Brain Research 891 (2001) 123–129www.elsevier.com/ locate /bres

Research report

Striatal manganese accumulation induces changes in dopaminemetabolism in the cirrhotic rat

a,b a b a ,*´Sergio Montes , Mireya Alcaraz-Zubeldia , Pablo Muriel , Camilo Rıosa ´ ´ ´Departamento de Neuroquımica, Instituto Nacional de Neurologıa y Neurocirugıa, ‘‘Manuel Velasco Suarez’’ Mexico D.F. Mexico

b ´ ´ ´Seccion Externa de Farmacologıa, Centro de Investigacion y de Estudios Avanzados del I.P.N., Mexico D.F., Mexico

Accepted 31 October 2000

Abstract

Manganese (Mn) is an essential metal that, in excess, causes an extrapyramidal syndrome consisting in tremor, rigidity and akinesia.Recently, Mn was found to accumulate in brains of cirrhotic patients who also present motor abnormalities. Manganese altersdopaminergic transmission promoting an increase in the turnover of dopamine (DA). In this study, we studied the changes in dopamineand its main metabolite homovanillic acid (HVA) to evaluate DA turnover following administration of manganese to bile-duct obstructed

21rats. Some groups of rats were treated with manganese chloride in two concentrations: 0.5 and 1 mg/ml of Mn in their drinking water.Four weeks after surgery and treatment with manganese, striatal Mn, DA and HVA were assessed. Marked increases (P,0.05) of striatalmanganese content were observed in cirrhotic rats treated and untreated with manganese, these augments were dependent on the Mnconcentration in water. Striatal contents of DA in cirrhotic rats diminished by 30% (P,0.05), administration of 0.5 mg/ml of manganesein drinking water to these rats returned dopamine to the basal level and 1 mg/ml of manganese increased dopamine content by 27%. Therelationship of Mn content and DA turnover (HVA:DA) in the same animal showed a positive and statically significant correlation(P,0.05), with differences in slope for sham (b 5 0.1528) and cirrhotic rats (b 5 0.0174). These results suggest that manganese brain1 1

accumulation observed in liver failure could be a key element to understand dopamine metabolism in cirrhotic condition of humans. 2001 Elsevier Science B.V. All rights reserved.

Theme: Neurotransmitters modulators, transporters and receptors

Topic: Catecholamines

Keywords: Dopamine; Turnover; Manganese; Cirrhosis; Hepatic encephalopathy

1. Introduction tissue from patients dying of cirrhosis showed neitherdopamine nor octopamine brain content alterations [5,12].

Hepatic encephalopathy (HE) is a common complication However, elevated HVA content was found in frontalof long-term cirrhosis. One of the main features observed cortex and striatum [5]. These results could reflect in-in this disease is motor deficit which include rigidity, creased synthesis and metabolism of dopamine in theseasterixis (flapping tremor) and poor muscular coordination brain regions, that have been attributed to increases in[10]. Because of the similarities in symptoms, HE is monoamine oxidase (MAO) activity which are also foundthought to involve an extrapyramidal syndrome similar to augmented in postmortem tissue of cirrhotic patients [40].Parkinson’s disease that consists in depletion of dopamine Another biochemical feature associated to the enhancedin basal ganglia [14]. The mechanism of dopamine deple- DA turnover in patients with hepatic encephalopathy is antion in HE was considered to be caused by false neuro- increased brain concentration of aromatic amino acidstransmitter accumulation [17]. Studies carried out with phenylalanine and tyrosine [6,23] both precursors of the

neurotransmitter dopamine.It has been observed that cirrhotic patients show a signal

*Corresponding author. Correspondence address: Ave. Insurgentes Surhyperintensity on magnetic resonance in globus pallidusNo. 3877, Mexico 14269, Mexico. Tel.: 152-5-606-3822, ext. 2005; fax:[9,20] that has been correlated with the presence of152-5-528-0095.

