments [3,9]. In the present investigation, isoflurane anesthesia increased the extracellular concentration of DA and its metabolites. During anesthesia, DA turn over was accelerated. Whereas at the condition that high extracellular concentration of DA is induced, isoflurane decreased that of

DA and metabolites. These results could be explained by the two possible different effects of isoflurane anesthesia. First, isoflurane increased neural activity and DA release like as halothane anesthesia [2,13,16,22]. Second, isoflurane, however, might inhibit DA synthesis. When the extracellular concentration of DA was increased, the concentration of intracellular DA was also elevated by re-uptake and negative feedback of DA synthesis was potentiated [12]. In the settings, isoflurane might enhance the negative feedback. Chloral hydrate, a commonly used anesthetic for animal experiments, was reported to block the feedback control of DA [21]. Chloral hydrate was believed to produce no neuroprotective effect [17]. Maintaining of feedback system and homeostasis are important for the neuroprotective effect [11,23,26]. The increases of extracellular concentration of 3-MT were preserved in all experiments. The negative feedback loop was activated by presynaptic and postsynaptic DA receptor [12]. Since 3-MT is a catabolic product of the postsynaptic enzyme, catechol-o-methyltransferase (COMT) [7], the difference of changes in metabolites between 3-MT and DOPAC might suggest the target of isoflurane modulation. Released DA into synaptic cleft was quickly defused to both pre- and postsynaptic extracellular space [27,28]. However, the biphasic change was found only in the change in DOPAC, that was

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Fig. 3. Effect of 75 mg kg−1 pargyline treatment on the extracellular concentrations of DA and its metabolites with or without isoflurane anesthesia. Only 3-MT was significantly increased by the anesthesia. DA, DOPAC and HVA were decreased by isoflurane anesthesia. * p < 0.05 against control value.

mainly oxidized by MAO, not by COMT. We speculated that isoflurane activates presynaptic DA receptor more than postsynaptic one at axon terminal. Although volatile anesthetics reduces the release of neurotransmitter after cytotoxic event, excess DA metabolism and auto-oxidation may not contribute to neurotoxicity. We previously reported that halothane anesthesia enhanced methamphetemine-induced DA release [2]. Methamphetamine-induced brain damage is a wellestablished model for neurodegeneration, especially with reference to Parkinson’s disease. However, it still remains unclear how this increased formation of DA is linked to the other biochemical changes. Gassen et al. [6] reported that flupirtine reduced the methamphetamine-induced striatal DA release but not influence the increase of free radical formation. Neuroprotective effect of volatile anesthetics requires further investigations. In summary, we demonstrated that isoflurane anesthesia showed a biphasic effect on the changes in the extracellular concentration of DA and metabolites induced by pargyline in the rat striatum. Isoflurane anesthesia antagonized DA increase when the pharmacological manipulation was applied. The opposite results of isoflurane might make it difficult to understand the neuroprotective effect of volatile anesthetics in vivo microdialysis study.

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