(Stroke. 1995;26:1101-1106.)
© 1995 American Heart Association, Inc.
Articles |
Changes in Striatal Dopamine Metabolism After Microsphere Embolism in Rats
From the Department of Pharmacology, Tokyo College of Pharmacy, Hachioji, Tokyo, Japan.
Correspondence to Satoshi Takeo, PhD, Department of Pharmacology, Tokyo College of Pharmacy, Hachioji, Tokyo 192-03, Japan.
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Abstract |
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Background and Purpose Dopamine plays an important role in striatal function. The present study was undertaken to elucidate the pathophysiological changes in striatal dopamine metabolism after microsphere embolism.
Methods Microspheres (48 µm) were injected into the right internal carotid artery of rats. Extracellular levels of dopamine and its metabolites were measured by in vivo microdialysis with the aid of high-performance liquid chromatography. In vivo striatal tyrosine hydroxylation and turnover (catabolism) rate of dopamine were estimated on the first and third days after the embolism. These were estimated by measuring tissue dopa or dopamine content in the presence of either an aromatic L-amino acid decarboxylase inhibitor or a tyrosine hydroxylase inhibitor, respectively.
Results In the microdialysis study, a 190-fold increase in the release of dopamine from the right striatum was observed 40 minutes after microsphere embolism, whereas the striatal dopamine metabolites decreased during the first 180 minutes after the embolism. Microsphere embolism decreased the striatal dopamine content throughout the experiment (28 days), whereas it increased tissue dopamine metabolites on the first day, followed by a decline in the metabolites on the third day or later. The in vivo turnover rate of dopamine decreased both on the first and third days, whereas the in vivo tyrosine hydroxylation decreased only on the third day after the embolism.
Conclusions The results suggest that microsphere embolism induces severe damage to striatal dopaminergic metabolism 3 to 28 days after the embolism. Dopamine synthesis may be more resistant to the embolism-induced ischemic insults than its catabolism.
Key Words: cerebral ischemia • embolism • dopamine • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dopamine is a major monoaminergic neurotransmitter in the striatum, and its metabolism in nerve terminals is regulated by synthesis, storage, reuptake to presynapse, and catabolism. Because these are mostly energy-dependent processes, dopamine metabolism in the striatum is deranged when the striatal region is oligemic or ischemic. In fact, several reports have shown disturbance in striatal dopaminergic neurotransmitter metabolism, which induces neurological dysfunction, in experimental models of brain ischemia in various species.1 2 3 Furthermore, in several brain ischemia models, excessive release of dopamine into the extracellular space has been demonstrated.4 5 Most of these experimental observations, however, concerned pathophysiological changes in the dopaminergic neurotransmitter metabolism during a short period of brain ischemia or during a period of reflow after transient global brain ischemia. Information concerning the dysfunction of dopaminergic neurotransmitter metabolism in vivo (including dopamine synthesis and catabolism) in sustained brain ischemia is poorly understood.
In previous studies, we have shown that cerebral embolism with microspheres induced a marked decrease in blood flow, a disturbance of energy metabolism, and a pronounced reduction in acetylcholine and neurotransmitter amino acid in the cortex, striatum, and hippocam-pus.6 7 8 9 In addition to this physiological and biochemical damage, microsphere embolism was also associated with the development of an area of infarct 3 days, but not 1 day, after the embolism.6 Thus, microsphere embolism is capable of inducing progressive and sustained cerebral ischemia that leads to cerebral infarction and eventually to degeneration of neuronal cells.
Naritomi10 suggested that multiple small infarction induced by microsphere embolism resembles clinical vascular dementia more closely than the infarction induced by middle cerebral artery occlusion. Cerebral embolism induced with microspheres may therefore provide useful information concerning the development of, protection against, and therapy for ischemic brain diseases such as cerebrovascular disease, cerebral infarction, stroke, and multi-infarct dementia.
The purpose of the present study was to elucidate the pathophysiological changes in striatal dopaminergic neurotransmitter metabolism after microsphere embolism. In particular, alterations in dopamine synthesis and turnover (catabolism) rate in microsphere-embolized rats during progressive and sustained ischemia were examined.
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Materials and Methods |
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Two hundred eighty-nine male Wistar rats weighing 180 to 220 g (Charles River Japan, Inc) were used in the present study. The animals were maintained under artificial conditions at 23±1°C with a constant humidity of 55±5% and a 12-h light/dark cycle and had free access to food and tap water according to the guidelines of experimental animal care issued by the Prime Minister's Office of Japan.
