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Dopamine (DA) is released in large quantities from the striatum during cerebral ischemia. Along with excitatory neurotransmitters, DA plays a role in cellular neuronal ischemic injury. In this study we examined the role of nitric oxide (NO) in the ischemia-induced release of DA. A microdialysis probe was stereotactically placed into the corpus striatum of 16 Sprague-Dawley rats for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) level determinations. After probe stabilization, the animals received either NG-nitro-L-arginine-methyl ester (L-NAME), a NO synthase inhibitor, or vehicle through the microdialysis probe. Temporary global forebrain ischemia was induced using bilateral carotid artery ligature tightening and controlled hemorrhagic hypotension for 15 min. L-NAME administration caused a reduction in ischemic estimated extraneuronal DA concentration by 60% (P < 0.005) compared with control. There was an increase in both DOPAC and HVA concentrations during the recovery period compared to baseline values in the control group (P < 0.05). L-NAME also caused a reduction in HVA concentration compared to vehicle administration during the latter part of recovery (P < 0.05). These data support the concept that ischemic dopamine release may be mediated by NO. This NO-modulated DA release may contribute to the previously reported deleterious neurotoxic effects of NO during ischemia.

Dopamine (DA) is released in large quantities into the corpus striatum during cerebral ischemia and may exacerbate tissue damage. Using cerebral microdialysis, we studied the effect of etomidate on in vivo ischemia-induced DA release in rat corpus striatum. Reversible cerebral ischemia was induced by using carotid ligatures and hypovolemic hypotension, and monitored with laser Doppler flowmetry. After baseline measurements, 20 normothermic, anesthetized rats were subjected to three separate periods of cerebral ischemia, interrupted by 45- to 75-min periods of reperfusion. The rats were randomized into two groups. All rats received 400 mg/kg of intraperitoneal chloral hydrate for induction of anesthesia. In Group I (n = 10) anesthesia was maintained using additional intraperitoneal chloral hydrate 100 mg/kg every 2 h. Group II received etomidate 0.6 mg/kg 10 min before the first episode of cerebral ischemia, followed by an infusion of 60 micrograms.kg-1 x min-1. Before each subsequent period of induced ischemia, an additional dose of etomidate (0.6 mg/kg) was administered. DA levels were approximately 350 times above baseline in Group I during the three ischemic episodes (IS1, IS2, and IS3). In Group II, ischemia-induced DA release was significantly attenuated (by 79%) during IS1, IS2, and IS3 compared to Group I (P < 0.01). DA levels did not significantly change in magnitude during the three ischemic episodes in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Dopamine is released in large quantities into the corpus striatum during cerebral ischemia and may exacerbate tissue damage., Methods: Using cerebral microdialysis, the effect of isoflurane on in vivo ischemia-induced dopamine release was studied in rat corpus striatum. Reversible cerebral ischemia was induced using carotid ligatures and induced hypovolemia and was monitored with laser-Doppler flowmetry. Following baseline measurements, 28 normothermic, anesthetized rats were subjected to cerebral ischemia followed by reperfusion. The rats were divided into four groups. Group 1 (n = 10) was anesthetized using chloral hydrate. Groups 2 and 3 received 1.5% end-tidal isoflurane. In group 2 (n = 6), hypotension was left untreated during the reperfusion period, and in group 3 (n = 6), mean arterial pressure was maintained using phenylephrine. Group 4 (n = 6) received 1-1.2% end-tidal halothane., Results: Compared with pre-ischemic levels, large quantities of dopamine (350 x baseline levels) were released in group 1 animals during cerebral ischemia. Compared with group 1, ischemia-induced dopamine release was significantly reduced in group 2 (by 58%) and in group 3 (by 56%), but not in group 4. Group 2 animals were uniformly hypotensive during reperfusion and continued to release substantial amounts of dopamine (8 x baseline levels). In groups 1, 3, and 4, dopamine release decreased to near baseline levels during reperfusion. In group 3, dopamine metabolite production was significantly increased during ischemia, suggesting that enzymatic function and neuronal reuptake of dopamine was preserved., Conclusions: Isoflurane, compared with chloral hydrate and halothane, inhibits the release of the neurotransmitter dopamine during cerebral ischemia.

We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intact striata. These results suggest that the striatum with a reduction in DA nerve terminals is deficient both in the capacity to synthesize DA and in the storage mechanisms necessary to protect the newly synthesized DA from oxidative metabolism.

The cerebral dialysis technique was employed to monitor extracellular concentrations of dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the dorsal hippocampus of gerbils before and after cerebral ischemia induced by carotid artery occlusion. Extracellular concentrations of DA and NE in the dorsal hippocampus increased from baseline levels of less than 35 fmol/collection interval to 180 and 200 fmol/collection, respectively, within 36 minutes following carotid artery ligation (n = 8 animals). Extracellular concentrations of the DA metabolites, DOPAC and HVA, did not change significantly following carotid artery ligation. These data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE. This release may contribute to the selective vulnerability of the dorsal hippocampus to neuronal damage during ischemia.