´E-mail address: camilorc@intersky.com (C. Rıos). extrapyramidal symptoms [25,27]. Blood manganese was

0006-8993/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0006-8993( 00 )03208-X

124 S. Montes et al. / Brain Research 891 (2001) 123 –129

also related to the hyperintensity on MRI [19]. Finally, Results are expressed as the mean intake in milliliters perdirect measurement of manganese in the globus pallidus, rat.putamen and caudate of patients dying of cirrhosis showed Four weeks after surgery, the weight of the animals wasseveral fold increases in concentration of this metal when recorded and then the rats were killed under ether anes-compared with controls [24,38,43]. thesia. Blood was collected by heart puncture, and liver

Manganese is a well-known neurotoxic metal, that in and brain were removed immediately. From brain, thelong-term exposure, produces neurologic alterations in- lateral striatum was dissected out according to Glowinskycluding rigidity, gait abnormalities and tremor [29]. Man- and Iversen [18].ganese alters dopaminergic transmission [11,15]. Studies inworkers occupationally exposed to Mn have shown posi- 2.2. Serum alanine aminotransferase activity andtive correlation between HVA and Mn urinary elimination, bilirubins content determinationwhich suggest increased catecholamine turnover elicited byMn [8]. In fact, manganese in exposed workers [31] and Serum was obtained for determinations of alaninenon-human primates [16] show the same pattern of hy- aminotransferase (ALT) activity [41] and bilirubins contentperintensity in magnetic resonance as that observed in (kit from Merck, Mexico) by using a Shimadzu UV 1203cirrhotic patients. This has been associated with man- spectrophotometer. Results are reported in mmol / l min forganese accumulation in basal ganglia [3,4]. ALT activities and mmol / l for bilirubins.

The main objective of this study is to search for therelationship among cirrhosis, manganese brain accumula- 2.3. Collagen quantificationtion and striatal dopamine and metabolites in the rat. Weused a model of cirrhosis consisting in bile duct obstruc- Collagen concentrations were determined by measuringtion during 4 weeks plus manganese in drinking water by hydroxyproline content in fresh liver samples after diges-using three concentrations of the metal: 0, 0.5 and 1 tion with acid and toluene extraction [30]. Results aremg/ml. expressed as mg of hydroxyproline per gram of wet tissue.

2.4. Analysis of striatal manganese2. Materials and methods

Manganese content was measured in the right striata of2.1. Animal treatments and biliary obstruction rats by digesting tissue in 1 ml of concentrated nitric acid

´(Suprapur Merck, Mexico) according to Rojas and RıosMale Wistar rats weighing about 200 g were used [42], using a Perkin-Elmer 3110 atomic absorption spec-

throughout; animals had free access to food (Formulab trophotometer with HGA-600 graphite furnace and AS-60Diet 5008 with 70.7 ppm of manganese content, reported autosampler. The content of Mn in tissue was reported asby the supplier) and either water or MnCl ?4H O solution mg of metal per gram of wet tissue.2 2

21(0.5 and 1 mg/ml of Mn ) immediately after surgery andduring the experiment. Extra hepatic cholestasis was 2.5. Striatal DA and HVA contentinduced by double ligation and section of the common bileduct. Rats were randomly allocated in one of six groups Left striata of rats from all treatment groups wereeach of n510. The animals of the first group were sham homogenized in 500 ml of perchloric acid–sodiumoperated (Sham). In the second group the animals were metabisulfite solution 1 M (0.1%, w/v). Samples werebile duct ligated (BDL). Rats in the third group were sham then centrifuged at 4000 g for 10 min and supernatantsoperated and received manganese in their drinking water at were kept at 2708C until analyzed. The striatal contents of

210.5 mg/ml of Mn (Sham Mn-0.5). The fourth group had dopamine (DA) and homovanillic acid (HVA) were ana-biliary obstruction plus manganese in their drinking water lyzed using a Perkin-Elmer pump LC-250, a Metrohmat 0.5 mg/ml (BDL Mn-0.5). The fifth group of rats electrochemical detector (mod. 641-VA) and a Hewlett-consisted in sham-operated animals and manganese in their Packard 3396-II integrator as described previously [42].

21drinking water, 1 mg/ml concentration of Mn (Sham Results were expressed as mg of catecholamine per gramMn-1). Finally, group six consisted in bile duct ligated rats of wet tissue.with manganese in their drinking water in a 1 mg/ml

21concentration of Mn (BDL Mn-1). A control group 2.6. Statistical analysiswithout sham operation and manganese was also carriedout. The results of this group are not included since they A two-way analysis of variance was used, with Dun-were not significantly different from the sham group (data nett’s test as posthoc to compare the effects of thenot shown). concentrations of manganese used. Simple linear regres-

