Turnover of Dopamine and Dopamine Metabolites in Rat Brain: Comparison Between Striatum and Substantia Nigra

Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.     

An In Vivo Study of Dopamine Release and Metabolism in Rat Brain Regions Using Intracerebral Dialysis

Intracerebral dialysis was used with a specifically designed HPLC with electrochemical detection assay to monitor extracellular levels of endogenous 3,4-dihydroxyphenylethylamine (dopamine, DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in brain regions of the halothane-anesthetized rat. Significant amounts of DA, DOPAC, and HVA were detected in control perfusates collected from striatum and n. accumbens whereas the medial prefrontal cortex showed lower monoamine levels. The ratio of DA in perfusate to DA in whole tissue suggests that in f. cortex, compared to n. accumbens and striatum, there is a greater amount of DA in the extracellular space relative to the intraneuronal DA content. The DOPAC/HVA ratio in control perfusates varied between regions in accordance with whole tissue measurements. This ratio was highest in n. accumbens and lowest in f. cortex. The monoamine oxidase inhibitor pargyline (100 mg/kg i.p.) caused an exponential decline in DOPAC, but not of HVA, in regional perfusates, an effect that was associated with an increase in DA. The data indicated a higher turnover of extracellular DOPAC in n. accumbens than in striatum and the lowest DOPAC turnover in f. cortex. The rate of decline in extracellular DA metabolite levels was slow compared to whole tissue measurements. In the perfusates there was no statistical correlation between basal amounts of DA in the perfusates and DOPAC and HVA levels or DOPAC turnover for any of the areas, indicating that measurement of DA metabolism in the brain under basal conditions does not provide a good index of DA release. In summary, this study shows clear regional differences in basal DA release and metabolite levels, metabolite patterns, and DOPAC turnover rates in rat brain in vivo.     

Methamphetamine-elicited alterations of dopamine- and serotonin-metabolite levels within μ-opioid receptor knockout mice: a microdialysis study

μ-Opioid receptors (μ-ORs) modulate methamphetamine (MA)-induced behavioral responses, increased locomotor activity and stereotyped behavior in the mouse model. We investigated the changes in dopamine (DA) and serotonin (5-HT) metabolism in the striatum following either acute or repeated MA treatment using in vivo microdialysis. We also studied the role of μ-ORs in the modulation of MA-induced DA and 5-HT metabolism within μ-OR knockout mice. Subsequent to either acute or repeated intraperitoneal administration of MA, wild-type mice revealed decreases in extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a dose-dependent manner. Moreover, wild-type mice had reductions in basal concentrations of DOPAC and HVA following repeated MA treatment with a higher dose. The effects of acute, repeated or challenge MA administration upon extracellular levels of DOPAC and HVA within μ-OR knockout mice significantly differed from the wild-type controls. The duration of recovery to the basal levels of extracellular DA and 5-HT metabolites induced by MA were much longer in wild-type mice than for μ-OR knockout mice. These findings suggest that μ-ORs play a modulatory role in MA-induced DA and 5-HT metabolism in the mouse striatum. This possible mechanism of MA-induced behavioral change as modulated by μ-OR merits further study.     

Intracerebrally administered (6r)-l-erythro-tetrahydrobiopterin does not affect extracellular levels of dopamine and serotonin metabolites in rat striatum in vivo during measurement by brain micro-dialysis system

By the use of the brain micro-dialysis technique combined with HPLC, the changes in the extracellular levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and a serotonin(5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were examined in the rat striatum before and after intracerebral injection of a vehicle or (6R)-l-erythro-tetrahydrobiopterin (6R-BH₄), the natural form of the cofactor for the tryrosine hydroxylase and tryptophan hydroxylase. No apparent change after the 6R-BH, treatment was found in the levels of DA, DOPAC, HVA and 5-HIAA in the striatal dialysate. In contrast, the levels of total biopterin in both the operated (dialysis probe-implanted) and unoperated striatum of 6R-BH₄-treated rats increased by 23- and 93-fold, respectively, when compared with those of the control, vehicle-treated rats. The results indicate that increased levels of the tetrahydrobiopterin cofactor may not affect the release of DA and the extracellular level of DA and 5-HT metabolites in the physiologically normal brain.     