Microsphere-induced cerebral embolism was performed by the method previously described.6 Briefly, 199 rats were anesthetized with 35 mg/kg sodium pentobarbital IP and fixed in the supine position on an operation plate. After cervical incision, the right common carotid artery was isolated. The right external carotid and right pterygopalatine arteries were ligated with string. A polyethylene catheter (3F, 1.0 mm in diameter; Atom Co) was inserted into the right common carotid artery. Nine hundred microspheres (47.5±0.5 µm in diameter; NEN-005, New England Nuclear Inc) suspended in 20% dextran solution were injected into the right internal carotid artery through this cannula. Fifty-seven rats that had undergone sham operation were injected with the same volume of vehicle without microspheres. The control group comprised 26 nonoperated rats.
The procedure for intracerebral microdialysis was similar to that described by other investigators.5 11 12 Seven rats were anesthetized with chloral hydrate (400 mg/kg IP) and were then placed in a stereotaxic frame for microdialysis probe implantation. The skull was exposed, and a 1-mm hole was made in the right part of the skull by minidrill (model 28400, Proxxon). A guide cannula for the microdialysis probe was inserted into the right striatum at the following coordinates: 0.2 mm anterior and 3 mm lateral to bregma and 3.5 mm below dura according to the atlas of Paxinos and Watson.13 After surgery, the microdialysis probe with a 2-mm-long membrane (Eicom) was inserted into the striatum through the guide cannula. The microdialysis probe was perfused with Ringer's solution at a flow rate of 2 µL/min with a microinfusion pump (EP-60, Eicom). After a 2-hour stabilization period, cerebral embolism was induced by microsphere injection as described earlier. To determine the extracellular concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) fractions of the microdialysis perfusate were injected onto a high-performance liquid chromatograph with an electrochemical detector (HPLC-ECD) by an autoinjector (AS-10, Eicom), at 20-minute intervals, from 60 minutes before to 180 minutes after microsphere embolism. The HPLC-ECD system was composed of a reverse-phase column (MA-5 ODS, 150x4.6-mm ID, Eicom), a model L-6000 pump (Hitachi), and an electrochemical detector (ECD-100, Eicom). The mobile phase contained 0.1 mol/L citric acid–0.1 mol/L sodium acetate, 5 mg/L disodium EDTA, 230 mg/L sodium octane sulfonate, and 5% methanol in deionized and distilled water; the pH was adjusted to 3.5.
Sixteen hours after the operation, the behavior of the rats was scored on the basis of paucity of movement, truncal curvature, and forced circling during locomotion, which are considered to be typical symptoms of stroke in rats.14 15 The score of each item was ranked from 3 to 0 (3, very severe; 2, severe; 1, moderate). The rats that scored more than 7 points were considered to be type A; 6 to 4 points, type B; and less than 4 points, type C. In the present study, we used only type A animals for the studies on the striatal dopaminergic neurotransmitter metabolism.
Dopamine and its metabolites were measured in 7 control, 49 microsphere-injected, and 42 sham-operated rats at appropriate times in the experimental sequence. The animals were killed with a focal irradiation of microwave to the head at a strength of 5 kW for 0.85 seconds with a microwave applicator (TMW-6402C, Muromachikikai Co). After decapitation, the head of the animal was immersed in liquid nitrogen and left for 10 seconds (near freezing). The cerebral hemispheres were isolated, and the striatum was separated. The tissues were homogenized in 0.2 mol/L HClO4 and 0.01% disodium EDTA with a Polytron homogenizer (PT-10, Kinematica). The homogenate was centrifuged at 10 000g for 15 minutes at 4°C. The supernatant fluid was filtered through a membrane filter (0.45 µm). A 5-µL aliquot of the supernatant fluid was applied to an HPLC-ECD to determine the concentrations of dopamine, DOPAC, and HVA.
Tyrosine hydroxylase is the rate-limiting enzyme in dopamine biosynthesis.16 Inhibition of aromatic L-amino acid decarboxylase activity in vivo results in the accumulation of dopa in the striatum. In vivo tyrosine hydroxylation was estimated by measuring the accumulation of dopa after inhibition of aromatic L-amino acid decarboxylase with 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015).17 Fourteen microsphere-embolized rats were given 100 mg/kg IP NSD-1015 at different time intervals (days 1 and 3) after the operation. Seven rats that underwent no surgery were included as controls. Thirty minutes later, the rats were killed with a focal irradiation of microwave as described above. After decapitation and near freezing of the heads in liquid nitrogen, the cerebral hemispheres were isolated, and the striatum was separated. Tissue content of dopa in the striatum was determined by HPLC-ECD as described above.