Water intake of rats was measured every day through the sion analyses were applied to relate striatal Mn and DAmanganese exposure and during the 4 weeks postsurgery. turnover rate. Statistical significances were considered

S. Montes et al. / Brain Research 891 (2001) 123 –129 125

when P,0.05. All statistical analyses were performed groups with 4 weeks of biliary obstruction as previouslyusing SPSS software. reported in this model [30]. Serum ALT activity is a

well-recognized marker of hepatic cell death due to itscitosolic location [36]. Bile-duct obstruction (BDL) pro-

3. Results duced significant increases in the ALT activity, in the sameway, groups of rats with biliary duct obstruction plus

3.1. Animals manganese (0.5 and 1 mg/ml) augmented their serumALT activity in the same extent as BDL group. Again,

At the end of treatment, body weights in the different manganese did not modify ALT activity in sham-operatedgroups were recorded as follows (g mean6standard error rats receiving both concentrations of manganese (Table 1).of the mean): Sham5390613.86, Sham-Mn0.55 As can be seen in Table 1, prolonged hepatic damage leads38664.01, Sham-Mn1536266.74, BDL532967.14, to increments of about 150% in collagen content (P,

BDL-Mn0.55324611.17, BDL5326611.61. The two- 0.05), indicating fibrosis and cirrhosis. Treatment withway ANOVA showed an important effect only for the BDL manganese does not produce any effect on collagen(F543.07, P,0.001). Neither the Mn treatment nor the content either in BDL groups or in sham-operated rats.interaction showed statistical significance.

Rats in the different groups varied their water intake3.3. Effects on Mn brain accumulation

according to the treatment as follows (milliliters per ratmean6S.E.M.): Sham544.1861.07, Sham-Mn0.55

After 4 weeks of treatment with manganese in sham47.8960.97, Sham Mn-1540.8661.35, BDL5

operated rats, striatal Mn content rose by 77 and 137% for38.5961.01, BDL-Mn0.5531.0861.60 and BDL-Mn15 210.5 and 1 mg/ml Mn , respectively, when compared with25.8661.13. In this case, statistical analysis showed a clear

the sham without treatment (control). On the other hand,effect for BDL (F5162.33, P,0.001), the Mn treatment

cirrhotic rats without treatment with manganese increased(F525.17, P,0.001) and the interaction between opera- 21its Mn striatal content by 57%. Cirrhotic rats receivingtion and Mn (F512.9, P,0.001). 21manganese, increased their striatal Mn content depend-

Based on the water intakes, the concentration of man-ing on the concentration of manganese used, thus, 0.5

ganese used, and the duration of treatment we were able to 21mg/ml of Mn in drinking water provoked a 357% ofestimate the cumulative dose of manganese for each group 21striatal metal accumulation and 1 mg/ml of Mn pro-(mg Mn/kg6S.E.M.): Sham-Mn0.551704638, Sham-

moted by 873% versus control group (Fig. 1). StatisticalMn1531556112, BDL-Mn0.551342669.3 and BDL-

two-way ANOVA test revealed significant effects for theMn152221697.

biliary obstruction (F5140.38, P,0.001), the manganesetreatment (F578.69, P,0.001) and the interaction be-

3.2. Indicators of liver damage 21tween Mn and liver damage (F540.72, P,0.001).

Table 1 shows that sham operated rats do not increasetheir serum concentration of bilirubins when treated with 3.4. Effects on dopamine and HVAmanganese at the two concentrations used. On the otherhand, total, conjugated and unconjugated bilirubins in- Dopamine was measured after 4 weeks of biliarycreased about 80, 180 and 70 fold, respectively, in those obstruction, which is considered a severe liver damage

Table 1aHepatic function measurements

Treatment Bilirubins (mmol / l) ALT Collagen(mmol/ l /min) (mmol /g tissue)

Total Conjugated Unconjugated

Sham 2.5760.49 2.2760.37 0.2960.83 35.3061.68 0.090560.01BDL 216.62614.06* 168.85612.11* 47.7762.99* 58.8161.35* 0.221460.01*

Sham-Mn 6.69161.29 3.5160.47 3.1761.12 39.5162.62 0.078660.000.5 mg/mlBDL-Mn 214.06614.24* 157.35610.64* 56.7164.63* 59.8465.87* 0.288960.05*0.5 mg/mlSham-Mn 4.0960.52 3.4660.53 0.6260.80 37.1961.66 0.084560.021 mg/mlBDL-Mn 174.00613.60* 124.02610.09* 49.9863.59* 49.7462.9* 0.215860.01*1 mg/mla Data are expressed as mean6S.E.M. values. BDL, bile-duct ligation; ALT, alanine aminotransferase; *, P,0.05, significantly different from sham group.Two-way ANOVA followed by Dunnett’s test.

