DOPA causes glutamate release and delayed neuron death by brain ischemia in rats

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.     

黄芪提取物对大鼠海马神经元迟发性死亡的影响

目的探讨黄芪提取物(Extractofastragalus,EA)对全脑缺血再灌注7d引起的大鼠海马神经元迟发性死亡的作用。方法用四动脉阻断法造模,观察背侧海马神经元的超微结构;CA1区神经元结构、正常神经元计数;免疫组化法检测胶质纤维酸性蛋白(GFAP)的表达。结果与缺血再灌(I/R)组比较,EA能改善背侧海马神经元超微结构;抑制CA1区正常神经元数目的减少,I/R组为38±11.5,EA(20、40mg·kg-1)分别为63±12.8(P<0.05)和77±16(P<0.01);降低GFAP的表达,I/R组GFAP阳性细胞数为69±10.7,EA三个剂量组分别为53±5.6(P<0.05)、39±7.1(P<0.01)、46±7.6(P<0.05)。结论EA能抑制全脑缺血再灌注7d大鼠海马迟发性神经元死亡,可能与其抑制海马CA1区星形胶质细胞(AS)过度增生有关。     

益智胶囊对大鼠脑弥散性缺血再灌注后海马CA1区神经元迟发性死亡的影响

目的 :观察益智胶囊对大鼠全脑缺血后海马CA1区神经元迟发性死亡及学习功能的影响。方法 :使用四血管闭塞 (4 VO)法制成大鼠急性全脑缺血再灌注模型。采用免疫组织化学方法计数脑缺血再灌注脑损伤后 1、2、4、8及 4 0d后 ,大鼠海马CA1区正常神经元数量 ;并用Morriss水迷宫观察脑缺血再灌注脑损伤后 4 0d时各组大鼠的学习记忆功能。结果 :从缺血再灌注后d 2起 ,益智胶囊(10 0mg·kg-1)组大鼠海马CA1区正常神经元数量明显多于缺血对照组大鼠海马CA1区正常神经元数量 ,差异有明显统计学意义 (P <0 .0 1)。同时 ,Morris水迷宫法检测全脑缺血再灌注脑损伤后 4 0d时各组大鼠记忆功能 ,益智胶囊 (10 0mg·kg-1)组大鼠明显好于缺血对照组大鼠 (P <0 .0 1)。结论 :益智胶囊对全脑缺血后大鼠海马CA1区神经元具有保护作用 ,并可改善大鼠的记忆功能障碍     

Effects of prolyl endopeptidase inhibitors and neuropeptides on delayed neuronal death in rats.

We investigated the effects of the prolyl endopeptidase inhibitors 1-[1-(Benzyloxycarbonyl)-L-prolyl]prolinal (Z-Pro-Prolinal) and N-benzyloxycarbonyl-thioprolyl-thioprolinal-dimethylaceta l (ZTTA) on delayed neuronal death induced by four-vessel-occlusion transient ischemia in rats. We also examined the effects of [pGlu4, Cyt6, ArgS]vasopressin (vasopressin-(4-9)) and thyrotropin-releasing hormone (TRH) on the delayed neuronal death. Furthermore, we investigated the role of vasopressin receptors in the effects of vasopressin and prolyl endopeptidase inhibitors. Z-Pro-Prolinal, vasopressin-(4-9) and TRH protected pyramidal cells in the CA1 subfield of the rat hippocampus from delayed neuronal death after 10-min ischemia. The effect of vasopressin-(4-9) was abolished by vasopressin receptor antagonists. The effect of Z-Pro-Prolinal was also abrogated by the antagonists. These results suggest that the neuroprotective effect of prolyl endopeptidase inhibitors is mediated by neuropeptides such as [Arg8]vasopressin and TRH, and indicate the involvement of vasopressin receptors in the neuroprotective effect of vasopressin-(4-9) and prolyl endopeptidase inhibitors.     