Turnover of Dopamine and Serotonin and Their Metabolites in the Striatum of Aged Rats

Turnover of dopamine (DA), serotonin [5-hydroxytryptamine (5-HT)], and their metabolites has been measured in adult and aged rats. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxy-3-indoleacetic acid (5-HIAA) have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase (MAO) and from the accumulation rates by probenecid inhibition of the probenecid-sensitive transport system. DA and 5-HT turnover rates have been measured as accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015) and as accumulation rates of DA and 5-HT after pargyline inhibition of MAO. The DA turnover rate after NSD-1015 was 23.9% lower in aged rats than in adults, whereas after pargyline there was no significant difference between the two age groups. The HVA fractional rate constant and turnover after pargyline were lower in aged rats than in adults, and HVA turnover after probenecid was higher in aged rats than in adults. The DOPAC-HVA pathway seems to be reinforced at the expense of DOPAC conjugation. In aged and adult rats whose 5-HT steady-state levels were not statistically different, the 5-HT turnover rate after pargyline and NSD-1015 treatment was lower in aged rats than in adults. An increase of 5-HIAA levels after pargyline and probenecid treatment in aged rats could be due to the handling stress.     

Intracerebral dialysis: direct evidence for the utility of 3-MT measurements as an index of dopamine release

Intracerebral dialysis was used to monitor the in vivo efflux of striatal dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the pentobarbital anesthetized rat. In untreated rats, there were low levels of extra-cellular DA and 3-MT which were increased 15-fold by treatment with amphetamine. Under basal and drug-stimulated conditions, 3-MT concentrations were maintained at approximately 30% of the extracellular DA levels. These data agree with in vivo turnover estimates which indicate that 20 to 30% of DA turnover is through the 3-MT pool in the striatum. In contrast, extracellular DOPAC and HVA levels were reduced only slightly by amphetamine and with a delayed onset. Our data support the hypothesis that striatal DOPAC is an accurate index of intraneuronal DA metabolism and that 3-MT is an index of the extracellular concentration of DA.     

Development of Haloperidol-Induced Dopamine Release in the Rat Striatum Using Intracerebral Dialysis

Haloperidol-induced dopamine (DA) release and metabolism were studied in the rat striatum at 10-11, 21-22, and 35-36 days of age using intracerebral dialysis and HPLC with electrochemical detection. There was an age-related increase in basal DA release and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), with the greatest increases occurring between 10-11 and 21-22 days of age. Haloperidol (0.1 mg/kg, i.p.) significantly increased DA release at each age compared to control. Also, haloperidol produced a significantly greater increase in DA release at 10-11 days than at 21-22 or 35-36 days of age when expressed as percentage of predrug release. Haloperidol increased DA release over 60 min to 235%, 138%, and 158% above baseline at 10-11, 21-22, and 35-36 days of age, respectively, after which time the levels remained relatively constant. Haloperidol significantly increased extracellular DOPAC and HVA levels at each age compared to controls, but there were no significant differences in DOPAC or HVA levels between ages in response to haloperidol. The results indicate that, at 10 days of age, DA release in the striatum is physiologically functional and that the regulatory feedback control of DA release and metabolism in the striatum develops prior to 10 days of age.     

Acute Stimulatory Effect of Estradiol on Striatal Dopamine Synthesis

Abstract: The acute effect of physiological doses of estradiol (E2) on the dopaminergic activity in the striatum was studied. In a first series of experiments, ovariectomized rats were injected with 17α or 17β E2 (125, 250, or 500 ng/kg of body weight, s.c.), and in situ tyrosine hydroxylase (TH) activity (determined by DOPA accumulation in the striatum after intraperitoneal administration of NSD 1015) was quantified. A dose-dependent increase in striatal TH activity was observed within minutes after 17β (but not 17α) E2 treatment. To examine whether E2 acts directly on the striatum, in a second series of experiments, anesthetized rats were implanted in the striatum with a push-pull cannula supplied with an artificial CSF containing [³H]tyrosine. The extracellular concentrations of total and tritiated dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured at 20-min intervals. Addition of 10^?9M 17β (but not 17α) E2 to the superfusing fluid immediately evoked an ～50% increase in [³H]DA and [³H]DOPAC extracellular concentrations, but total DA and DOPAC concentrations remained constant. This selective increase in the newly synthesized DA and DOPAC release suggested that E2 affects DA synthesis rather than DA release. Finally, to determine whether this rapid E2-induced stimulation of DA synthesis was a consequence of an increase in TH level of phosphorylation, the enzyme constant of inhibition by DA (K_{i DA}) was calculated. Incubation of striatal slices in the presence of 10^?9M 17β (but not 17α) E2 indeed evoked an approximate twofold increase in the K_{i DA} of one form of the enzyme. It is concluded that physiological levels of E2 can act directly on striatal tissue to stimulate DA synthesis. This stimulation appears to be mediated, at least in part, by a decrease in TH susceptibility to end-product inhibition, presumably due to phosphorylation of the enzyme. The rapid onset of this effect, and the fact that the striatum does not contain detectable nuclear E2 receptors, suggest a nongenomic action of the steroid.     

