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Brain Research Bulletin 89 (2012) 223– 230

Contents lists available at SciVerse ScienceDirect

Brain Research Bulletin

jo u r n al hom epage : www.elsev ier .com/ locate /bra inresbul l

esearch report

he effect of aging on dopamine release and metabolism during sevofluranenesthesia in rat striatum: An in vivo microdialysis study

aori Kimura-Kuroiwaa, Yushi U. Adachib,∗, Soichiro Mimuroc, Yukako Obatac,ikito Kawamatad, Shigehito Satoe, Naoyuki Matsudaf

2nd Department of Anesthesia, Nagano Red Cross Hospital, 5-22-1, Wakasato, Nagano, Nagano 380-8582, JapanDepartment of Emergency Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, JapanIntensive Care Unit of University Hospital, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanThe Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, JapanDepartment of Anesthesia and Resuscitation, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanDepartment of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

r t i c l e i n f o

rticle history:eceived 8 August 2012ccepted 22 August 2012vailable online 7 September 2012

eywords:opaminegingat brainicrodialysis

a b s t r a c t

We have previously reported that halothane anesthesia increases extracellular concentrations ofdopamine (DA) metabolites in rat striatum using in vivo microdialysis techniques. Aging induces manychanges in the brain, including neurotransmission. However, the relationship between aging and changesin neurotransmitter release during inhalational anesthesia has not been fully investigated. The aim of thepresent investigation was to evaluate the effect of sevoflurane on methamphetamine (MAPT)-induced DArelease and metabolism in young and middle-aged rats. Male Sprague–Dawley rats were implanted witha microdialysis probe into the right striatum. The probe was perfused with a modified Ringer’s solutionand 40 �l of dialysate was directly injected to an HPLC every 20 min. Rats were administered saline, thesame volume of 2 mg kg−1 MAPT intraperitoneally, or 5 �M MAPT locally perfused. After treatments, the

ethamphetamine rats were anesthetized with 1% or 3% sevoflurane for 1 h. Sevoflurane anesthesia significantly increasedthe extracellular concentration of DA only in middle-aged rats (52-weeks-old). In young rats (8-weeks-old), sevoflurane significantly enhanced MAPT-induced DA when administered both intraperitoneallyand perfused locally, whereas no significant additive interaction was found in middle-aged rats. Theseresults suggest that aging changes DA release and metabolism in rat brains primarily by decreasing theDA transporter.

. Introduction

Aging induces many changes in organisms, including neuro-ransmission in the brain (Reeves et al., 2002). Parkinson’s disease isne of most alarming conditions in humans, and aging is a primaryisk factor (Collier et al., 2011). Similar cellular mechanisms maye involved in the degeneration of dopaminergic neurons throughhe course of normal aging and in the aging-related changes thatead to Parkinson’s disease. Midbrain dopamine (DA) neurons are

ore vulnerable to degeneration than are other neurons (Marrasnd Lang, 2008). The progressive loss of dopaminergic neurons andhe subsequent decrease in DA release in the nigrostriatal pathway

esults in major disruptions to connections between the thalamusnd motor cortex, and leads to Parkinsonian symptoms, such asradykinesia.

∗ Corresponding author. Tel.: +81 52 744 2659; fax: +81 52 744 2978.E-mail address: yuadachi@med.nagoya-u.ac.jp (Y.U. Adachi).

361-9230/$ – see front matter © 2012 Elsevier Inc. All rights reserved.ttp://dx.doi.org/10.1016/j.brainresbull.2012.08.006

© 2012 Elsevier Inc. All rights reserved.

We have previously reported that halothane anesthesiaincreases extracellular concentrations of DA metabolites in rat stri-atum, using in vivo microdialysis techniques (Adachi et al., 2005a,2001c). Inhalational anesthetics likely exert a biphasic effect on DAregulation through potentiation of DA release and the inhibition ofDA synthesis (Adachi et al., 2005b). Methamphetamine (MAPT) isa well-known psychotropic stimulant and produces vast changesin DA release in rat striatum. Volatile anesthetics alone mimicthe effects on extracellular DA concentration. However, inhala-tion anesthetics markedly enhance MAPT-induced DA release fromaxon terminals in rat striatum (Adachi et al., 2005a, 2001c). Wehypothesized that volatile anesthetics accelerate DA turnover at apresynaptic site in the brain and that DA metabolites are increasedduring anesthesia (Adachi et al., 2001c, 2005b).