Turnover (catabolism) rate of striatal dopamine in vivo was estimated
after depletion of dopamine by 
-methyl-p-tyrosine
(-MT). Fourteen type A rats were treated with 250 mg/kg IP -MT in
saline at different time intervals (days 1 and 3) after the operation.
Seven control rats were also treated with -MT. Four hours later, the
rats were irradiated by the microwave applicator, and the
-MT–induced depletion of dopamine in the striatum was estimated by
HPLC-ECD by the same procedure as described above. Turnover rate was
calculated as [DA]0
(log[DA]0-log[DA])/0.434t, where
[DA]0 and [DA] indicate dopamine contents in 0-mg and
250-mg -MT–treated groups, respectively, and
t=4.18
For determination of the infarct area, the rats were lightly anesthetized with ether and decapitated at different time intervals (days 1, 3, and 7) after the operation. The brains were rapidly isolated and cooled in a stainless-steel container immersed in ice. Each brain was positioned on a brain holder and coronally sectioned 3 mm from the frontal pole with razor blades. This procedure sections optimally faced striatal regions of the rat brain. The sections of brain tissue were incubated at 37°C for 30 minutes with 2% 2,3,5-triphenyltetrazolium chloride (TTC) in physiological saline, according to the method described previously.6 The tissue slices were transiently immersed into a 10% formalin solution and then photographed. The TTC-stained and TTC-unstained (including weakly stained) areas of the striatal region were estimated by a planimetric method.
We examined the possibility that dopaminergic activity plays a role in
behavioral symptoms of animals after microsphere embolism with -MT,
a dopamine-synthesis inhibitor, and haloperidol, a dopamine
D2 receptor antagonist. Fourteen rats were pretreated with
dopamine-depleting agent -MT. -MT (200 mg/kg IP) was injected
twice (4 and 2 hours) before the microsphere injection. Twelve rats
were treated with haloperidol (1 mg/kg IP) just before the microsphere
injection. The behavior of rats with type A symptoms was inspected and
scored daily for 3 days.
The results are expressed as mean±SEM. Statistical significance for comparison of dopamine and its metabolite contents in time course, tyrosine hydroxylation, and turnover rate studies was evaluated by ANOVA followed by Dunnett's multiple comparison. The mean values of the extracellular dopamine and its metabolite concentrations at each point were compared with pre-embolic values by a single-factor ANOVA using Fisher's protected least-significant difference test.19 The Wilcoxon rank sum test was used for comparison of changes in behavioral scores with and without drug treatment. P<.05 was considered to be statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of microsphere embolism on the extracellular concentration of dopamine and its metabolites are shown in Fig 1
. There was a marked increase in the extracellular
dopamine concentration of the right striatum after microsphere
embolism. The peak dopamine release was observed at 40 minutes after
microsphere embolism (a 190-fold increased compared with the
pre-embolic value). Thereafter, the release gradually attenuated
and returned to basal levels 180 minutes after microsphere embolism.
Dopamine metabolites, DOPAC and HVA, of the right striatum decreased
markedly after microsphere embolism, and this decrease was maintained
up to the end of the experiment (180 minutes).
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Microsphere injection induced type A strokelike symptoms in 124 (62%) of the operated rats. Among these rats, 11 (9%) of type A rats died by the third day after the operation. Forty (20%) rats died during the first day after the operation (before their symptoms were assessed). Twenty-five rats (13%) showed type B symptoms, and 10 rats (5%) showed type C symptoms. The sham-operated rats showed no strokelike symptoms and all survived.
The time courses of changes in striatal dopamine and its
metabolites (DOPAC and HVA) of both hemispheres in
microsphere-embolized and sham-operated rats are shown in Fig 2. Striatal dopamine contents of right and left
hemispheres in the controls were 7224±309 and 7682±296 ng/g frozen
tissue (n=7), respectively. In the sham-operated rats, there were no
appreciable changes in dopamine and its metabolites in the striatum of
both hemispheres throughout the experiment. In the microsphere-injected
rats, striatal dopamine content of the right hemisphere decreased to
58.8% and 2.6% of control on the first and third days after
microsphere embolism, respectively. The striatal dopamine content of
the right hemisphere 14 and 28 days after the operation remained at a
low level compared with the control level. The striatal dopamine
content of the left hemisphere of the microsphere-embolized
rats was not different from that of the controls.
