Halothane enhances dopamine metabolism at presynaptic sites in a calcium-independent manner in rat striatum

Y. U. Adachi1,*, M. Satomoto2, H. Higuchi3, K. Watanabe4, S. Yamada5 and T. Kazama5

1 Medical Clinic of Hamamatsu Base, Japan Air Self Defense Force, Hamamatsu, 2 Self Defense Force, Gifu Hospital, Kagamihara, 3 Department of Anesthesiology, Self Defense Force, Hanshin Hospital, Kawanishi, 4 Department of Anesthesia, Shiki Citizen Hospital, Shiki and 5 Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan

* Corresponding author: Medical Clinic of Hamamatsu Base, Nishiyama-cho-1, Hamamatsu city, Shizuoka, 432-8551 Japan. E-mail: yuadachi{at}poppy.ocn.ne.jp

Accepted for publication May 15, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. We have previously reported that halothane anaesthesia increases the extracellular concentration of dopamine (DA) metabolites in the rat striatum with no change in DA. Although the metabolism of catecholamines is a source of oxidative stress, there is little information about DA metabolism and anaesthesia. We assessed the mechanism(s) of enhanced DA metabolism induced by halothane.

Methods. Microdialysis probes were implanted into male Sprague–Dawley rats and perfused with artificial cerebrospinal fluid (CSF). The dialysate was injected directly into an HPLC every 20 min. Each group of rats (n=5–7) was administered saline, apomorphine 100 µg kg–1, pargyline 7.5 or 75 mg kg–1, reserpine 2 mg kg–1 or {alpha}-methyl-p-tyrosine (AMPT) 250 mg kg–1. Another set of rats was perfused with artificial CSF containing tetrodotoxin (TTX) 1 µM or calcium-free CSF containing 10 mM EGTA. Rats were anaesthetized with halothane 0.5 or 1.5% 1 h after pharmacological treatments.

Results. In rats pretreated with apomorphine, despite a decrease in DA concentration, halothane induced a increase in DA metabolites. Pargyline (high dose) and reserpine completely and AMPT partially antagonized the increase in DA metabolites induced by halothane anaesthesia. TTX perfusion reduced the increase in DA, whereas calcium-free CSF perfusion did not.

Conclusions. Our data suggest that halothane accelerates DA metabolism at presynaptic sites by releasing DA from reserpine-sensitive storage vesicles to the cytoplasm in a calcium-independent manner. The metabolic oxidative stress of inhalation anaesthesia requires future investigation.

Keywords: anaesthetics volatile, halothane ; measurement techniques, microdialysis ; model, rat brain ; pharmacology, dopamine


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Oxidative stress may play a key role in the neurodegenerative process.1 The metabolism of dopamine (DA) is a well-known source of oxidative stress that leads to cell death in Parkinson's disease (PD). Previously, we studied the effect of halothane anaesthesia on changes in the concentrations of extracellular DA and DA metabolites in rat striatum using in vivo microdialysis.2 3 Halothane did not change the extracellular concentration of DA, but markedly increased the concentrations of oxidative DA metabolites, including 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).25 Thus, DA metabolism was accelerated during halothane anaesthesia.

It is widely believed that anaesthesia modulates synaptic communication within the CNS.610 Dopamine is a major CNS neurotransmitter,11 and numerous experiments have been carried out to examine the effects of anaesthetic drugs on dopaminergic neural activity,4 5 8 9 12 mainly by examining the release of DA from nerve terminals. In addition, changes in the extracellular concentrations of DA metabolites are also thought to result from the modification of dopaminergic activity.13

Fink-Jensen et al.5 speculated that halothane anaesthesia might increase DA release from axon terminals and might simultaneously accelerate DA reuptake via a proportional increase in the activity of DA transporters, thereby maintaining a steady extracellular concentration of DA and increasing the production of DA metabolites. Although an increase in dopaminergic neuronal activity causes an increase in DA release and enhances the subsequent metabolism of DA, the increase in the concentrations of DA metabolites that occurs during anaesthesia may be independent of DA release.2 3 We hypothesized that halothane might act by enhancing the metabolism of presynaptically stored or synthesized DA within axon terminals, rather than by affecting the metabolism of DA taken up from the extracellular space.