Oxidative stress followed by inadequate production of reac-

tive oxygen species generates neurodegeneration. DA is usuallymetabolized, not only by monoamine oxidase-mediated enzymaticoxidation (Adachi et al., 2001a), but also by auto-oxidation toneuromelanin (Fedorow et al., 2005). These metabolic complexes

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roduce reactive substances; for example, hydrogen peroxide,uperoxide anions and hydroxyl radicals. Free radicals react withembrane lipids and produce toxic lipid peroxidation (Ahlskog,

005). These free radicals are increased in the substantia nigraf patients with Parkinson’s disease (Ahlskog, 2005). Increases inxidative and metabolic products may indicate an escalation ofeurotoxicity and might play an important role in neurodegenera-ion.

The efficacy and toxicity of psychotropic drugs almost certainlyhange with age since body size and organ maturity are both impor-ant factors in determining drug effects (Wynne and Blagburn,010). Recently, the potential toxicity of volatile anesthetics onhe developing brain has been an area of focus in anesthesiologyJevtovic-Todorovic et al., 2003; Satomoto et al., 2009). Just liken the neonatal central nervous system, geriatric neurons mighte more susceptible to psychotropic drugs, including anestheticsnd hallucinogens (Wynne and Blagburn, 2010). Geriatric patientsave many opportunities to receive general anesthesia, followedy psychotropic medications. However, the effects of aging andeneral anesthesia on the release of neurotransmitters, includingA, have rarely been investigated due to the difficulty and techni-al limitations involved in conducting in vivo experiments in agednimals.

The aim of the present investigation was to evaluate the effectf inhaled sevoflurane anesthesia and MAPT on extracellular DAoncentrations and DA metabolites in young and middle-aged rattriatum using an in vivo microdialysis technique. We examinedhether aging discernibly affects extracellular DA homeostasisuring general anesthesia.

. Materials and methods

.1. Materials

Male Sprague–Dawley rats, 8 weeks old and weighing 280–320 g as young ratsnd 52–54 weeks old and weighing 560–780 g as middle-aged rats, were used in thexperiments (CLEA Japan, Tokyo, Japan). The animals were gently housed in an ani-al room at 20–22 ◦C and illuminated with a 12-h light/dark cycle (light from 07:00

o 19:00 h). All animals had free access to food and drinking water. The experimentsere approved by the Committee for Animal Research in the institute.

.2. Microdialysis

Rats were anesthetized with sevoflurane and surgery was performed with theopical application of 1% lidocaine. Using a stereotaxic apparatus, a unilateral guideannula was implanted just above the striatum (AP +0.6 mm, ML +3.0 mm, DV3.8 mm) following the atlas of Paxinos and Watson (1998). The rats were allowed

o recover for at least 3 days before the experiment began. After each experiment,he rats were killed by excess inhalation of isoflurane and intravenous injectionf thiopental. The brain was removed, and the placement of the microdialysisrobe was identified histologically. Microdialysis probes were obtained from EICOMKyoto, Japan) (o.d. 0.22 mm, membrane length 3 mm, polycarbonate tubing, cut-ff mol. wt. 50,000). At about 07:00 a.m. on the day of experiment, the probe wasnserted carefully into the striatum through a guide cannula and fixed to the can-ula with a screw, and the rat was immediately placed in a clear open Plexiglas box

or recovery. The probe was continuously perfused with modified Ringer’s solution145.4 mequiv. L−1 Na+, 2.8 mequiv. L−1 K+, 2.3 mequiv. L−1 Ca2+, 150.5 mequiv. L−1

l−) at a flow rate of 2 ml min−1 using a micro-infusion pump (ESP-64, EICOM, Kyoto,apan) to determine the baseline concentrations of DA and its metabolites. Samples

ere collected every 20 min and directly injected into an online analytical systemith an auto-injector (EAS-20, EICOM), as described elsewhere (Adachi et al., 2005a,

001c).The concentrations of DA, 3-methoxytyramine (3-MT), 3,4-

ihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in eachialysate (40 ml/20 min) were determined by HPLC with an electrochemicaletector (ECD-300, EICOM). These compounds were separated by reverse-phase

on-pair chromatography with a 5-mm C-18 column (MA5-ODS, 150 mm × 2.1 mm,ICOM) using an isocratic mobile phase (0.1 M sodium acetate, 0.1 M citric acid,.4 mM sodium 1-octanesulfonate, 5 mM EDTA-Na2 and methanol 13–14%, pH 3.9),

elivered at a flow rate of 230 ml min−1 by a high-pressure pump (EP-300, EICOM).

guard column (MA, 5 mm × 4 mm, EICOM) prevented deterioration and pluggingf the analytical column. The compounds were quantified by electrochemicaletection using a glassy carbon working electrode set at 650 mV against a Ag/AgCleference electrode. The detection limit for each of the compounds was roughly

rch Bulletin 89 (2012) 223– 230

0.5 pg per sample. DA and its metabolites reached stable baseline concentrationswithin about 4.5 h after implantation of the microdialysis probe. Therefore, atleast six dialysate samples (each 40 ml collected in 20 min) were collected beforestarting the pharmacological experiment. The mean value obtained from the lastthree samples was used as the baseline concentration. The time at which thepharmacological manipulation started is hereafter called “fraction number 1” (Fr.1, see figures).