126 S. Montes et al. / Brain Research 891 (2001) 123 –129

ganese concentration in their drinking water showed asuppression of the BDL-induced lowering effect. Further-more, cirrhotic rats which received the 1 mg/ml con-centration of manganese in their drinking water not onlyreversed the BLD effect, but also increased their striataldopamine levels by 27% when compared to sham group. Atwo-way ANOVA showed a significant effect for theinteraction between biliary obstruction and manganese indrinking water on striatal DA (F521.24, P,0.001).

Regarding striatal HVA, which is considered the mainmetabolite of dopamine, a clear effect of manganese at the1 mg/ml concentration was observed in the sham-operatedgroup (Sham Mn-1) as well as in bile-duct obstructed rats(BDL Mn-1) due to increases of 107 and 127%, respec-tively (P,0.05). These effects were not observed in thosegroups receiving manganese at the 0.5 mg/ml concen-tration (Fig. 3).Fig. 1. Striatal manganese content in Wistar rats with bile-duct ligation

(BDL) or sham-operated treated either with 0 (control), 0.5 (Mn-0.5) or Fig. 4 shows results concerning striatal dopamine turn-1.0 (Mn-1.0) mg/ml of manganese in drinking water for 4 weeks. Results over, expressed as HVA/dopamine ratio. Sham operatedare expressed as mean6S.E.M. of n55–9 independent experiments. *,

rats receiving manganese augmented their HVA:DA ratioStatistically significant effect of manganese (F578.69 P,0.001); **,in a concentration-dependent fashion, since it was ob-statistically significant effect of BDL (F5140.38, P,0.001); 1, statisti-served 66 and 164% increases in the 0.5 and 1 mg/mlcal significance for the interaction (F540.72, P,0.001), two-way

ANOVA. manganese concentrations, respectively. Cirrhosis in-creased DA turnover by 69%, as compared with sham-operated group. When cirrhotic rats were treated withmanganese in the 0.5 mg/ml concentration a non-signifi-

stage [26]. Fig. 2 shows that, after 4 weeks of treatment, cant increase in DA turnover was observed (46%). Inmanganese did not affect striatal DA levels in control contrast, cirrhotic rats receiving the 1 mg/ml concentration(sham-operated) rats, in any of the two concentrations of manganese in their drinking water augmented HVA:DAused. In contrast, cirrhotic rats (BDL) presented a decrease ratio 153% (P,0.05). In this case, two-way ANOVAin striatal DA of about 30% and resulted statistically statistical analyses revealed a significant effect for thesignificant when compared with sham group (P,0.05); manganese in drinking water (F557.53, P,0.001) as wellhowever, cirrhotic rats treated with the 0.5 mg/ml man- as for the interaction between manganese and biliary

obstruction (F57.57, P,0.05).Manganese content (right striatum) showed a direct

Fig. 2. Striatal dopamine content of Wistar rats with bile-duct ligation(BDL) or sham operated, treated either with 0 (control), 0.5 (Mn-0.5) or Fig. 3. Striatal homovanillic acid (HVA) content of Wistar rats with1.0 (Mn-1) mg/ml of manganese in drinking water during 4 weeks. bile-duct ligation (BDL) or sham-operated, treated either with 0 (control),Results are expressed as mean6S.E.M. of n55–9 independent experi- 0.5 (Mn-0.5) or 1.0 (Mn-1.0) mg/ml of manganese in drinking water forments. *, Statistically different from Sham group, P,0.05 two-way 4 weeks. Results are expressed as mean6S.E.M. of n55–9 independentANOVA, followed by Dunnett’s test; 1, statistical significance for the experiments. *, Statistically different from Sham group, P,0.05 two-wayinteraction (F521.24, P,0.001), two-way ANOVA. ANOVA, followed by Dunnett’s test.