Spatiotemporal pattern of neuronal injury induced by DFP in rats: a model for delayed neuronal cell death following acute OP intoxication

Organophosphate (OP) neurotoxins cause acute cholinergic toxicity and seizures resulting in delayed brain damage and persistent neurological symptoms. Testing novel strategies for protecting against delayed effects of acute OP intoxication has been hampered by the lack of appropriate animal models. In this study, we characterize the spatiotemporal pattern of cellular injury after acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats received pyridostigmine (0.1 mg/kg, im) and atropine methylnitrate (20 mg/kg, im) prior to DFP (9 mg/kg, ip) administration. All DFP-treated animals exhibited moderate to severe seizures within minutes after DFP injection but survived up to 72 h. AChE activity was significantly depressed in the cortex, hippocampus, subcortical brain tissue and cerebellum at 1 h post-DFP injection and this inhibition persisted for up to 72 h. Analysis of neuronal injury by Fluoro-Jade B (FJB) labeling revealed delayed neuronal cell death in the hippocampus, cortex, amygdala and thalamus, but not the cerebellum, starting at 4 h and persisting until 72 h after DFP treatment, although temporal profiles varied between brain regions. At 24 h post-DFP injection, the pattern of FJB labeling corresponded to TUNEL staining in most brain regions, and FJB-positive cells displayed reduced NeuN immunoreactivity but were not immunopositive for astrocytic (GFAP), oligodendroglial (O4) or macrophage/microglial (ED1) markers, demonstrating that DFP causes a region-specific delayed neuronal injury mediated in part by apoptosis. These findings indicate the feasibility of this model for testing neuroprotective strategies, and provide insight regarding therapeutic windows for effective pharmacological intervention following acute OP intoxication.     

Protective effects of extract of Coeloglossum viride var. bracteatum on ischemia-induced neuronal death and cognitive impairment in rats

Our earlier study demonstrated that Coeloglossum viride (L.) Hartm. var. bracteatum (Willd.) extract (CE) significantly improved the impaired memory in mice caused by permanent two-vessel occlusion. To investigate whether chronic treatment with CE could influence cerebral ischemia-induced neuronal and cognitive impairments, we examined the effects of CE on two different kinds of cerebral injury: transient middle cerebral artery occlusion model of focal cerebral ischemia; four-vessel occlusion model of transient global forebrain ischemia. CE treatment (5 mg/kg, orally) significantly reduced lesion volume, and improved the performance of passive avoidance and rotarod motor tasks in transient middle cerebral artery occlusion rats. In the four-vessel occlusion model, neuronal cell loss in CA1 of hippocampus was significantly decreased and the performance in the Morris water maze was significantly improved in rats administered CE. We conclude that treatment with CE attenuated learning and memory deficits, motor functional disability, and neuronal cell loss induced by global or focal cerebral ischemia. These results suggest that CE may be a potential candidate for the treatment of vascular dementia.     

Different effects of AT1 receptor antagonist and ET(A) receptor antagonist on ischemia-induced norepinephrine release in rat hearts

Angiotensin type 1 receptor (AT1R) antagonist and endothelin type A receptor (ET(A)R) antagonist were compared as regards their effects on ischemia-induced exocytotic or carrier-mediated norepinephrine (NE) release from cardiac sympathetic nerve endings. According to the Langendorff technique, isolated rat hearts were subjected to 20-minute or 40-minute global ischemia followed by 30-minute reperfusion. Candesartan (selective AT1R antagonist) and ABT-627 (selective ET(A)R antagonist) were perfused, beginning 15 minutes before ischemia. Candesartan (10 and 100 nM) and ABT-627 (3 μM) suppressed excessive NE overflow (exocytotic release) in the coronary effluent from the heart exposed to 20-minute ischemia. In addition, these agents improved postischemic cardiac dysfunction. On the other hand, the beneficial effects of ABT-627 (1 and 3 μM) on NE overflow (carrier-mediated release) and cardiac dysfunction were also observed in 40-minute ischemia, whereas those were not improved by treatment with candesartan (10 and 100 nM and 1 μM). These findings suggest that both AT1R antagonist and ET(A)R antagonist have ability to inhibit the exocytotic NE release, but the carrier-mediated NE release induced by prolonged ischemia cannot be avoided by AT1R antagonist. Thus, ET(A)R antagonist may be more useful than AT1R antagonist in the clinical settings of ischemic heart disease.     