We examined whether pentobarbital (PB) inhibited the acute extracellular release of dopamine that occurs in the striatum following the onset of ischemic injury in the gerbil model of stroke. The cerebral dialysis technique was employed to monitor striatal extracellular dopamine concentrations before and after carotid artery occlusion while perfusing either a control solution of artificial cerebrospinal fluid (CSF) or a 1 mM solution of pentobarbital in CSF (PB/CSF). During perfusion with CSF, extracellular dopamine increased from a baseline concentration of 0.40 +/- 0.09 (SEM) pmoles/10 minute collection interval to 30.0 +/- 9.0 pmoles/10 minutes after carotid artery occlusion. In contrast, during perfusion with PB/CSF, dopamine levels increased from a baseline of 1.37 +/- 0.3 pmoles/10 minutes to 8.30 +/- 2.6 pmoles/10 minutes; this increase was significantly less than the increase in controls. In animals with established ischemia, repeatedly alternating the perfusion fluid between CSF and PB/CSF demonstrated that dopamine concentrations were significantly increased with CSF alone and decreased with PB/CSF. These findings demonstrate that pentobarbital perfusion either before or following the onset of ischemia inhibits extracellular release of dopamine in the striatum. Inhibition of neurotransmitter release may, in part, be responsible for the protective effect of pentobarbital in ischemic brain injury.

Ischemic stroke was induced in the Mongolian gerbil by left common carotid ligation. No change in uptake of [3H]dopamine, [3H]gamma-aminobutyric acid ([3H]GABA), or [14C]glutamate in synaptosomes obtained from the ischemic hemisphere was observed for up to 8 h. At 16 h after ligation, marked decrements in uptake were observed in animals showing hemiparesis: Uptake values expressed as a percent of the corresponding control hemisphere were 15.2% for dopamine, 28.9% for GABA, and 47.5% for glutamate. The differential sensitivity of dopamine terminals compared with glutamate terminals was highly significant. Separate experiments performed with synaptosomes isolated from the corpus striatum showed that the greater sensitivity to damage was intrinsic to the dopamine nerve terminal and not the result of regional variations in ischemic damage in brain. No bilateral effect of ischemia on dopamine uptake was evident. In animals exhibiting milder behavioral deficits (circling), a smaller and comparable decrement in uptake of dopamine, GABA, and glutamate was evident at 16 h, whereas animals not affected behaviorally showed no decrement at 16 h. Following uptake, the subsequent fractional release of neurotransmitter stimulated by 60 mM-potassium ions was not affected at any time point studied. Therefore, the loss in uptake at 16 h probably represents overt destruction of nerve terminals. Experiments with urethane used in place of pentobarbital for anesthesia during carotid occlusion showed that "protection" by pentobarbital was not a factor in the delayed response to ischemia. These results show that damage or destruction of nerve terminals is a delayed event following ischemia and that dopamine terminals are intrinsically more sensitive than glutamate terminals.

Dopamine release into the extracellular space was measured with in vivo electrochemical detection in the ipsilateral and contralateral striata in Mongolian gerbils that suffered a stroke after acute unilateral carotid artery ligations. A sevenfold increase in the dopamine signal occurred within 15 minutes of carotid ligation in the ischemic side, while the unlesioned side had no significant change. Increased extracellular levels of dopamine persisted throughout the 3-hour recording period. Pretreatment with alpha-methyl-p-tyrosine 6 hours prior to recording significantly attenuated the signal increase. This study is the first direct demonstration of the marked, continuous dopamine release that occurs during acute cerebral ischemia.

Unilateral ligation of the left common carotid artery in anesthetized Mongolian gerbils resulted in a steep rise in extracellular dopamine in the ipsilateral striatum in 9 out of 19 animals. Extracellular dopamine was measured by cerebral dialysis in vivo and reached a peak of 0.19 mM at 40 min. At the same time, the level of homovanillic acid fell, whereas the levels of ascorbate and 3,4-dihydroxyphenylacetic acid remained relatively constant. In a separate group of animals studied with a combined dialysis/electrochemistry probe, a rise in the in vivo chronoamperometric signal in three out of six animals correlated with a rise in extracellular dopamine. The number of animals responding in these experiments (roughly 50%) corresponds to the frequency of incompetent Circle of Willis, as well as literature reports of the frequency of signs of stroke in unanesthetized gerbils. These results show a remarkable accumulation of dopamine in extracellular fluid in response to cerebral ischemia. Released dopamine appears to be responsible for the elevated in vivo electrochemical signal previously reported.

We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intract striata. These results suggest that the striatum with a reduction in DA nerve terminals is deficient both in the capacity to synthesize DA and in the storage mechanisms necessary to protect the newly synthesized DA from oxidative metabolism. [ABSTRACT FROM AUTHOR]