S. Montes et al. / Brain Research 891 (2001) 123 –129 127

4. Discussion

Manganese is an essential metal, cofactor for variousenzymes [44]. Deficiency of Mn during developmentcauses growing abnormalities, bone malformations, re-productive alterations and ataxia [45]. Manganese isobtained physiologically from food, excess is excreted bybiliary route [34]. Accumulation of manganese has beenobserved in basal ganglia of cirrhotic patients [38,43]attributed to the limited ability of a cirrhotic liver toeliminate this metal. Therefore, it was anticipated that theutilization of a model of cirrhosis would increase man-ganese in brain basal ganglia, as shown by Rose et al. [43].Our results showed that 4 weeks of biliary obstructionincreased striatal Mn content by 57% (Fig. 1), as it hasFig. 4. Striatal dopamine turnover, assessed as HVA:DA ratio, in Wistar

rats with bile-duct ligation (BDL) or sham operated, treated either with 0 been reported in 6 weeks cirrhotic rats by using a model of(control), 0.5 (Mn-0.5) or 1.0 (Mn-1.0) mg/ml of manganese in drinking biliary duct obstruction plus thioacetamide [43]. In order towater during 4 weeks. Results are expressed as mean6S.E.M. of n55–9 accelerate manganese brain accumulation, we sup-independent experiments. *, Statistically different from Sham group,

plemented cirrhotic rats with manganese at concentrationsP,0.05 two-way ANOVA, followed by Dunnett’s test; 1, statisticalpreviously reported for rats in studies of exposure: 0.5 andsignificance for the interaction (F57.57, P,0.05) two-way ANOVA.

211 mg of Mn per ml [35]. In fact, the cumulative doseachieved by using these concentrations of manganese liesin the range of 1000–5000 mg/kg, already reported in

relationship against the dopamine turnover (left striatum) exposure studies [32]. We observed that striatal manganesein the same animal, this correlation proved to be statistical- accumulation was potentiated in rats with biliary-obstruc-ly significant (P,0.05) and dependent on animal liver tion depending on the concentration of manganese used.

2status. In sham rats striatal Mn content explains (r ) 57% These increments could be explained as a result of bileof the HVA:DA effect, whereas in cirrhotic rats Mn duct obstruction, which is the physiological route of

2explains (r ) 48% of DA turnover (Fig. 5). Differences in excretion of this metal [34].slopes of the adjusted regression lines were based on 95% Previous studies on catecholamines in experimentalconfidence intervals: (0.0851, 0.2204) for sham and hepatic encephalopathy have led to conflicting results(0.0055, 0.0238) for cirrhotic rats. [28,21], and in human postmortem studies there does not

seem to be a difference in striatal dopamine betweencirrhotic patients and controls [5,12]. Such differences canbe explained by examining the models and methods used.In this study we decided to use a rat cirrhosis modelconsisting of bile-duct ligation for 4 weeks, in order tosimulate a long term liver failure in humans, ethiologicallyrelated to biliary obstruction.

In our study cirrhotic rats not receiving manganese,decreased their striatal dopamine by 30% (Fig. 2); thiscould be the result of an altered catecholamine metabolismfound in experimental [28] and human encephalopathy[40]. Cirrhotic rats that received low manganese con-centration in drinking water showed a similar dopamineconcentration to the sham group and even in the groupwith the highest concentration of manganese an increasedstriatal dopamine content was observed. A similar patternof reverting low dopamine content by manganese waspreviously observed by our group, in a model of Parkison’sdisease in mice [42]. In both cases, manganese accumula-Fig. 5. Scatter plot of manganese content versus dopamine turnover of

Wistar rats with biliary duct ligation (BDL) and treated either with 0 tion could be acting by stimulating the synthesis of(control), 0.5 (Mn-0.5) or 1.0 (Mn-1.0) mg/ml of manganese in drinking dopamine, since augmentation of HVA was also found.water for 4 weeks. A change of slope was observed in both the sham and These findings have been associated with the capability ofcirrhotic. Relationships showed statistical significance in simple correla-

manganese to modify L-tyrosine hydroxylase activity [7],tion (P,0.05) with coefficients r50.756 and r50.694 for sham andwhich is the rate-limiting enzyme involved in the synthesisbile-duct ligated rats, respectively. Slopes showed statistically different

values (P,0.05) 95%CI. n55–9 independent experiments. of dopamine. It is noteworthy that in sham-operated rats

128 S. Montes et al. / Brain Research 891 (2001) 123 –129

manganese administration did not affect striatal dopamine Acknowledgementscontent.