Effects of hepatocyte growth factor on phosphorylation of extracellular signal-regulated kinase and hippocampal cell death in rats with transient forebrain ischemia

Hepatocyte growth factor (HGF) has been implicated in protection against several types of cell injuries. We investigated the effects of human recombinant HGF (hrHGF) on the selective neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in rats and explored the nature of the intracellular signaling pathway for the protection against this neuronal injury. hrHGF was injected continuously into the hippocampal CA1 region directly using an osmotic pump from 10 min to 72 h after the start of reperfusion. The marked increase in the number of TUNEL-positive cells found in the CA1 region after ischemia was almost completely abolished by the hrHGF treatment. Akt phosphorylation as well as IkappaB phosphorylation, which has been implicated in events downstream of the Akt, was not affected by hrHGF treatment. Extracellular signal-regulated kinase (ERK) phosphorylation was decreased in the CA1 region with time after ischemia. hrHGF increased or recovered ERK phosphorylation without changing the total amount of ERK protein. Immunohistochemical analysis demonstrated that phosphorylated ERK was colocalized with a neuronal nucleus marker NeuN in the hippocampal CA1 region of ischemic rats with hrHGF treatment at the early period after reperfusion. These results suggest that the protective effects of hrHGF against neuronal death in the hippocampal CA1 after transient forebrain ischemia could be related to an ERK-dependent pathway.     

Arsenic-induced cell death in liver and brain of experimental rats

Arsenic is a well established human carcinogen and is ubiquitous in the environment. The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats. Sodium arsenite was administered orally at doses of 6.3 mg/kg, 10.5 mg/kg and 12.6 mg/kg of body weight on the basis of a lethal dose 50% (LD50) for 24 hr. After administration of arsenites, liver and brain were analyzed for various parameters of oxidative stress, histopathological changes and caspase-3 activity. Glutathione levels were decreased significantly in the liver at all doses. In liver the following biochemical changes were observed, a significant lipid peroxidation and cytochrome-P450 induction along with significant decrease in catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione peroxidase was increased significantly at all doses. In brain, no significant change was observed at 6.3 mg/kg. However, a significant increase in lipid peroxidation and glutathione peroxidase activity along with significant decrease in the activity of glutathione, catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione-S-transferase was decreased significantly in both liver and brain at 10.5 and 12.6 mg/kg. No significant alteration in the activity of glucose-6-phosphate dehydrogenase and glutathione reductase was observed in either liver or brain at any dose. Dose-dependent histopathological changes, observed in both liver and brain are also described. A significant increase in caspase-3 activity was observed at all doses in liver and at 10.5 and 12.6 mg/kg in brain. Sodium arsenite caused DNA cleavage into fragments and manifested as "DNA laddering", a hallmark of apoptosis.     

Carbon monoxide neurotoxicity: transient inhibition of avoidance response and delayed microglia reaction in the absence of neuronal death