In the present study, we used in vivo microdialysis to examine the mechanism(s) by which the concentrations of DA metabolites are increased during halothane anaesthesia.2 3 We investigated the relationships between halothane anaesthesia and the effects of apomorphine (a DA D2 receptor agonist),14 pargyline (an inhibitor of monoamine oxygenase, MAO),15 reserpine (an inhibitor of catecholamine transport into vesicles),16 {alpha}-methyl-p-tyrosine (AMPT; a tyrosine hydroxylase inhibitor),17 tetrodotoxin (TTX) and calcium-free artificial cerebrospinal fluid (CSF).


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Materials
The experiments were approved by the Committee for Animal Research at our institute. 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). All animals had free access to food and drinking water.

Microdialysis
Rats were anaesthetized with sevoflurane and ventilated through an orotracheal tube. Surgery was performed by topical application of lidocaine 1%. Using a stereotaxic apparatus, 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 began. After each experiment, the rats were killed by inhalation of isoflurane and i.v. injection of thiopental. The brain 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). At about 7:00 a.m. on the day of the experiment, the rat was briefly anaesthetized with sevoflurane. The probe was inserted carefully into the striatum through a guide cannula and fixed to the cannula with a screw. This procedure was performed within 5 min of brief anaesthesia, after which the rat was immediately placed in a clear open Plexiglas box (15 litres capacity, 27 cm diameter x 26 cm high) for recovery. The rats regained consciousness within approximately 3 min. After recovery, the probe was continuously perfused with artificial CSF (Na+ 145.4 mEq litre–1, K+ 2.8 mEq litre–1, Ca2+ 2.3 mEq litre–1, Mg2+ 2.2 mEq litre–1, 23.1 mEq litre–1, Cl 128.5 mEq litre–1, P 1.1 mmol litre–1, glucose 61 mg dl–1) at a flow rate of 2 µl min–1 using a microinfusion pump (ESP-64, EICOM, Kyoto, Japan) to determine the baseline concentrations of DA and its metabolites. Samples were collected every 20 min and injected directly into an online analytical system with an auto-injector (EAS-20; Eicom), as described elsewhere.2 3 The concentrations of DA, 3-MT, DOPAC and HVA in each dialysate fraction (40 µl per 20 min) were determined by HPLC with an electrochemical detector (ECD-300; Eicom). These compounds were separated by reverse-phase ion-pair chromatography with a 5-µm C-18 column (MA5-ODS, 150 x 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 µM EDTA-Na2 and methanol 13–14%, pH 3.9), delivered at a flow rate of 230 µl min–1 by a high-pressure pump (EP-300; Eicom). A guard column (MA, 5 x 4 mm; Eicom) prevented deterioration and plugging of the analytical column. 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 0.5 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 (each 40 µl collected in 20 min) were collected before starting the experiment. The mean value obtained from the last three samples was used as the baseline concentration. The time at which manipulation started is hereafter called ‘fraction number 1’ (Fr. 1).

Experimental procedure
Each group consisted of five to seven rats. The rats were given saline (2 ml kg–1), the same volume of apomorphine 100 µg kg–1, pargyline 7.5 or 75 mg kg–1, reserpine 2 mg kg–1 and AMPT 250 mg kg–1 intraperitoneally with or without 1-h halothane anaesthesia (0.5 or 1.5%). Apomorphine was administered at the time of induction of anaesthesia and administration of other drugs was followed by anaesthesia after 80 min for pargyline, 24 h for reserpine and 4 h for AMPT, in order to acquire the maximum pharmacological effects. Two other groups were perfused with a different dialysate starting 1 h before anaesthesia, with TTX 10 µM or with calcium-free artificial CSF containing 10 mM EGTA (Ca2+-free CSF).

Each rat was anaesthetized in a semi-closed Plexiglas box, into which halothane 3% was initially introduced at a rate of 3 litre min–1 for about 5 min until a steady state was achieved. Subsequently, halothane 0.5 or 1.5% was applied at a rate of 2 litre min–1, using air (23% oxygen) as a carrier. The rectal temperature of the rat was monitored and maintained at 37°C with an electrical heating pad, except in the control and 0.5% halothane groups, because the animals were consistently awake during inhalation. The concentrations of volatile gas and oxygen in the box were monitored using an infrared anaesthetic gas analyser (Capnomac Ultima; Datex, Helsinki, Finland). Immediately after the 1-h anaesthesia, the gas in the box was exchanged with room air by forced ventilation.