´It has been proposed that manganese III complexes may The authors wish to thank Patricia Gonzalez, Ramon´react with dopamine [1,13] to form reactive species that Hernandez and Benjamin Salinas for their technical assis-

would lead to toxic side reactions. This does not seem to tance. This Work was supported by CONACYT fellowshipbe the case in the present study, since we observed No. 138631 to Sergio Montesrecuperation of dopamine concentrations in cirrhotic ratstreated with manganese. Reactions of manganese withcathecholamines may depend on the time of exposure to Referencesthe metal and cell’s redox status.

Groups treated with a high concentration of manganese [1] F.S. Archibald, C. Tyree, Manganese poisoning and the attack oftrivalent manganese upon catecholamines, Arch. Biochem. Biophys.statistically increased their HVA concentrations, as already256 (1987) 638–650.observed in workers exposed to the metal, who presented

´[2] J.A. Arias-Montano, D. Martınez-Fong, J. Aceves, GABAB receptorincreased urinary HVA elimination that correlated withactivation partially inhibits N-methyl-D-aspartate mediated tyrosine

urinary manganese [8]. It is also known that manganese is hydroxylase stimulation in rat slices, Eur. J. Pharmacol. 218 (1992)able to increase MAO activity after short-term exposure 335–338.[11]. Manganese also inhibits dopamine reuptake, in fact, [3] M. Aschner, K.E. Vrana, W. Zheng, Manganese uptake and dis-

tribution in the central nervous system (CNS), NeuroToxicology 20manganese could be transported into dopaminergic pre-(1999) 173–180.synaptic terminal by dopamine reuptake system [22].

[4] M. Aschner, J.L. Aschner, Manganese transport across the blood–Inhibition of dopamine reuptake may lead to the increased brain barrier: relation to iron homeostasis, Brain Res. Bull. 24dopamine extra-neuronal oxidation. These two activities of (1990) 857–860.manganese could account for increased striatal HVA found [5] M. Bergeron, T.A. Reader, G. Pomier-Layrargues, R.F. Butterworth,

Monoamines and metabolites in autopsied brain tissue from cirrhoticin those groups treated with the highest manganese con-patients with hepatic encephalopathy, Neurochem. Res. 14 (1989)centration.853–859.

Regarding dopamine turnover, we observed that cir- [6] M. Bergeron, T.A. Reader, G. Pomier-Layrargues, R.F. Butterworth,rhotic rats increased their ratio in relation to the fall in Aromatic and branched-chain amino acids in autopsied brain tissuestriatal dopamine content. Manganese also caused in- from cirrhotic patients with hepatic encephalopathy, Metab. Brain

Dis. 4 (1989) 169–176.creases in dopamine turnover but, due to its capability of[7] E. Bonilla, L-Tyrosine hydroxylase activity in the rat brain afterincreasing TH and MAO activities, since sham groups

chronic oral administration of manganese chloride, Neurobehav.treated with manganese presented virtually the same Toxicol. 2 (1980) 37–41.dopamine striatal content as control group, but increased [8] J.P. Buchet, C. Magos, H. Roels, E. Ceulemans, R. Lauwerys,HVA content. Urinary excretion in urinary of homovanillic acid in workers

exposed to manganese, Int. Arc. Occup. Environ. Health 65 (1993)We observed that manganese content in striatum pre-131–133.sented a direct relationship with dopamine turnover; but

[9] R.F. Butterworth, L. Spahr, S. Fontaine, G.P. Layrargues, Man-this relation changed as a function of rat’s liver damage ganese toxicity, dopaminergic dysfunction and hepatic en-with slopes b 5 0.1528 for sham and b 5 0.0147 for cephalopathy, Metab. Brain Dis. 10 (1995) 259–267.1 1

cirrhotic rats. This means that brain manganese influences, [10] R.F. Butterworth, Complications of cirrhosis III. Hepatic en-cephalopathy, J. Hepatol. 32 (Suppl. 1) (2000) 171–180.at least in part, dopamine brain metabolism in