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and 
), sham-operated (
and
), and control (DOPAC content of the right striatum increased on the first day after microsphere embolism compared with control values (253.8% of control). In contrast, the DOPAC contents on the third and fifth days were markedly lower than control values (9.1% and 16.3% of control, respectively). In the left hemisphere of the microsphere-embolized rats, there were no appreciable changes in DOPAC content. HVA content of the right striatum also increased significantly on the first day after microsphere embolism (238.6% of control). In contrast, the HVA contents on the third and fifth days were markedly lower than control values (7.7% and 25.4% of control, respectively). The striatal DOPAC and HVA contents of the right hemisphere on the 14th and 28th days after the operation were significantly lower than control values.
Because microsphere embolism induced a pronounced alteration in dopamine and its metabolite contents 3 or more days after the embolism, we examined dopamine metabolism on the first and third days in greater detail in the following experiment.
Fig 3 shows changes in in vivo tyrosine
hydroxylation in the striatum on the first and third days after the
embolism. In vivo tyrosine hydroxylation was unchanged in the striatum
of both hemispheres on the first day. In contrast, tyrosine
hydroxylation in the right striatum was markedly inhibited on the third
day after microsphere embolism.
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Fig 4 shows the turnover rate of dopamine in the
striatum on the first and third days after microsphere embolism. The
turnover rate of dopamine of the right striatum was significantly lower
than that of control rats (2561±73 ng/g per hour, n=7) on the first
and third days (563±38 and 20±18 ng/g per hour, respectively; n=7),
but no change in the turnover rate was seen in the left hemisphere of
the microsphere-injected rats.
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TTC staining of the striatal region was performed to confirm the
development of cerebral infarction (Table 1).
TTC-unstained (including weakly stained) areas of the right striatal
region of microsphere-embolized rats were not observed on the first day
after the operation. Of the striatal areas, 80% were TTC-unstained on
day 3 after the operation. The striatal TTC-unstained area of the right
hemisphere on day 7 was almost the same as that on day 3. There was no
striatal TTC-unstained area in either hemisphere of the sham-operated
rats.
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Microsphere injection with -MT pretreatment induced type A
strokelike symptoms in 9 (64%) operated rats. Among these rats, 4
(44%) type A rats died by the third day after the operation. Five
(36%) of 14 rats died during the first day after the operation (before
their symptoms were assessed). No rats showed type B or C symptoms.
Microsphere injection with haloperidol treatment induced type A
strokelike symptoms in 10 (83%) of the rats that had undergone
operation. Among these rats, 2 (20%) type A rats died by the third day
after the operation. Two rats showed type B symptoms (17%), and no
rats showed type C symptoms. In the early stages (1 to 3 days), we
observed that there were no differences in the strokelike symptoms
irrespective of -MT or haloperidol treatment (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we show a marked increase in the striatal extracellular dopamine concentration after microsphere embolism in rats with the use of microdialysis. This finding is a new observation in the microsphere-embolized animal and is in agreement with the results of other cerebral ischemia models such as permanent middle cerebral artery occlusion,12 transient bilateral carotid artery occlusion,4 and four-vessel occlusion combined with systemic hypotension in rats.11 Yao et al20 have shown that ischemia-induced dopamine release was caused by energy and membrane failures following a reduction in regional cerebral blood flow. Because we observed in a previous study that high-energy phosphate levels were markedly decreased in the ipsilateral striatum after microsphere embolism,7 the dopamine release in the present study can be attributed to the reduction in high-energy phosphate in this brain region.
Several investigators suggest that excessive release of neurotransmitters after cerebral ischemia is associated with depletion of tissue monoamines.2 21 22 Thus, the excessive release of the striatal dopamine at an early stage of microsphere embolism may consequently lead to a sustained reduction of striatal dopamine content.
The microdialysis study also showed a marked reduction in striatal extracellular DOPAC and HVA concentrations of microsphere-embolized rats. A decrease in tissue energy stores may lead to inhibition of the energy-dependent reuptake process of dopamine. The reduced reuptake of dopamine may result in fewer dopamine metabolites in nerve terminals, and thus these metabolites are released from nerve terminals to a lesser degree. Release of dopamine metabolites may also be decreased by reduced catabolism by monoamine oxidase in the nerve terminals, since this enzyme activity is energy dependent.11 12 23
While examining the striatal dopamine content, we observed sustained low levels of the striatal dopamine content of the right hemisphere over a period of 28 days. The decrease in neurotransmitter dopamine is consistent with the observations of other experimental models of permanent brain ischemia in the cortical region.1 2 3 Because dopamine synthesis is an energy-dependent process, the decrease in dopamine content would be expected to be prolonged after microsphere embolism. Siesjö24 has shown that changes in monoamine levels are unaltered by a short period of ischemic insult and that reduction in their levels requires a longer ischemic insult. Thus, sustained reduction in the striatal neurotransmitter dopamine content over a period of 28 days is indicative of long-term brain ischemia. We also observed widespread TTC-unstained areas in the striatum of microsphere-embolized rats after the third day. This suggests that the embolism eventually leads to cerebral infarction or cell death.