Rat brain monoamine and serotonin S2 receptor changes during pregnancy

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were determined in 5 brain areas of non-pregnant, 15 and 20 day pregnant and 4 day post-partum rats. Striatal 5-HT content was significantly lower in 15 and 20 day pregnant rats than in estrous controls. A significant decrease in striatal and frontal cortex 5-hydroxyindole-3-acetic acid (5-HIAA) concentration was observed in 15 day pregnant rats. Significant increases in hypothalamic and hippocampal NA levels were observed at 4 days post-partum. Frontal cortex serotonin S2 receptorKd was reduced in 4 day post-partum rats. There was no significant change in S2 receptorB _max during pregnancy. Levels of progesterone were negatively correlated with striatal DA, homovanillic acid (HVA), 5-HT, and 5-HIAA levels, hypothalamic DA, hippocampal 5-HT, and frontal cortex 5-HIAA values as well as striatal HVA to DA, and HVA to 3,4-dihydroxyphenylacetic acid (DOPAC) ratios and amygdaloid HVA to DOPAC ratios. The limbic neurotransmitter changes might possibly contribute to mood changes which occur during pregnancy and post-partum.     

The effects of monoamine oxidase B inhibition on dopamine metabolism in rats with nigro-striatal lesions

The purpose of this study was to examine whether monoamine oxidase type B (MAO-B) has a role in striatal dopamine metabolism in animals with a unilateral lesion of the medial forebrain bundle, and whether 2-phenylethylamine (PE) could have a role in amplification of dopamine (DA) responses in DA depleted striatum. Inhibition of MAO-B did not alter DA metabolism in lesioned striata. PE accumulation decreased with loss of DA as long as there was no DA dysfunction. In lesioned striata with dysfunction of DA transmission at the synaptic level, PE accumulation increased,suggesting a compensatory increase in PE synthesis. This increase in PE levels does not appear to be mediated by an increase in the total striatal aromaticl-amino acid decarboxylase (AADC) activity. We conclude that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that PE could be involved in the antiparkinsonian action of MAO-B inhibitors.     

The Role of 3-<Emphasis Type="Italic">O</Emphasis>-Methyldopa in the Side Effects of <Emphasis Type="SmallCaps">l</Emphasis>-dopa

Long-term treatment of l-dopa for Parkinson’s disease (PD) patients induces adverse effects, including dyskinesia, on–off and wearing-off symptoms. However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of l-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in male Sprague–Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular (icv) injection of 1 μmol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration of 1 μmole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv) also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore, 3-OMD potentiated l-dopa toxicity and these toxic effects induced by both 3-OMD and l-dopa were blocked by vitamin E (α-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of l-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term l-dopa treatment may be involved in the adverse effects of l-dopa therapy. Moreover, l-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD.     

Conjugated Dopamine in Superfusates of Slices of Rat Striatum

Abstract: An acid-hydrolyzable conjugate of 3,4-dihydroxyphenylethylamine (dopamine, DA) was detected in superfusates from slices from rat striatum. The concentrations of endogenous free and conjugated DA, and of the acid metabolites (3,4-dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) in superfusates were measured using HPLC with electrochemical detection. Conjugated DA in superfusates represented 10–20% of the free DA under basal conditions and during release evoked by p -tyramine (5 × 10⁻⁶ M to 5 × 10⁻⁴ M ); much smaller amounts of conjugated DA overflowed into superfusate when DA was released by equimolar concentrations of β-phenylethyl-amine. Surprisingly, inhibition of monoamine oxidase by the inhibitors N -methyl- N -propargyl-3-(2,4-dichlorophenoxy)propylamine hydrochlo-ride (clorgyline) or N -methyl- N -2-propynylbenylamine (pargyline) had little effect on the amounts of conjugated DA present in superfusate. Under basal conditions, the amounts of conjugated DA in superfusate were always less than the amounts of DOPAC but quite similar to the amounts of HVA. However, during release of DA evoked by p -tyramine the concentrations of conjugated DA in superfusate showed much more pronounced increases than those of the acidic metabolites.     