[11] S.V. Chandra, G.S. Shukla, Concentration of striatal catecholaminespathophysiological conditions. The influence of manganesein rats given manganese chloride through drinking water, J. Neuro-

on catecholamines metabolism changes in the presence of chem. 36 (1981) 683–687.a preexistent metabolic disturbance, for example, liver [12] G. Cuilleret, G. Pomier-Layrargues, F. Pons, J. Cadilhac, H. Michel,damage. Changes in brain catecholamine levels in human cirrhotic hepatic

encephalopathy, Gut 21 (1980) 565–569.One possibility to explain differences in slopes in Fig. 5[13] J. Donaldson, D. McGregor, F. LaBella, Manganese toxicity: acould be the enhanced GABAergic tone preexistent in both

model for free radical mediated neurodegeneration?, Can. J. Physiol.rats and humans with hepatic encephalopathy that has been 60 (1982) 1398–1405.associated with increased endogenous benzodiacepine [14] H. Ehringer, O. Hornykiewicz, Verteilung von noradrenalin undagonists [33,37]. Experiments conducted in animals have dopamin (3-hydroxytyramin) im gehirn des menschen und ihr

verhalten bei erkrankungen des extrapyramidalen systems, Klin.shown that increased GABAergic tone in striatum inhibitsWochenschr. 38 (1960) 1236–1239.dopamine release [46] and negatively regulates tyrosine

[15] H. Eriksson, S. Lenngren, E. Geilbronn, Effects of long-termhydroxylase activity [2]. Combination of the two mecha- administration of Mn on biogenic amine levels in discrete striatalnisms of influencing dopamine metabolism such as cir- regions of rat brain, Arch. Toxicol. 59 (1987) 426–431.rhosis and manganese are reflected as differences in slopes [16] H. Eriksson, J. Tedroff, K.A. Thuomas, S.M. Aquilonious, P.

Hartvig, K.J. Fasth, P. Bjurling, B. Langstrom, K.G. Hedstrom, E.for sham and cirrhotic rats.Heilbronn, Manganese-induced brain lesions in Macaca fascicularisThe results in this study suggest that manganese ac-as revealed by positron emission tomography and magnetic reso-

cumulation in brain of cirrhotic rats has direct effects in nance imaging, Arch. Toxicol. 66 (1992) 403–407.dopamine metabolism and this would help to explain the [17] J.E. Fischer, R.J. Baldessarini, False neurotransmitters and hepaticsymptoms observed in patients with cirrhosis. failure, Lancet 2 (1971) 75–80.

S. Montes et al. / Brain Research 891 (2001) 123 –129 129

[18] J. Glowinski, L.L. Iversen, Regional studies of catecholamines in the [32] M.C. Newland, Animal models of manganese’s neurotoxicity,3 3 3rat brain. Disposition of H-norepinephrine, H-dopamine and H- NeuroToxicology 20 (1999) 415–432.

DOPA in various regions of the brain, J. Neurochem. 13 (1966) [33] M. Olasmaa, J.D. Rothstein, A. Guidott, R.J. Weber, S.M. Paul, S.665–669. Spector, M.L. Zerenoli, M. Baraldi, E. Costa, Endogenous benzo-

[19] R. Hauser, T. Zesiewicz, C. Martinez, A. Rosemurgy, C. Olanow, diazepine receptors ligands in human and animal hepatic en-Manganese intoxication and chronic liver failure, Ann. Neurol. 36 cephalopathy, J. Neurochem. 55 (1990) 2015–2023.(1994) 871–875. [34] P.S. Papavasiliou, S.T. Miller, G.C. Cotzias, Role of liver in

[20] R. Hauser, T. Zesiewicz, C. Martinez, A. Rosemurgy, C. Olanow, regulating distribution and excretion of manganese Am, J. Physiol.Blood manganese correlates with brain magnetic resonance imaging 211 (1966) 211–216.changes in patients with liver disease, Can. J. Neurol. Sci. 23 (1996) [35] B.A. Pappas, D. Zhang, C.M. Davidson, T. Crowder, G.A.S. Park,95–98. T. Fortin, Perinatal manganese exposure: behavioral, neurochemical

[21] P.M. Herlin, J.H. James, C.A. Nachbauer, J.E. Fischer, Effect of and histopathological effects in the rat, Neurotoxicol. Teratol. 19total hepatectomy and administration of branched-chain amino acids (1997) 17–25.on regional norepinefrine, dopamine and amino acids in rat brain, [36] G.L. Plaa, W.R. Hewitt, Detection and evaluation of chemicallyAnn. Surg. 198 (1983) 172–177. induced liver injury, in: W. Hayes (Ed.), Principles and Methods of