Drugs
Halothane was obtained from Takeda Chemical Industries (Osaka, Japan). Apomorphine, reserpine, AMPT and TTX were purchased from Sigma (St Louis, MO, USA). Pargyline was purchased from ICN (ICN Biomedicals, Costa Mesa, CA, USA).

Statistics
Data are presented as mean (SEM). Data were analysed by two-way analysis of variance with drugs as between-subjects variable and time as within-subject variable. The values of fractions between 3 and 8 were calculated as the effect of anaesthesia. For significant (P<0.05) drug or time interactions, a subsequent Newman–Keuls post hoc multiple comparison test was performed (NCSS 2000; Number Cruncher Statistical Systems, Kaysville, UT, USA).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Halothane anaesthesia did not change extracellular DA concentration during anaesthesia, but increased the concentration of each metabolite (3-MT, DOPAC and HVA) in a dose-dependent manner (Fig. 1). Apomorphine decreased the extracellular concentration of DA and its metabolites (Fig. 2). With apomorphine pretreatment, subsequent halothane anaesthesia increased only DA metabolites. Moreover, with halothane the apomorphine-induced decrease in DA was not observed (Fig. 2).



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Fig 1 Effect of halothane anaesthesia on extracellular concentrations of (A) dopamine (DA) and its metabolites: (B) 3-methoxytyramine (3-MT); (C) 3,4-dihydroxyphenylacetic acid (DOPAC); and (D) homovanillic acid (HVA). In this and the following figures, the ordinate of each graph shows the concentration of DA or a metabolite expressed as the percentage of the baseline concentration, which is the mean of three consecutive values immediately before pharmacological manipulations. *P<0.05 compared with control value at each fraction. Each point is the mean (SEM) (n=5–7 per group). Dialysate fractions were obtained every 20 min. Halothane anaesthesia did not change the extracellular concentration of DA, whereas halothane significantly increased those of metabolites (3-MT, DOPAC, HVA) in a concentration-dependent manner compared with control.

 


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Fig 2 Effects of apomorphine treatment on extracellular concentrations of (A) DA and (B), (C) and (D) its metabolites with and without halothane anaesthesia. DA, DOPAC and HVA were significantly reduced by pretreatment with apomorphine. Halothane plus apomorphine increased DOPAC and HVA without a reduction in DA concentration induced by apomorphine. *P<0.05 compared with control; #P<0.05 compared with the group given apomorphine without halothane.

 
Pargyline increased DA and 3-MT concentrations and decreased DOPAC and HVA concentrations. Pargyline 7.5 mg kg–1 diminished the halothane-induced changes in metabolite concentrations (Fig. 3) and the 75 mg kg–1 dose abolished this response (Fig. 4) with the exception of the increase in 3-MT. Reserpine pretreatment decreased DA concentration to below the detection limits (Table 1), and maintained this during the entire experiment. Pretreatment with reserpine 2 mg kg–1 abolished the increases in DOPAC and HVA under halothane anaesthesia (Fig. 5). AMPT decreased DA and metabolite concentrations (Table 1, Fig. 5). The concentrations of DOPAC and HVA were significantly increased during halothane anaesthesia (Fig. 5).



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Fig 3 Effect of 7.5 mg kg–1 pargyline on extracellular concentrations of (A) DA and (B), (C) and (D) its metabolites with and without halothane anaesthesia. DA and 3-MT were significantly increased by pretreatment. Halothane increased DA and 3-MT release. DOPAC and HVA decreased after pretreatment. #P<0.05 compared with the group given pargyline without halothane.

 


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Fig 4 Effect of 75 mg kg–1 pargyline treatment on extracellular concentrations of (A) DA and (B), (C) and (D) its metabolites with and without halothane anaesthesia. DA and 3-MT were markedly increased by pretreatment. Halothane increased DA and 3-MT release. DOPAC and HVA were decreased by pretreatment, and the halothane-induced change was completely abolished. #P<0.05 compared with the group given pargyline without halothane.

 

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Table 1 Extracellular DA and metabolite levels before halothane anaesthesia (fraction 0). Data are mean (SD) (pg 40 µl–1). ND, not determined. AMPT, {alpha}-methyl-p-tyrosine; 3-MT, 3-methoxytyramine; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid.