2.3. Experiments

Rats were given saline (0.6 ml) or the same volume of MAPT 2 mg kg−1

(0.6 ml/300 g) intraperitoneally with or without 1-h sevoflurane anesthesia (1.0 or3.0%). In other groups, MAPT was dissolved in Ringer’s solution to give a concentra-tion of 5 �M. Each rat was anesthetized in a semi-closed Plexiglas box, into which 3%sevoflurane was initially introduced at a flow rate of 3 L min−1 for about 5 min untila steady state was achieved. Subsequently, 1.0% or 3.0% sevoflurane was applied ata rate of 2 L min−1, using air (23% oxygen) as the carrier for avoiding hypoxia (Orsetet al., 2005). The rectal temperature of the rat was monitored and maintained at37 ◦C with an electrical heating pad, except in the control groups, because the ani-mals were consistently awake during experiments. The concentrations of volatilegas and oxygen in the box were monitored using an infrared anesthetic gas analyzer(Capnomac Ultima, Datex, Helsinki, Finland) during each anesthesia. The samplingprobe was placed near to rats nose and respiratory pattern was monitored by capno-gram. Immediately after the 1-h anesthesia, the gas in the box was exchanged withroom air by forced ventilation.

2.4. Statistics

Data were analyzed by two-way analysis of variance with drugs as a between-subjects variable and time as a within-subject variable. For significant (P < 0.05) drugor time interactions, a subsequent Newman–Keuls post hoc multiple comparisontest was performed (NCSS 2000, Number Cruncher Statistical Systems, Kaysville, UT,USA). The data were presented as mean ± SEM using percent changes from baselinevalues.

2.5. Drugs

Sevoflurane was obtained from Maruishi (Maruishi Pharmaceutical Col, Ltd.,Osaka, Japan). Methamphetamine was purchased from Dainippon Pharmaceutical(Osaka, Japan).

3. Results

Sevoflurane anesthesia significantly increased the extracellularconcentration of DA metabolites, 3-MT, DOPAC and HVA in both8-week old young rats (Fig. 1) and 52-week old middle-aged rats(Fig. 2) in a dose-dependent manner. After inhalation, the con-centration of metabolites returned to pre-anesthetic levels. DAconcentration was not significantly changed in young rats followinganesthetic inhalation. However, in middle-aged animals, inhala-tion of high concentrations of sevoflurane increased DA levels in amanner consistent with anesthesia duration.

Intraperitoneal administration of MAPT markedly increased theextracellular concentration of DA and 3-MT and decreased thatof DOPAC and HVA in all animals (Figs. 3 and 4). Sevofluraneanesthesia enhanced DA and 3-MT concentrations in young ratsadministered MAPT. In middle-aged animals, there were no sig-nificant differences in DA and 3-MT concentrations between thenon-anesthetized and anesthetized groups. Sevoflurane counter-acted the MAPT-induced reduction of HVA in both young andmiddle-aged animals; however, the small but significant increase inDOPAC was reduced by MAPT administration only in middle-agedrats.

Perfusion of MAPT also significantly increased extracellular DAand 3-MT concentrations (Figs. 5 and 6). This effect was significantin young animals but not in middle-aged rats. However, there wasno apparent change in DOPAC and HVA in either age group.

4. Discussion

In this study, we demonstrate that sevoflurane anesthesia hasa tendency to slightly increase extracellular DA in young rats;however, in middle-aged rats, a much larger increase in DA was

K. Kimura-Kuroiwa et al. / Brain Research Bulletin 89 (2012) 223– 230 225

Fig. 1. In young rats, effect of sevoflurane anesthesia on the extracellular concentrations of dopamine (DA, upper left) and its metabolites, 3-methoxytyramine (3-MT, upperright), 3,4-dihydroxyphenylacetic acid (DOPAC, lower left) and homovanillic acid (HVA, lower right). In this and the following figures, the ordinate of each graph showsthe concentration of DA or a metabolite expressed as the percentage of the baseline concentration, which is the mean of three consecutive values immediately beforepharmacological 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 obtainedevery 20 min. Sevoflurane anesthesia did not change the extracellular concentration of DA, whereas sevoflurane significantly increased those of metabolites (3-MT, DOPAC,HVA) in a concentration-dependent manner compared with control in young rats.

Fig. 2. In middle-aged rats, effect of sevoflurane anesthesia on the extracellular concentrations of dopamine and its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. *P < 0.05 compared with control value at each fraction. Each point is the mean (SEM) (n = 5–7 per group). Sevofluraneanesthesia increased the extracellular concentration of DA in middle-aged rats as same as those of other DA metabolites in a concentration-dependent manner comparedwith control group.

