J. Martínez-Tica

Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine

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 <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.

In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-DOPA and dopamine metabolism

SummaryUtilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nervertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism underbasal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the “cheese effect” such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinsons disease is discussed.

Catechol‐O‐methyltransferase inhibition increases striatal L‐dopa and dopamine An in vivo study in rats

We administered Ro 40–7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of 1-dopa. Acute administration of Ro 40–7592 increased basal levels of 1-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels. In rats treated with Ro 40–7592, 1-dopa administration produced a greater increase in striatal levels of 1-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated. We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of 1-dopa.

Striatal L-dopa metabolism studied in vivo in rats with nigrostriatal lesions.

SummaryWe 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.

Effect of Isoflurane and Halothane on In Vivo Ischemia-induced Dopamine Release in the Corpus Striatum of the Rat A Study Using Cerebral Microdialysis

BackgroundDopamine is released in large quantities into the corpus striatum during cerebral ischemia and may exacerbate tissue damage. MethodsUsing 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. ResultsCompared with pre-ischemic levels, large quantities of dopamine (350 × 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 × 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. ConclusionsIsoflurane, compared with chloral hydrate and halothane, inhibits the release of the neurotransmitter dopamine during cerebral ischemia.

Effect of etomidate on in vivo ischemia-induced dopamine release in the corpus striatum of the rat : a study using cerebral microdialysis

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)

Low and high dose bromocriptine have different effects on striatal dopamine release: An in vivo study

SummaryWe wished to determine if low and high doses of bromocriptine produce distinct patterns of dopamine release and metabolism. Accordingly, we administered bromocriptine (0, 2.5, 5, and 10 mg/kg, IP) to rats and monitored extracellular concentrations of dopamine and dopamine metabolites in the corpus striatum with the technique of cerebral microdialysis. Extracellular dopamine levelsincreased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levelsdecreased following 10 mg/kg bromocriptine. Dopamine metabolite levels decreased 45 minutes following all doses of bromocriptine. Bromocriptine administration had no effect on the levels of 5HIAA, the major serotonin metabolite. These findings with high dose bromocriptine fit the predicted profile of a dopamine D2 receptor agonist. The delayed decrease in dopamine metabolites at all bromocriptine doses is consistent with the known dopamine synthesis inhibiting action of bromocriptine. In contrast, the increased dopamine release observed following low and medium doses of bromocriptine is not readily explainable by current theories of bromocriptine action which predict decreased dopamine release and therefore decreased striatal extracellular dopamine levels with both high and low-doses of bromocriptine. Our findings indicate that bromocriptine has a complex pharmacological action that extends beyond simple agonism at dopamine D2 receptors.

Effect of dietary protein on striatal dopamine formation following L-dopa administration: An in vivo study

We varied the diet of rats and monitored extracellular levels of dopamine in the striatum. Following L-dopa administration, the increase in striatal dopamine levels was attenuated by 78% in rats that had consumed a high protein diet as opposed to a low protein diet. Similarly, the increase in striatal dopamine levels was attenuated by 61% in rats that had just eaten a protein-containing meal as compared to fasting animals. These findings demonstrate that dietary protein strongly affects brain dopamine formation from exogenous L-dopa.

Effect of yohimbine on brain monoamines : an in vivo study

SummaryFollowing the administration of yohimbine, an α2-adrenoreceptor antagonist, the levels of norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) increased significantly in the lateral ventricular fluid of rats. These increases were abolished when animals were pretreated with α-methyl-para-tyrosine or reserpine. Dopamine (DA) was not detected in ventricular fluid either before or after yohimbine administration. Yohimbine administration did, however, increase intracellular DA levels in the corpus striatum. These findings indicate that yohimbine promotes NE and DA release in the brain and suggest that it also modifies the activity of the serotonin system.

Changes in body temperature markedly affect striatal dopamine release and metabolism : an in vivo study

Dopamine release and metabolism in the corpus striatum increased markedly when the core body temperature of anesthetized rats was increased from 35 ° to 41 °C while temperatures below 34 ° were associated with a marked attenuation of dopamine release. These observations may have clinical relevance in cases where alterations in body temperature are associated with extrapyramidal dysfunction.