[22] R.T. Ingersoll, E.B. Montgomery, H.V. Aposhian, Central nervous Toxicology, Raven Press, New York, pp. 407–445.`system toxicity of manganese II: Cocaine or reserpine inhibit [37] G. Pomier-Layrargues, J.F. Giguere, J. Lavoie, P.P. Perney, S.

manganese concentration in rat brain, NeuroToxicology 20 (1999) Ganong, M. D’Amour, Clinical efficacy of Ro-15-7788 (flumazenil)467–476. in cirrhotic patients with hepatic coma: results of a randomized,

[23] K. Jellinger, P. Riederer, W.D. Rausch, P. Kothbauer, Brain mono- double-blind placebo-controlled crossover trial, Hepatology 19amines in hepatic encephalopathy and other types of metabolic (1994) 32–37.coma, J. Neural Transm. Suppl. 14 (1978) 103–120. [38] G. Pomier-Layrargues, L. Spahr, R.F. Butterworth, Increased man-

[24] D. Krieger, S. Krieger, O. Janssen, P. Grass, L. Theilmann, H. ganese concentrations in pallidum of cirrhotic patients, Lancet 345Lichtnecker, Manganese and chronic encephalopathy, Lancet 346 (1995) 735.

`(1995) 270–274. [40] V.L. Raghavendra Rao, J. F Giguere, G.P. Layrargues, R.F. Butter-´[25] J. Kulisevsky, J. Pujol, J. Balauzo, C. Junque, J. Deus, A. Capdevil- worth, Increased activities of MAOA and MAOB in autopsied brain

la, C. Villanueva, Pallidal hiperintensity on magnetic resonance tissue from cirrhotic patients with hepatic encephalopathy, Brainimaging in cirrhotic patients: clinical correlations, Hepatology 16 Res. 621 (1993) 349–352.(1992) 1382–1388. [41] S. Reitman, S. Frankel, A colorimetric method for determination of

[26] J. Kountaras, H. Barbara, J.S. Billing, P. Billing, Prolonged bile duct serum oxalacetic and glutamic pyruvic transaminases, Am. J. Clin.obstruction: a new experimental model for cirrhosis in the rat, Br. J. Pathol. 28 (1957) 56–63.

´Exp. Pathol. 65 (1984) 305–311. [42] P. Rojas, C. Rıos, Short-term manganese pretreatment partially[27] E. Malecki, A. Devenyi, T. Barron, T. Mosher, P. Eslinger, C. protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neuro-

Flaherty-Craig, L. Rossaro, Iron and manganese homeostasis in toxicity, Neurochem. Res. 20 (1995) 1217–1223.chronic liver disease: Relations to pallidal T1-weighted magnetic [43] C. Rose, R.F. Butterworth, J. Zayed, L. Normandin, K. Todd, A.resonance signal hyperintensity, NeuroToxicology 20 (1999) 647– Michalak, L. Spahr, P.M. Huet, G. Pomier-Layrargues, Manganese652. deposition in basal ganglia structures results form both portal-

[28] A.M. Mans, R.A. Hawkins, Brain monoamines after portacaval systemic shunting and liver dysfunction, Gastroenterology 117anastomosis, Metab. Brain Dis. 1 (1986) 45–52. (1999) 640–644.

[29] I. Mena, O. Marin, S. Fuenzalida, G.C. Cotzias, Chronic manganese [44] J.R.J. Sorenson, L.S.F. Soderberg, L.W. Chang, Radiation protectionpoisoning: clinical picture and manganese turnover, Neurology 17 and radiation recovery with essential metalloelement chelates, Proc.(1967) 128–136. Soc. Exp. Biol. Med. 210 (1995) 191–204.

[30] P. Muriel, Role of nitric oxide in the antifibrotic and the cholestatic [45] E.J. Underwood, in: Trace Elements in Human and Animal Nutri-actions for interferon Alpha2b, Drug Devel. Res. 48 (1999) 45–52. tion, Academic Press, New York, 1977, pp. 170–195.

[31] K. Nelson, J. Glodnick, T. Korn, C. Angle, Manganese en- [46] P.L. Wood, Actions of GABAergic agents on dopamine metabolismcephalopathy: utility of early magnetic resonance imaging, Br. J. in the nigro–estriatal pathway of the rat, J. Pharmacol. Exp. Ther.Indust. Med. 50 (1993) 510–513. 222 (1982) 674–679.