226 K. Kimura-Kuroiwa et al. / Brain Research Bulletin 89 (2012) 223– 230

Fig. 3. In young rats, effect of sevoflurane anesthesia and intraoperative administration of methamphetamine on the extracellular concentrations of dopamine and itsmetabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. *P < 0.05 compared with control value at each fraction. # P < 0.05 compared withvalues in the methamphetamine treatment group at each fraction. Each point is the mean (SEM) (n = 5–7 per group). Sevoflurane anesthesia increased the extracellularconcentration of DA in middle-aged rats as same as those of other DA metabolites in a concentration-dependent manner compared with control group.

Fig. 4. In middle-aged rats, effect of sevoflurane anesthesia and intraoperative administration on the extracellular concentrations of dopamine and its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. *P < 0.05 compared with control value at each fraction. #P < 0.05 compared with values in themethamphetamine treatment group at each fraction. Each point is the mean (SEM) (n = 5–7 per group). Sevoflurane anesthesia increased the extracellular concentration ofDA in middle-aged rats as same as those of other DA metabolites in a concentration-dependent manner compared with control group.

K. Kimura-Kuroiwa et al. / Brain Research Bulletin 89 (2012) 223– 230 227

Fig. 5. In young rats, effect of sevoflurane anesthesia and local administration of methamphetamine as perfusate on the extracellular concentrations of dopamine and itsmetabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. *P < 0.05 compared with control value at each fraction. #P < 0.05 compared withvalues in the methamphetamine treatment group at each fraction. Each point is the mean (SEM) (n = 5–7 per group). Sevoflurane anesthesia increased the extracellularconcentration of DA in middle-aged rats as same as those of other DA metabolites in a concentration-dependent manner compared with control group.

Fig. 6. In middle-aged rats, effect of sevoflurane anesthesia and local administration of methamphetamine as perfusate on the extracellular concentrations of dopamineand its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. *P < 0.05 compared with control value at each fraction. #P < 0.05 comparedwith values in the methamphetamine treatment group at each fraction. Each point is the mean (SEM) (n = 5–7 per group). Sevoflurane anesthesia increased the extracellularconcentration of DA in middle-aged rats as same as those of other DA metabolites in a concentration-dependent manner compared with control group.

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easured. These changes cannot be attributed to an increased DAetabolism with age since the increases in DA metabolites were

imilar in both young and middle-aged rats. The results in youngats were consistent with previous experiments using halothaneAdachi et al., 2005a, 2001c), but not isoflurane (Adachi et al., 2008,005b). Isoflurane significantly increased extracellular DA concen-ration after high-dose inhalation, as did sevoflurane anesthesia in

iddle-aged rats in the current investigation. We cannot explainhe differing results with distinct anesthetics. However, the poten-iation of DA release and the acceleration of DA metabolism couldertainly be a common basal effect of volatile anesthetics on DAegulation (Fink-Jensen et al., 1994; Opacka-Juffry et al., 1991) andn DA homeostasis modulated by aging.

Profound and excess anesthesia can induce ischemia andypoxia as a result of cardiovascular insufficiency in experimen-al animals. Anesthetics cause circulatory (Raner et al., 1994) andespiratory depression (van den Elsen et al., 1998). Subsequentschemic and hypoxic changes might induce neuronal damage inhe brain, which impairs the regulation of release and reuptakef neurotransmitters such as DA (Toner et al., 2001). In the cur-ent investigation, we administered sevoflurane to experimentalnimals with 23% oxygen to prevent hypoxia-induced neuronalamage (Toner et al., 2001), and to avoid the acceleration of DAetabolism by high concentrations of oxygen (Adachi et al., 2001a).

o our knowledge, there is no evidence that the anesthetic protocolsed here leads to the development of severe ischemic or hypoxicrain injury in vivo (Orset et al., 2005). However, changes in bloodressure, heart rate and partial pressure of arterial carbon diox-

de were not investigated during anesthesia. All rats showed nopparent behavioral changes after anesthesia recovery, and fatalell damage in the central nervous system could not be induced inhe whole experiments.

