Utilizing 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. Nevertheless, 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 under basal 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 Parkinson's disease is discussed.

We 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 levels increased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levels decreased 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.

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 l-dopa. Acute administration of Ro 40-7592 increased basal levels of l-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, l-dopa administration produced a greater increase in striatal levels of l-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 l-dopa.

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.

This study sought to determine the maximum tolerable limit of anemia for the brain during halothane anesthesia. Using a multiparameter sensor, we continuously monitored brain tissue oxygen tension (PO2), carbon dioxide tension (PCO2), and pH during profound hemodilution and subsequent transfusion. Twelve New Zealand White rabbits were anesthetized, intubated, and mechanically ventilated at a fraction of inspired oxygen (FiO2) of 21% to produce an arterial carbon dioxide tension (PaCO2) of 35 to 40 mm Hg. The femoral artery was cannulated to continuously monitor arterial blood pressure and to intermittently measure arterial blood gases. The electroencephalogram (EEG) was recorded throughout the course of the study. A fiberoptic sensor was inserted into the brain for the continuous measurement of brain PO2, PCO2, pH, and temperature. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Severe anemia was induced by repeatedly withdrawing 50-mL aliquots of blood and infusing an equal volume of 6% hetastarch. This procedure was performed four times for each rabbit. After the forth blood draw and fluid infusion, a total of 60 mL of packed red blood cells were transfused. Upon completion of the hemodilution, the hemoglobin concentration was 2.4 +/- 0.3 g/dL (mean +/- SEM). Brain tissue PO2 decreased from 27 +/- 3 mm Hg to a minimum of 12 +/- 2 mm Hg. Brain tissue pH also decreased from 7.22 +/- 0.03 to 7.12 +/- 0.05 and returned to the baseline value with transfusion. Brain PCO2 did not change significantly during the experiment. Cerebral blood flow increased from 37 +/- 3 to 66 +/- 15 mL x 100 g(-1) x min(-1) during hemodilution and returned to baseline after infusion of red blood cells. There was some loss of EEG amplitude and the calculated cerebral metabolic rate (CMRO2) decreased from 4.3 +/- 0.6 to 1.9 +/- 0.3 mL x 100 g(-1) x min(-1) at the most profound level of anemia. This is the first report of which the authors are aware of continuous monitoring of brain tissue pH, PCO2, and PO2 during profound hemodilution and transfusion. Hemodilution results in a decrease in brain tissue PO2. Increases in CBF and oxygen extraction can only partially compensate for the decreased oxygen carrying capacity of the blood. Decreases in brain tissue PO2, pH, CMRO2, and a loss of EEG amplitude suggest that the maximum tolerable limit of hemodilution was achieved in this study.