The effect of benserazide on the peripheral and central distribution and metabolism of levodopa after acute and chronic administration in the rat

Abstract

1 The effects of levodopa alone (50mgkg-')and levodopa (10mgkg-1) plus benserazide (5Omgkg 1) were tested on the levels of dopa, dopamine, 3-methoxytyrosine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), measured by h.p.l.c. with electrochemical detection, in samples of plasma, CSF, urine, striatum and hypothalamus of rats taken 30min after injection. Levodopa plus benserazide produced significantly higher levels of dopa in plasma and brain than levodopa alone and reduced the peripheral synthesis and metabolism of dopamine. 2 When given chronically over 6 weeks the advantages of adding benserazide (50mg kg1 day 1) to levodopa (40 mg kg'-day -1) were less marked and although more dopamine was present in the striatum than with levodopa given alone (200 mg kg'-day-1) there was no evidence of any increase in its metabolites (HVA and DOPAC) and therefore of its turnover and utilisation. 3 The most striking effect of chronic treatment with levodopa plus benserazide was the appearance of large quantities of 3-MT in plasma, CSF and brain. 4 When levodopa alone, or levodopa plus benserazide, was given as an acute challenge to animals receiving the same treatment chronically, it was found that levodopa alone still produced increases in striatal dopamine, DOPAC and HVA in those animals dosed chronically on levodopa, but it was less effective in this respect when given with benserazide to the animals dosed with levadopa plus benserazide. 5 It is concluded that this difference in levodopa distribution may depend on the persistence in benserazide-treated animals of 3-MT, which has a long half-life and may compete with dopa for transport into the blood and brain. 6 The implication of these findings to the treatment of Parkinsonism is discussed.

L-DOPA Preloading Increases the Uptake of Borophenylalanine in C6 Glioma Rat Model: A New Strategy to Improve BNCT Efficacy

“…This large dose of L-DOPA and the long time gap were chosen to obtain a prolonged L-DOPA availability than that observed at lower doses (37), with negligible competition effects for BBB transport between L-DOPA and its metabolites and for BPA. Indeed, a 15-hour half-life has been estimated for the 3-MT metabolite in rats treated with L-DOPA (38). Each rat was then anesthetized again as described earlier, and its right internal carotid was catheterized using a 0.7-mm cannula.…”

Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization

“…16 It is most probable that 3-MT is formed peripherally and transported into the brain, implying an important correlation between plasma and brain 3-MT levets. 17 Thus, the elevated 3-MT levels during flashbacks may in some way reflect increased dopaminergic activity. Stressful stimuli have been found to sensitize 3-MT release.…”

The Role of Noradrenergic and Dopaminergic Hyperactivity in the Development of Spontaneous Recurrence of Methamphetamine Psychosis and Susceptibility to Episode Recurrence

“…Preclinical data indicate that brain 3‐MT levels are a more sensitive index of preferential DA release 15,16. In rats, administration of benzedrine, which is a peripheral decarboxylase inhibitor, results in simultaneous synthesis of 3‐MT in plasma, in cerebrospinal fluid, and in the brain 17. A peripheral origin of 3‐MT can be postulated 18.…”

“…First, plasma monoamine metabolite levels do not accurately reflect central monoamine neurotransmitter function. Plasma levels of NE22 and 3‐MT,23 respectively, reflect at best gross changes in whole‐brain noradrenergic and dopaminergic metabolism. Second, the elevated levels of NE24 and 3‐MT19 might be due to heightened autonomic arousal related to stress or anxiety.…”