In the striatum, basal DA levels are reported to be lower inged rats than in young animals (Gerhardt and Maloney, 1999).owever, stimulus-evoked overflow of DA is not diminished inged rats, and dopaminergic neurons may compensate for the pro-ressive changes that occur with aging (Gerhardt and Maloney,999; Stanford et al., 2001). Volatile anesthetics exert smallhanges in impulse-dependent DA release and induce significanthanges in cytoplasmic and non-vesicular DA release (Adachi et al.,001b; Diniz et al., 2007). Sevoflurane might potentiate cytoplas-ic DA release from axon terminals. Significant and consistent

ncreases in DA metabolites, particularly the concentration of 3-T, support this hypothesis (Adachi et al., 2005a,b, 2001c). The

nesthesia-induced modification of DA homeostasis could leado unexpected symptoms. Iselin-Chaves et al. (2009) reported

case of naloxone-responsive acute dystonia and Parkinsonismmmediately after general anesthesia. In a clinical setting, anes-hesia is associated with the administration of multiple drugs,ncluding opiates, which cause instability in neurotransmissionWalsh et al., 2010). Even in young animals, stressful events alteropaminergic function (Novick et al., 2011). Cruz-Muros et al.2009) reported decreased expression of the DA transporter intriatal dopaminergic-cells of aged rats. Striatal DA transporterunction has also been reported to decline with aging, leadingo reduced DA reuptake in the brain of rats (Salvatore et al.,003) and humans (Erixon-Lindroth et al., 2005). We hypothesizehat dopaminergic neurons activate compensatory mechanismsirected at maintaining DA transporter function and that theseechanisms may be associated with preserved motor function in

ormal geriatrics. However, sevoflurane anesthesia might enhanceA release and inhibit the reactive increase of DA reuptake by

he transporter, which declines with aging. This is supportedy the results of this study; i.e., the increased extracellular DAoncentration in middle-aged, but not young, rat brains duringnesthesia.

rch Bulletin 89 (2012) 223– 230

General anesthesia with isoflurane (Jansson et al., 2004) orpropofol (Wang et al., 2000) has been shown to decrease acetyl-choline (ACh) release in the brain of aged rats. These changes havebeen touted as a mechanism of promotion of peri-operative impair-ment of brain function in geriatric patients (Avidan and Evers,2011). Since ACh release from striatal cholinergic interneurons isinhibited by DA release from nigrostriatal axon terminals (Vizi andLabos, 1991), anesthesia-induced increases in DA release into theextracellular space might be followed by decreases in ACh (Adachiet al., 2002). Recently, Whittington and Virág (2010) reported thatwhen an age-adjusted equipotent dose of inhaled anesthetic sim-ilarly decreased ACh levels in young and aged rats. This suggeststhat the relative anesthetic potency could be adjusted for agingby altering the minimum alveolar concentration (MAC) (Gregoryet al., 1969). However, numerous variables, including effects onthe inter-neuronal system, cannot be fully explained by the MAC(Tanifuji, et al.). The nigrostriatal dopaminergic system plays animportant role in motor activity and cognitive function during anes-thesia (Erixon-Lindroth et al., 2005; Solt et al., 2011), which affectsthe MAC. In general, anesthesia increases DA release in rat brainsand these changes are followed by a decrease in ACh release.

Nomifensine, a DA reuptake inhibitor (Eshleman et al., 1994),has been reported to enhance DA outflow in young rats (Opacka-Juffry et al., 1991; Stanford et al., 2001). Methamphetamine releasesDA from the intracellular pools by reversing the DA transporter(Eshleman et al., 1994; Fink-Jensen et al., 1994). Volatile anestheticsreportedly enhance the effect of MAPT on DA release (Adachi et al.,2005a, 2001c; Fink-Jensen et al., 1994; Opacka-Juffry et al., 1991).In the current investigation, the enhancement of MAPT-induced DArelease with sevoflurane anesthesia was observed only in youngrats. We hypothesized that anesthesia-driven DA release mightbecome apparent only when the DA transporter was reversely acti-vated by MAPT. The feedback regulation of DA by reuptake throughthe DA transporter was more dramatic in young rats than in agedrats (Cruz-Muros et al., 2009; Erixon-Lindroth et al., 2005; Salvatoreet al., 2003). Thus, the change in DA would be more robust in younganimals during anesthesia by reuptake inhibition. Another possi-ble explanation is that sevoflurane might accelerate MAPT-inducedreversal of DA release through the DA transporter (Diniz et al.,2007), and the enhancement would be negligible due to the DAtransporter decline in the aged rat brain (Cruz-Muros et al., 2009;Salvatore et al., 2003). However, the latter hypothesis does not sup-port the increased DA concentration during anesthesia that occurswithout MAPT in middle-aged rats.

We found no additive effect of sevoflurane anesthesia onMAPT-induced changes in middle-aged rats. Due to maturity andthe marked difference in body weight, MAPT could possibly beadministered at a larger dose in aged rats when given intraperi-toneally, if corrected for actual body weight. The effect of MAPTon dopaminergic neurons might be modified by pharmacokineticand pharmacodynamic parameters, which consist of many vari-ables, including aging, body weight, cardiac function, circulatoryvolume and clearance capacity. Moreover, the effects of MAPT andnomifensine on DA release are dependent on the method of admin-istration (Adachi et al., 2001c). Thus, we applied MAPT to rats withboth an intraperitoneal bolus injection and continuous microdial-ysis perfusion, the latter of which was independent of animal size.Despite these differences in drug administration, we observed con-sistent changes in DA and 3-MT during anesthesia, which supportour results regarding the effect of MAPT.