 


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Fig 5 (A) and (C) Effect of pretreatment with reserpine 2 mg kg–1 (24 h before experiment) on extracellular concentrations of DA metabolites with and without halothane anaesthesia. No significant difference was found among groups during the whole experiments. (B) and (D) Effect of pretreatment (4 h before experiment) with {alpha}-methyl-p-tyrosine (AMPT) 250 mg kg–1 on extracellular concentrations of DA metabolites with and without halothane anaesthesia. Halothane anaesthesia significantly increased the concentrations of DOPAC and HVA. #P<0.05 compared with the group pretreated with AMPT without halothane.

 
Locally administered TTX decreased DA concentration (Fig. 6). With TTX perfusion, halothane anaesthesia increased metabolite concentrations, but this was not concentration-dependent (Fig. 6). Ca2+-free CSF perfusion also reduced the extracellular concentration of DA (Fig. 7). Ca2+-free CSF did not affect the increase in metabolites induced by halothane anaesthesia (Fig. 7).



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Fig 6 Effect of tetrodotoxin (TTX) perfusion on the extracellular concentrations of (A) DA and (B), (C) and (D) its metabolites with and without halothane anaesthesia. DA decreased after TTX perfusion. Metabolites increased during anaesthesia at both concentrations. #P<0.05 compared with the group perfused with TTX fluid without halothane.

 


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Fig 7 Effect of calcium-free perfusion with EGTA (Ca2+-free) on extracellular concentrations of (A) DA and (B), (C) and (D) its metabolites with and without halothane anaesthesia. DA decreased after Ca2+-free perfusion, whereas the increases in metabolites during anaesthesia were maintained. #P<0.05 compared with the group perfused with Ca2+-free fluid without halothane.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The effects of halothane anaesthesia on changes in the extracellular concentrations of DA and DA metabolites were studied using in vivo microdialysis.19 The halothane-induced increase in the concentrations of DOPAC and HVA was abolished by pretreatment with pargyline or reserpine and was reduced by pretreatment with AMPT or TTX. The increase in the concentrations of DA metabolites during halothane anaesthesia was unchanged in the absence of extracellular calcium ions.

It has been proposed that the marked increase in the concentrations of DA metabolites during halothane anaesthesia is attributable to an increase in DA turnover, including the release and reuptake of DA.4 5 In our previous studies,2 3 halothane increased the concentrations of extracellular DA metabolites and markedly enhanced the DA release that was induced by the systemic administration of nomifensine.2 3 However, the increase in DA concentration after local administration of nomifensine into the striatum was not increased by halothane anaesthesia.3 The local administration of nomifensine might have been sufficient to inhibit DA transport,20 which suggested that halothane probably did not accelerate DA turnover from the intra- to extracellular space at the axon terminal.5 Furthermore, halothane anaesthesia increased the extracellular concentrations of DA metabolites in rats that were given nomifensine both systemically and locally.3 We hypothesized that halothane might act by enhancing the metabolism of presynaptically stored or synthesized DA released from the axon terminal, rather than by altering the metabolism of DA that is returned to the terminal from the synaptic cleft.

In the first experiment, we confirmed that the extracellular concentrations of DA and DA metabolites were modulated independently by halothane anaesthesia. Apomorphine is an agonist of presynaptic DA D2 receptors. Pretreatment with apomorphine reduces the release of DA and decreases the extracellular concentrations of DA and DA metabolites by potentiating the negative feedback regulation of DA.14 In the present study, halothane did not affect the apomorphine-induced reduction in extracellular DA concentrations. The increase in the concentrations of DA metabolites was independent of extracellular DA and was not regulated by the DA D2 receptor. Therefore, the origin of the DA metabolites that increase in concentration in the presence of halothane is likely to be unrelated to released or transported DA.

Pargyline, an inhibitor of MAO, increases the extracellular concentration of DA by inhibiting the oxidation of DA to DOPAC and by inhibiting the oxidation of 3-MT to HVA.15 21 In our study, pretreatment with pargyline decreased the concentrations of DOPAC and HVA and increased the concentrations of DA and 3-MT (Figs 3 and 4). The 3-MT is synthesized from DA by catechol-o-methyltransferase (COMT).15 22 COMT is found only at the postsynaptic site,23 and changes in the concentration of 3-MT have been reported to be a good indicator of dopaminergic neural activity.13 In the present study, the increase in the concentrations of both DA and 3-MT due to the inhibition of MAO was enhanced during halothane anaesthesia. Halothane anaesthesia itself might increase dopaminergic activity and accelerate DA release and turnover; however, the extracellular concentration of DA was maintained at a constant level during anaesthesia by the oxidation of DA in the absence of pargyline.