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: I. Levels of dopamine and metabolites

Effects of acute and subacute cocaine administration on dopamine (DA) and its metabolites in striata and nucleus accumbens of nine week-old Wistar-Kyoto and spontaneously hypertensive rats were studied. Levels of DA,3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC. There were no differences in DA levels in striata and nucleus accumbens between control WKY and SHR. Levels of DA in two brain regions were unaffected in groups treated acutely with cocaine. Both strains showed a significant increase in striatal HVA 2 hr after cocaine injection. Seven day treatment declined DA levels in striatum of WKY and in nucleus accumbens of SHR. However, only WKY treated subacutely with cocaine showed significantly increased HVA either with or without changes in DOPAC in nucleus accumbens and striatum, respectively. Increased DOPAC/DA and HVA/DA ratios appeared only in striatum of WKY and in nucleus accumbens of SHR following subacute treatment. These results suggest that subacute cocaine administration affects DA levels in striata and nucleus accumbens differently between WKY and SHR.     

2-Guanidinoethanol increased dopamine release and 3,4-dihydroxyphenylacetic acid content,but not homovanillic acid content in the rat brain: Electroneurochemical and enzymological studies

The effects of 2-guanidinoethanol (GEt) on the release of monoamines and on the activity of their degrading enzymes were studied in order to investigate why 3,4-dihydroxyphenylacetic acid (DOPAC) increased to a much greater extent than homovanillic acid (HVA) after GEt injection into rat brain. In differential pulse voltammograms recorded using an electrochemically treated carbon fiber electrode, two distinct oxidation peaks, one at 130mV (DOPAC peak) and the other at 300 mV (5-hydroxyindoleacetic acid (5-HIAA) peak), were observed. In the hippocampus, the DOPAC peak increased markedly compared to the peak height recorded prior to the intracerebroventricular injection of GEt (6mol). Although the DOPAC peak height increased to 350% 4 hours after GEt injection, the 5-HIAA peak showed no change. In the striatum, the DOPAC peak increased to 150% 3 hours after GEt injection. Serial changes in the extracellular levels of DOPAC, HVA, and 5-HIAA were monitored in the striatum after GEt injection, using an in vivo brain micro-dialysis technique. Although the DOPAC levels strated to increase 80 minutes after GEt injection, HVA and 5-HIAA levels showed no change. On the other hand, monoamineoxidase, which metabolizes dopamine to DOPAC, was not activated and catechol-0-methyltransferase, which metabolizes DOPAC to HVA, were not inhibited by 5 mM of GEt in vitro. These data suggested that GEt increased the release of dopamine, but not of serotonin, and that GEt might restrict the DOPAC transport system.     

Brain Dialysis: In Vivo Metabolism of Dopamine and Serotonin by Monoamine Oxidase A but Not B in the Striatum of Unrestrained Rats

A dialysis cannula was implanted into rat striatum while the animals were anesthetized, and the area was perfused with Ringer solution while the animals were unanesthetized after at least 3 days following surgery. Concentrations of the metabolites of 3,4-dihydroxyphenylethylamine (DA) and 5-hydroxytryptamine (5-HT) in the perfusate were determined by HPLC with electrochemical detection. Levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perfusate significantly decreased after pargyline administration (50 mg/kg i.p.), which may inhibit not only monoamine oxidase (MAO)-B but also MAO-A in these high doses. The level of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) also decreased after pargyline treatment, although change in the relative level of 5-HIAA was less than that of DOPAC or HVA. To clarify the mechanisms for the metabolism of monoamines in rat striatum, highly specific MAO-A and -B inhibitors were used in the following experiments. Treatment with l-deprenyl (10 mg/kg), a specific inhibitor for MAO-B, did not cause any statistically significant change in DOPAC, HVA, and 5-HIAA levels. No significant change was found in rat striatal homogenates at 2 h after the same treatment with l-deprenyl. In contrast, low-dose treatment (1 mg/kg) with clorgyline, a specific inhibitor for MAO-A, caused a significant decrease in levels of these three metabolites in both the perfusates and tissue homogenates. In addition to the above three metabolites, the level of 3-methoxytyramine, which is an indicator of the amount of DA released, greatly increased after treatment with a low dose (1 mg/kg) of clorgyline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of dopamine, homovanillic acid and 3,4-dihydroxyphenylacetic acid in rat brain striatum by high-performance liquid chromatography with electrochemical detection

Two procedures using liquid chromatography with electrochemical detection are described for the determination of dopamine (DA) and its two acidic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), in subregions of rat striatum and nucleus accumbens. A strong cation-exchange column was used for DA analysis and a C₁ reversed-phase column was used for the analysis of the metabolites. Effects of pH, temperature and percentage of methanol on the retention time of HVA and DOPAC were studied. Levels of these compounds in the subregions of rat striatum and nucleus accumbens are reported.     