Oxidative stress is responsible for the major changes thatoccur in aging (Barja, 2004). Excess release of neurotransmitter is

followed by increases in free radicals through sequential oxidativemetabolism (Ahlskog, 2005). One of the supplemental drugs forParkinson’s disease is selegiline, a monoamine oxidase inhibitor,and entacapone, a catechol-o-methyltransferase inhibitor. These

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nhibitors suppress metabolism of DA administered as l-DopaAdachi et al., 2001a). Although no curative effect in Parkinson’satients has been demonstrated, these inhibitors do reduce the for-ation of reactive substances. A reduction in hydrogen peroxide,

uperoxide anions and hydroxyl radicals could prevent neuronalamage. In our study, neither peri-anesthetic behavioral nor cog-itive dysfunction was determined. However, the increase in DAetabolites was consistent in both young and middle-aged rats.e would expect that if neuronal cells were vulnerable and begin-

ing to degenerate with age, additional oxidative stress would beore harmful in aged animals than in young animals.The in vivo microdialysis experiments used in this study have

series of technical limitations (Adachi et al., 2005a, 2001c; Fink-ensen et al., 1994; Opacka-Juffry et al., 1991), which differ from

any in vitro investigations (Adachi et al., 2001b, 2002). The actualoncentration or amount of DA and its metabolites in the brainould not be measured, because the recovery rate of neurotrans-itters in the perfusate from the extracellular space into the

ialyzing probe through the membrane was not predetermined.owever, any alterations in DA recovery or release that mightave occurred in the current study were consistent in all exper-

ments and with previous reports (Adachi et al., 2005a,b, 2001c).oreover, non-synaptic communication and chemical messaging

hrough the extracellular space are the primary controls of brainunction (Vizi et al., 2010). Neurotransmission could be considered

long pathway in the brain; e.g., inter-hemispheric connectionsLieu and Subramanian, 2012) and direct intranasal absorptionChao et al., 2012). We could not separate the effect of sevoflu-ane anesthesia on central nervous system function from that onltered consciousness, the subsequent analgesia or the nature ofleep during anesthesia. Thus, further investigations are required.

. Conclusion

Our findings suggest that aging reduces the sensitivity of the DAransporter to sevoflurane anesthesia and increases the extracel-ular DA concentration. The risk of anesthesia-induced apoptoticeurodegeneration in the developing brain has been of interestecently (Jevtovic-Todorovic et al., 2003). Thus, the increased extra-ellular DA concentration during anesthesia may damage neuronsn aged animals in a manner similar to that seen in neonatesSatomoto et al., 2009).

onflict of interest

None declared.

eferences

dachi, Y.U., Satomoto, M., Higuchi, H., Watanabe, K., Yamada, S., Kazama, T., 2005a.Halothane enhances dopamine metabolism at presynaptic sites in a calcium-independent manner in rat striatum. British Journal of Anaesthesia 95, 485–494.

dachi, Y.U., Watanabe, K., Higuchi, H., Satoh, T., Vizi, E.S., 2001a. Oxygen inhala-tion enhances striatal dopamine metabolism and monoamineoxidase enzymeinhibition prevents it: a microdialysis study. European Journal of Pharmacology422, 61–68.

dachi, Y.U., Watanabe, K., Higuchi, H., Satoh, T., Zsilla, G., 2001b. Halothanedecreases impulse-dependent but not cytoplasmic release of dopamine fromrat striatal slices. Brain Research Bulletin 56, 521–524.

dachi, Y.U., Watanabe, K., Higuchi, H., Satoh, T., Zsilla, G., 2002. Halothane enhancesacetylcholine release by decreasing dopaminergic activity in rat striatal slices.Neurochemistry International 40, 189–193.

dachi, Y.U., Watanabe, K., Satoh, T., Vizi, E.S., 2001c. Halothane potentiates the effectof methamphetamine and nomifensine on extracellular dopamine levels in ratstriatum: a microdialysis study. British Journal of Anaesthesia 86, 837–845.

dachi, Y.U., Yamada, S., Satomoto, M., Higuchi, H., Watanabe, K., Kazama,

T., Mimuro, S., Sato, S., 2008. Isoflurane anesthesia inhibits clozapine-and risperidone-induced dopamine release and anesthesia-induced changesin dopamine metabolism was modified by fluoxetine in the rat stri-atum: an in vivo microdialysis study. Neurochemistry International 52,384–391.

rch Bulletin 89 (2012) 223– 230 229

Adachi, Y.U., Yamada, S., Satomoto, M., Higuchi, H., Watanabe, K., Kazama, T., 2005b.Isoflurane anesthesia induces biphasic effect on dopamine release in the ratstriatum. Brain Research Bulletin 67, 176–181.