Dopamine metabolism on the first day after microsphere embolism was extensively studied. It should be noted that tyrosine hydroxylation, which is the initial and rate-limiting step of dopamine biosynthesis in the striatum, was unchanged on the first day after microsphere embolism. As discussed earlier, microsphere embolism depletes energy levels.7 Such a depletion in energy could inhibit the energy-dependent synthesis of dopamine in the striatum. Tyrosine hydroxylation therefore might be expected to be impaired after microsphere embolism. Our findings do not, however, support this proposal. It is conceivable that the lack of alteration in tyrosine hydroxylation on the first day may be due to preservation of neurotransmitter dopamine levels in synaptic vesicles. Hypoxic conditions are known to activate tyrosine hydroxylase.25 Furthermore, it has been suggested that a hypoxia-induced increase in tyrosine hydroxylase activity may be an adaptive response to maintain steady-state neurotransmitter synthesis when tissue oxygen is decreased.26 27 Thus, it is likely that tyrosine hydroxylation is unchanged in the present study because the suppression of energy-dependent dopamine synthesis is balanced by the embolism-induced increase in tyrosine hydroxylation.
We observed a marked increase in the striatal dopamine metabolite content on the first day after embolism. The results are in agreement with the observations of other investigators in different ischemia models.28 It has been suggested that an increase in dopamine metabolites may result from extensive release of dopamine, an increase in degradation of dopamine at an early stage (1 to 6 hours) of cerebral ischemia,18 29 30 and/or a decrease in transport of metabolites out of ischemic brain.31 The increase in degradation of dopamine is unlikely because dopamine turnover is decreased on the first day after embolism. Although we have not provided any information concerning the effects of microsphere embolism on transport of metabolites out of ischemic brain, an increase in the release of dopamine may, at least in part, contribute to the increase in striatal dopamine metabolites after microsphere embolism.
On the third day, a decline in tyrosine hydroxylation and a decrease in the striatal dopamine content in the ipsilateral hemisphere of microsphere-embolized rats were observed. This is probably due to inhibition of both synthesis and energy-dependent reuptake of dopamine32 33 as a result of prolonged depletion of cerebral energy stores.6 7 We also found that microsphere embolism suppressed dopamine turnover and depleted dopamine metabolites in the striatum on the third day. This may be caused by depletion of the dopamine store and impairment of dopamine catabolism.
It has been suggested that the behavioral symptoms in cerebral ischemia may be attributed to released dopamine in the striatum34 and that the striatal dopamine release is modulated by the D2 receptor.35 We examined the role of microsphere embolism–induced release of dopamine in the striatum in the behavioral symptoms using a dopamine-synthesis inhibitor and a D2 receptor antagonist. We failed to demonstrate an effect of these agents on the behavior of the microsphere-embolized rats. At present, we cannot determine whether the lack of effect is due to inadequate potency of these agents or whether altered dopaminergic activity plays only a minor role in the behavioral changes that follow microsphere embolism. Further studies are required to elucidate the role of dopaminergic systems and receptors in microsphere-induced pathogenesis.
In conclusion, like focal and global ischemia, an excessive release of striatal neurotransmitter dopamine was induced at an early stage of microsphere embolism. The excessive release of dopamine may be partially responsible for the subsequent depletion of the striatal dopamine content and dopamine metabolites. Microsphere embolism–induced pathophysiological changes are characterized by changes in dopamine catabolism that precede changes in tyrosine hydroxylation. Tyrosine hydroxylase may be resistant to microsphere embolism–induced cerebral ischemia because tyrosine hydroxylase exhibits a high affinity for oxygen.36
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Acknowledgments |
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This work was in part supported by grant-in-aid for general scientific research C from the Japanese Ministry of Education, Science, and Culture.
Received October 17, 1994; revision received February 8, 1995; accepted March 3, 1995.
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