Effect of chloral hydrate on in vivo KCl-induced striatal dopamine release in the rat

The release of striatal dopamine (DA) and its metabolites in response to locally-induced K⁺ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P<0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P<0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P<0.05). Furthermore, the basal level of extracellular HVA in chloral hydrateanesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.     

谷氨酸和MK-801对正常和帕金森模型大鼠纹状体内多巴胺代谢的影响

采用微透析和高效液相色谱一电化学(HPLC-ECD)技术研究了谷氨酸和MK-801对正常和帕金森模型人鼠纹状体内多巴胺代谢的影响。用微透析技术在大鼠纹状体内分别定位给以左旋多巴、L-谷氨酸和／或MK-801,同时收集透析液,用HPLC-ECD方法测定透析液中多巴胺代谢产物的浓度。微透析和HPL-ECD分析结果表明：纹状体内定位给以序旋多巴,正常大鼠和帕金森模型大鼠纹状体内多巴胺代谢产物的浓度均升高;纹状体内定位给以L-谷氨酸,可使正常大鼠纹状体内多巴胺代谢产物的浓度降低,但对帕金森火鼠模型纹状体内多巴胺代谢产物浓度的降低不显著;纹状体内定位给以MK-801,正常人鼠纹状体内多巴胺代谢产物的浓度升高：但对帕金森人鼠模型纹状体内多巴胺代谢产物浓度的升高不显著：纹状体内同时定位给以MK-80l和L-谷氨酸,可以有效防止L-谷氨酸所致正常人鼠纹状体内多巴胺代谢产物浓度的降低。结果提示,谷氦酸可以通过NMDA受体调节多巴胺的代谢。尽管非竞争性NMDA拈抗剂MK-801可以有效防止L-谷氨酸所敛正常人鼠纹状体内多巴胺代谢产物浓度的降低,但却不能有效地改善帕金森大鼠模型纹状体内多巴胺的代谢水平。因此存正常及帕金森病情况下,谷氮酸一多巴胺相互作用机制和MK-801改善帕金森病的机制还有待进一步研究。     

Modulation of striatal dopamine release in cerebral ischemia byL-arginine

The effect ofL-arginine, the precursor of nitric oxide, on ischemic dopamine release from the striatum was investigated in Mongolian gerbils subjected to bilateral carotid artery occlusion (15 min) alone or with reflow (2 h). Dopamine and its metabolites were measured in the striatal extracellular space dialysate after continuous perfusion (2 l/min) of artificial extracellular fluid in the presence or absence of 15 mmol/literL- orD-arginine or 1 mmol/liter nitro-L-arginine.L-Arginine but notD-arginine increased the striatal content of dopamine in pre- and postischemia whereas it lowered the levels of dopamine and 3-methoxytyramine induced by ischemia. In contrast, nitro-L-arginine reduced the preischemic levels of dopamine and 3,4-dihydroxyphenyl-acetic acid, and had no effect on the ischemic release of dopamine. These findings indicate thatL-arginine stereospecifically modified the ischemic release and metabolism of dopamine. The data also suggest that the basal level of nitric oxide is not involved in dopamine release during ischemia but may participate in regulating dopamine release under physiological conditions.Presented in part at the 19th International Joint Conference on Stroke and Cerebral Circulation, San Diego, California, February 17–19, 1994.     

Release of arachidonic acid by NMDA-receptor activation in the rat hippocampus

In hippocampal slices arachidonic acid released after NMDA post-synaptic receptor activation is thought to act as a retrograde trans-synaptic messenger which facilitates the pre-synaptic release of L-glutamate to be involved in the expression of long-term synaptic potentiation (LTP). We measured the mass amount of arachidonic acid released from hippocampal slices incubated under conditions which maintain the electrophysiological responsiveness of the slice. Melittin released arachidonic, oleic and docosahexaenoic acids by phospholipase A₂ activation but not palmitic or stearic acids. Of greater interestl-glutamate, N-methyl-d-aspartate and incubation conditions known to induce LTP selectively and rapidly increased the release of archidonic acid in amounts over basal levels of 200–300 ng/mg protein. This is the first direct determination of the mass amount of arachidonic acid released following NMDA receptor activation in the hippocampus.Special issue dedicated to Dr. Louis Sokoloff.