Ahlskog, J.E., 2005. Challenging conventional wisdom: the etiologic role of dopamineoxidative stress in Parkinson’s disease. Movement Disorders 20, 27182.

Avidan, M.S., Evers, A.S., 2011. Review of clinical evidence for persistent cogni-tive decline or incident dementia attributable to surgery or general anesthesia.Journal of Alzheimer’s Disease 24, 201–216.

Barja, G., 2004. Free radicals and aging. Trends in Neurosciences 27, 595–600.Collier, T.J., Kanaan, N.M., Kordower, J.H., 2011. Ageing as a primary risk factor

for Parkinson’s disease: evidence from studies of non-human primates. NatureReviews Neuroscience 12, 359–366.

Chao, O.Y., Mattern, C., Sliva, A.M., Wessler, J., Ruocco, L.A., Nikolaus, S., Huston, J.P.,Pum, M.E., 2012. Intranasally applied l-DOPA alleviates parkinsonian symptomsin rats with unilateral nigro-striatal 6-OHDA lesions. Brain Research Bulletin 87,340–345.

Cruz-Muros, I., Afonso-Oramas, D., Abreu, P., Pérez-Delgado, M.M., Rodríguez,M., González-Hernández, T., 2009. Aging effects on the dopamine trans-porter expression and compensatory mechanisms. Neurobiology of Aging 30,973–986.

Diniz, P.H., Silva, J.H., Gomez, M.V., Guatimosim, C., Gomez, R.S., 2007. Halothaneincreases non-vesicular [(3)H]dopamine release from brain cortical slices. Cel-lular and Molecular Neurobiology 27, 757–770.

van den Elsen, M., Sarton, E., Teppema, L., Berkenbosch, A., Dahan, A., 1998. Influenceof 0.1 minimum alveolar concentration of sevoflurane, desflurane and isofluraneon dynamic ventilatory response to hypercapnia in humans. British Journal ofAnaesthesia 80, 174–182.

Erixon-Lindroth, N., Farde, L., Wahlin, T.B., Sovago, J., Halldin, C., Bäckman, L., 2005.The role of the striatal dopamine transporter in cognitive aging. PsychiatryResearch 138, 1–12.

Eshleman, A.J., Henningsen, R.A., Neve, K.A., Janowsky, A., 1994. Release of dopaminevia the human transporter. Molecular Pharmacology 45, 312–316.

Fedorow, H., Tribl, F., Halliday, G., Gerlach, M., Riederer, P., Double, K.L., 2005.Neuromelanin in human dopamine neurons: comparison with peripheralmelanins and relevance to Parkinson’s disease. Progress in Neurobiology 75,109–124.

Fink-Jensen, A., Ingwersen, S.H., Nielsen, P.G., Hansen, L., Nielsen, E.B., Hansen, A.J.,1994. Halothane anesthesia enhances the effect of dopamine uptake inhibitionon interstitial levels of striatal dopamine. Naunyn-Schmiedeberg’s Archives ofPharmacology 350, 239–244.

Gerhardt, G.A., Maloney Jr., R.E., 1999. Microdialysis studies of basal levels andstimulus-evoked overflow of dopamine and metabolites in the striatum of youngand aged Fischer 344 rats. Brain Research 16, 68–77.

Gregory, G.A., Eger, E.I.I.I., Munson, E.S., 1969. The relationship between age andhalothane requirement in man. Anesthesiology 30, 488–491.

Iselin-Chaves, I.A., Grotzsch, H., Besson, M., Burkhard, P.R., Savoldelli, G.L., 2009.Naloxone-responsive acute dystonia and parkinsonism following general anaes-thesia. Anaesthesia 64, 1359–1362.

Jansson, A., Olin, K., Yoshitake, T., Hagman, B., Herrington, M.K., Kehr, J., Permert,J., 2004. Effects of isoflurane on prefrontal acetylcholine release and hypothal-amic Fos response in young adult and aged rats. Experimental Neurology 190,535–543.

Jevtovic-Todorovic, V., Hartman, R.E., Izumi, Y., Benshoff, N.D., Dikranian, K.,Zorumski, C.F., Olney, J.W., Wozniak, D.F., 2003. Early exposure to commonanesthetic agents causes widespread neurodegeneration in the develop-ing rat brain and persistent learning deficits. Journal of Neuroscience 23,876–882.