Carbon monoxide exposure produces neurobehavioral effects associated with the level of carboxyhemoglobin (COHb) in the blood. A threshold has been proposed of approximately 35% COHb for the manifestation of disruption in neurobehavioral tasks. The effects of CO exposure producing 30-40% carboxyhemoglobin (COHb) levels in young adult male Fischer 344 rats were examined with regard to clinical signs of toxicity, performance on a previously learned avoidance procedure, and neuronal and glia histopathology. High levels of exposure (4000 ppm) for 15 min were imposed on either a background blood COHb level of 5% produced by a 2 h exposure to 50 ppm CO or a control background from conditioned-air exposure. Upon removal from the nose-only inhalation holder, signs of mild lethargy and decreased activity were evident for 2 min for conditioned-air controls and 50 ppm CO exposure groups and 3-4 min following 4000 ppm CO. Performance on a two-way shuttle box active avoidance task showed no differences between 50 ppm CO rats and conditioned-air controls while the 4000 ppm CO exposed groups showed a significant decrease in avoidance and escape responses. Histological examination showed no evidence of delayed neuronal death or astrocyte reactivity in the hippocampus or cerebellum; however, a distinct focal staining of reactive microglia in both regions was evident in animals exposed to 4000 ppm CO. While 50 ppm CO (5% COHb) alone produced no disruption in avoidance performance, microglia staining in the cerebellum was significantly increased over conditioned-air controls. This regional and focal response of microglia suggests the need for further study regarding such subtle cellular changes and their relationship with COHb levels.     

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

Icilin, a cooling compound, produces vigorous wet-dog shakes in rats. We have reported previously that icilin-induced wet-dog shakes are blocked by the kappa opioid receptor agonists, nalfurafine and U50,488H, and that icilin evokes a dose- and time-dependent increase in glutamate within the dorsal striatum. Since activation of kappa opioid receptors inhibits glutamate release intrastriatally, we targeted glutamate release within the dorsal striatum using nalfurafine and examined the role of the dorsal striatum in icilin-induced wet-dog shakes, more specifically, the effect that icilin-evoked intrastriatal glutamate release has on the overt stimulant behavior. We report that nalfurafine (0.04mg/kg) inhibits icilin (0.50mg/kg)-induced wet-dog shakes and that this inhibition is reversed by intrastriatal perfusion of the kappa opioid receptor antagonist, norbinaltorphimine (100nM). Furthermore,we antagonized icilin-evoked glutamate release with nalfurafine (0.04mg/kg), and reversed inhibition of glutamate release with intrastriatal norbinaltorphimine (100nM). These findings support a central component in the behavioral response to icilin and suggest that activation of kappa opioid receptors antagonizes icilin-induced wet-dog shakes in rats by inhibiting glutamate release within the dorsal striatum.     

JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats

Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.     

Effects of oxotremorine and pilocarpine on striatal acetylcholine release as studied by brain dialysis in anesthetized rats

• 1.1. The effects of oxotremorine and pilocarpine on striatal acetylcholine (ACh) release were investigated using brain microdialysis techniques in urethan-anesthetized rats.
• 2.2. Oxotremorine (0.1 and 0.5 mg/kg, IV), a preferential M₂ agonist, dose-dependently decreased ACh release in the striatum. On the other hand, pilocarpine, at 5 mg/kg (IV), showed a tendency to decrease ACh release in the striatum but, at 7.5 and 10 mg/kg (IV), significantly enhanced release in a dose-dependent manner.
• 3.3. The effect of oxotremorine was blocked by scopolamine (0.1 mg/kg, IV) but not by pirenzepine (10 mg/kg, IV), a selective M₁ antagonist.
• 4.4. Pilocarpine (10 mg/kg, IV) enhancement of striatal ACh release was not affected by 10 mg/kg pirenzepine, but 5 mg/kg pilocarpine significantly increased ACh release in scopolamine (0.1 mg/kg) pretreated rats without affecting the release by itself.
• 5.5. These results suggest that oxotremorine-induced decrease in striatal ACh release is due to stimulation of presynaptic M₂ autoreceptor, and that the increase of striatal ACh release by pilocarpine is mediated by mechanism(s) other than effects on muscarinic ACh receptors.