At nerve endings, reserpine depletes vesicular stores of catecholamines and inhibits the release of neurotransmitters.16 The administration of 2 mg kg–1 reserpine 24 h before halothane anaesthesia was sufficient to deplete DA in the present study. After reserpine administration, the extracellular concentration of DA was too low to be detected before and during anaesthesia, and the halothane- induced increase in the concentrations of DA metabolites was completely abolished (Fig. 5). Therefore, the increase in the concentrations of DA metabolites during anaesthesia may be attributable to the release of DA from vesicles.

AMPT inhibits the synthesis of 3-(3,4-dihydroxyphenyl)-DL-alanine from tyrosine by the enzyme tyrosine hydroxylase and depletes catecholamines such as DA at the axon terminal.17 Pretreatment with AMPT reduced the concentrations of DA and DA metabolites in the present study (Table 1). Parker and Cubeddu24 reported that the amphetamine-induced release of extracellular DA was reduced by inhibiting DA synthesis with AMPT and was increased by inhibition of MAO. Amphetamine-induced DA release depends mainly on a reserpine-resistant (non-vesicular) DA pool.16 In contrast to the effect of reserpine, AMPT failed to completely inhibit the increase in the concentrations of DA metabolites during halothane anaesthesia in the present study (Fig. 5).

The results of the present study indicate that halothane may stimulate the release of DA from a reserpine-sensitive vesicular store into the cytoplasm at the axon terminal. DA released in this way may be metabolized immediately in a compensatory manner by MAO within the cytoplasm.21 This hypothesis is supported by the results of Keita and colleagues,8 who investigated the effect of halothane on DA release in slice preparations and synaptosomes and demonstrated that halothane increased the spontaneous release of DA in vitro. In the present study, microdialysis was used to measure the extracellular concentrations of DA and DA metabolites, which included substances that were released or that diffused from axon terminals. Therefore, we could not distinguish between changes in the absolute amount of intracellular cytoplasmic DA and the total extracellular concentration of DA.21 However, the pharmacological manipulations that we used revealed the effects of halothane on DA release and metabolism.

Finally, we investigated the effects of TTX-containing or calcium-free perfusate on DA metabolism during halothane anaesthesia. TTX reduced the halothane-induced increase in the concentrations of DA metabolites (Fig. 6), whereas the calcium-free perfusate had no such effect (Fig. 7). As the increase in the concentrations of metabolites was sensitive to TTX, the effect of halothane on DA metabolism must be related to neuronal activity. Calcium-dependent release of vesicular DA into the extracellular space is reduced in calcium-free perfusates.2527 Our results indicate that the halothane-induced DA release from vesicles of the axon terminal might depend on neuronal activity and sodium channels,28 but is independent of calcium entry. The increase in the concentration of 3-MT during anaesthesia was reduced in the calcium-free perfusate. The calcium-sensitive exocytotic transport of DA into the extracellular space and the reuptake of DA into the postsynaptic site might be inhibited in the absence of extracellular calcium ions, and the halothane-induced acceleration of the metabolism of DA to 3-MT was diminished.25

Our results are similar to the findings of Woodward and colleagues,29 who suggested that the slow phase of potassium-stimulated DA release from rat striatal synaptosomes in vitro did not require calcium, but might be mediated via reversal of the sodium-linked DA transport system. Our experiments did not reveal any difference in the change of the phase of DA release, but it is possible that halothane induces the release of vesicular DA via a similar mechanism. It has been amply documented that during depolarization-evoked neurotransmitter release, a calcium-dependent fraction of neurotransmitter is released into the extracellular space via exocytosis, while a sodium-dependent fraction is released from the cytoplasm via a reversal in the activity of neurotransmitter transporters.26 30 Halothane decreases the nerve impulse-dependent release of exocytotic DA.8 31 but may increase the release of extravesicular DA into the cytoplasm and may accelerate the oxidation of DA by MAO.

In conclusion, we demonstrated that halothane enhanced DA metabolism at the axon terminal. DA was released from a reserpine-sensitive vesicular pool in a calcium-independent manner, and MAO simultaneously metabolized DA that was released into the cytoplasm at presynaptic sites.


    Acknowledgments
 
The authors would like to express sincere thanks to Dr Ikumasa Nishida, Professor and Chairman, 2nd Department of Physiology, National Defense Medical College, for reviewing this manuscript.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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