Lieu, C.A., Subramanian, T., 2012. The interhemispheric connections of the stri-atum: implications for Parkinson’s disease and drug-induced dyskinesias. BrainResearch Bulletin 87, 1–9.

Marras, C., Lang, A., 2008. Invited article: changing concepts in Parkinson disease:moving beyond the decade of the brain. Neurology 70, 1996–2003.

Novick, A.M., Forster, G.L., Tejani-Butt, S.M., Watt, M.J., 2011. Adolescent socialdefeat alters markers of adult dopaminergic function. Brain Research Bulletin86, 123–128.

Opacka-Juffry, J., Ahier, R.G., Cremer, J.E., 1991. Nomifensine-induced increase inextracellular striatal dopamine is enhanced by isoflurane anaesthesia. Synapse7, 169–171.

Orset, C., Parrot, S., Sauvinet, V., Cottet-Emard, J.M., Bérod, A., Pequignot, J.M.,Denoroy, L., 2005. Dopamine transporters are involved in the onset of hypoxia-induced dopamine efflux in striatum as revealed by in vivo microdialysis.Neurochemistry International 46, 623–633.

Paxinos, G., Watson, C., 1998. The Brain in Stereotaxic Coordinates, 4th ed. AcademicPress, San Diego, CA.

Raner, C., Biber, B., Lundberg, J., Martner, J., Winsö, O., 1994. Cardiovas-cular depression by isoflurane and concomitant thoracic epidural anes-thesia is reversed by dopamine. Acta Anaesthesiologica Scandinavica 38,136–143.

Reeves, S., Bench, C., Howard, R., 2002. Ageing and the nigrostriatal dopaminergicsystem. International Journal of Geriatric Psychiatry 17, 359–370.

Salvatore, M.F., Apparsundaram, S., Gerhardt, G.A., 2003. Decreased plasma mem-

brane expression of striatal dopamine transporter in aging. Neurobiology ofAging 24, 1147–1154.

Satomoto, M., Satoh, Y., Terui, K., Miyao, H., Takishima, K., Ito, M., Imaki, J., 2009.Neonatal exposure to sevoflurane induces abnormal social behaviors and deficitsin fear conditioning in mice. Anesthesiology 110, 628–637.

2 Resea

S

S

T

T

V

Whittington, R.A., Virág, L., 2010. The differential effects of equipotent doses of

30 K. Kimura-Kuroiwa et al. / Brain

olt, K., Cotton, J.F., Cimenser, A., Wong, K.F., Chemali, J.J., Brown, E.N., 2011.Methylphenidate actively induces emergence from general anesthesia. Anes-thesiology 115, 791–803.

tanford, J.A., Currier, T.D., Purdom, M.S., Gerhardt, G.A., 2001. Nomifensine revealsage-related changes in K(+)-evoked striatal DA overflow in F344 rats. Neurobi-ology of Aging 22, 495–502.

anifuji, Y., Zhang, Y., Liao, M., Eger 2nd, E.I., Laster, M.J., Sonner, J.M., 2006.Do dopamine receptors mediate part of MAC? Anesthesia and Analgesia 103,1177–1181.

oner, C.C., Connelly, K., Whelpton, R., Bains, S., Michael-Titus, A.T., McLaughlin,D., Pl Stamford, J.A., 2001. Effects of sevoflurane on dopamine, glutamate and

aspartate release in an in vitro model of cerebral ischaemia. British Journal ofAnaesthesia 86, 550–554.

izi, E.S., Fekete, A., Karoly, R., Mike, A., 2010. Non-synaptic receptors and trans-porters involved in brain function and targets of drug treatment. British Journalof Pharmacology 160, 785–809.

rch Bulletin 89 (2012) 223– 230

Vizi, E.S., Labos, E., 1991. Non-synaptic interactions at presynaptic level. Progress inNeurobiology 37, 145–163.

Walsh, S., Minich, K., Mackie, K., Gorman, A.M., Finn, D.P., Dowd, E., 2010. Lossof cannabinoid CB1 receptor expression in the 6-hydroxydopamine-inducednigrostriatal terminal lesion model of Parkinson’s disease in the rat. BrainResearch Bulletin 81, 543–548.

Wang, Y., Kikuchi, T., Sakai, M., Wu, J.L., Sato, K., Okumura, F., 2000. Age-relatedmodifications of effects of ketamine and propofol on rat hippocampal acetyl-choline release studied by in vivo brain microdialysis. Acta AnaesthesiologicaScandinavica 44, 112–117.

isoflurane and desflurane on hippocampal acetylcholine levels in young andaged rats. Neuroscience Letters 471, 166–170.

Wynne, H.A., Blagburn, J., 2010. Drug treatment in an ageing population: practicalimplications. Maturitas 66, 246–250.

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