     

8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release

In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT_1A agonist 8-OH-DPAT or the 5-HT_2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum. Received: 29 August 1996/Final version: 25 November 1996     

NMDA受体NR2A,NR2B亚基对大鼠脑缺血再灌注海马CA1区神经细胞损伤的作用

目的 观察N-甲基-D-天冬氨酸受体(NMDA)NR2A,NR2B亚基对脑缺血-再灌注后海马CA1区神经细胞存活的不同影响.方法 采用Pulsinelli-Brierley四动脉阻塞(4-VO)大鼠全脑缺血模型,缺血前连续3天脑室注射NR2A,NR2B反义寡核苷酸(AS ODN)后缺血15 min,复灌5 d,石蜡切片,以焦油紫染色,图像分析测定单位面积内焦油紫染色细胞面积总和,与缺血组及错义寡核仟酸组(MS ODN)进行形态学分析.结果 NR2A、NR2B反义寡核苷酸对脑缺血再灌注后海马 CA1神经细胞均有明显保护作用,以NR2A AS ODN保护作用更明显,与缺血组比较约有50%细胞仃活(P＜0.05).结论 NR2A,NR2B亚基的含量降低对脑缺血再灌注后海马神经细胞有明显保护作用.     

In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate

Although the 5-HT(6) receptor subtype was identified some 5 years ago, very little is known about its function within the brain. Here we demonstrate, for the first time, the neurochemical effects of a selective 5-HT(6) receptor ligand. Using in vivo microdialysis in the freely moving rat, we evaluated the effects of the selective 5-HT(6) receptor antagonist SB-271046 by simultaneous measurement of 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NA), glutamate and aspartate from the striatum and frontal cortex. SB-271046 did not alter basal levels of 5-HT, DA and NA in either brain region. Similarly, there was no change basal levels of either of the excitatory amino acids within the striatum. In contrast, administration of SB-271046 (10 mg kg(-1) s.c.) produced a significant (P<0.05), tetrodotoxin-dependent, increase in extracellular levels of both glutamate and aspartate within the frontal cortex, reaching maximum values of 375.4+/-82.3 and 215. 3+/-62.1% of preinjection values, respectively.     

Ethyl acetate soluble fraction of Cnidium officinale MAKINO inhibits neuronal cell death by reduction of excessive nitric oxide production in lipopolysaccharide-treated rat hippocampal slice cultures and microglia cells

In the present work, we found that the ethyl acetate-soluble fraction of Cnidium officinale MAKINO (COEA) decreased nitric oxide (NO) production in the lipopolysaccharide (LPS)-stimulated BV-2 and primary microglia and suppressed expression of inducible nitric oxide synthase (iNOS) in BV-2 cells with the same pattern of NO production. In addition, we showed that excessive NO production played an important role in neuronal cell death in LPS-treated rat hippocampal slice cultures. Our data suggest that the COEA inhibits neuronal cell death by reduction of excessive NO production in LPS-treated rat hippocampal slice cultures. The ethyl acetate-soluble fraction of C. officinale reduced propidium iodide uptake and NO production in cultured media at the same time.     

Effect of anticholinergic drugs on striatal acetylcholine release and motor activity in freely moving rats studied by brain microdialysis

We have studied effects of intraperitoneal administration of anticholinergic drugs on striatal acetylcholine release in association with motor activity in freely moving rats using brain microdialysis. A low dose of atropine (2.5 mg/kg) increased striatal acetylcholine release. A high dose of atropine (5 mg/kg) or scopolamine (2.5, 5 and 10 mg/kg) increased both striatal acetylcholine release and motor activity, while its quaternary ammonium compounds, atropine methylbromide (5 and 10 mg/kg) and methscopolamine bromide (5 and 10 mg/kg), increased striatal acetylcholine release without motor excitation. Scopolamine (2.5 mg/kg) produced no significant change in striatal acetylcholine content 4 hr after the injection followed by perfusion. These results suggest that anticholinergic drugs cause an increase in striatal acetylcholine release which does not always result in the increase of motor activity.     

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats,as determined by in vivo brain microdialysis

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na(+) channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na(+)-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species, generated via DA oxidation, the significant modification of the striatal DAergic neuronal system by CO exposure might participate in the neurological outcome following acute CO intoxication.