A possible mechanism for the beneficial effect of ethanol in essential tremor.

BACKGROUND: Essential tremor is one of the most common movement disorders in elderly people. The hypothesis of a disregulation of N-methyl-D-aspartate (NMDA) pathways has been suggested. It was shown experimentally that infusion of NMDA in cerebellar nuclei down-regulates glutamate release. METHODS: We assessed the effects of intranuclear administration of harmaline on the NMDA-mediated regulation of glutamate in rats using reverse dialysis. We hypothesized that ethanol, which improves essential tremor in the clinic, antagonizes the effect of harmaline upon glutamatergic transmission. We tested the interaction of ethanol and harmaline upon glycerol (a marker of membrane turn-over), lactate, and pyruvate concentrations. RESULTS: Harmaline increased the concentrations of glutamate and impaired the NMDA-mediated regulation of glutamate. Ethanol decreased the concentrations of glutamate during NMDA stimulation in case of pre-administration with harmaline. Concentrations of glycerol rose with harmaline. Glycerol levels markedly decreased during NMDA infusion when inhibitors of nitric oxide synthase, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonists or NMDA antagonists were administered. Harmaline increased lactate/pyruvate ratios during NMDA infusion but these ratios returned to normal values in presence of ethanol. DISCUSSION: We provide a possible mechanism for the beneficial effect of ethanol on essential tremor. The concept of glutamatergic disregulation underlying essential tremor is highlighted. Consequences for our understanding of essential tremor are discussed.

Pergolide potentiates L-DOPA-induced dopamine release in rat striatum after lesioning with 6-hydroxydopamine.

We used intrastriatal microdialysis to study the effect of pergolide, a D1/D2 dopamine (DA) receptor agonist on biotransformation of exogenous L-DOPA in hemi-Parkinsonian rats. DA and metabolites were assayed by microbore liquid chromatography. Pergolide (50 micrograms/kg, i.p.) caused a 67% and 87% decrease in striatal EC levels of DA in intact and denervated striatum respectively. In intact striatum but not in denervated striatum, pergolide decreased EC levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (53% and 42% decrease, respectively). L-DOPA (100 mg/kg, i.p.) produced significant increase in EC levels of DA, DOPAC and HVA in intact and denervated striatum with and without local perfusion of 10(-4) M pergolide. In denervated striatum, L-DOPA-induced DA increase was significantly higher in rats with pergolide. Our results suggest that, in an animal model of Parkinson's disease, pergolide in association with L-DOPA favors the restoration of striatal EC DA levels.

Microdialysis-HPLC for plasma levodopa and metabolites monitoring in parkinsonian patients.

We used in vitro microdialysis-HPLC to determine L-3,4-dihydroxyphenylalanine (L-DOPA) and its metabolites in plasma of patients with advanced Parkinson disease. Blood samples and clinical evaluations were obtained 0, 30, 60, 90, 120, and 150 min after oral administration of carbidopa/L-DOPA (25/100 mg, 12.5/125 mg, and 50/200 mg). In vitro recoveries for L-DOPA and metabolites ranged from 22% to 36%. Linear correlation was found between metabolite concentrations in the dialysate and in the surrounding medium. There was a significant positive correlation between L-DOPA dose and plasma concentration of L-DOPA and homovanillic acid (P < 0.04). Clinical response was maximum 60 min after L-DOPA administration. Threshold L-DOPA plasma concentration averaged 7.74 +/- 3.3 mumol/L. Motor effect is longer with the highest L-DOPA peak concentration (P < 0.01). Microdialysis-HPLC is readily applicable, reproducible, and allows monitoring of plasma L-DOPA and metabolites in parkinsonian patients.

Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat.

Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission.

Systemic and intrastriatal theophylline have opposite effects on dopamine and dopamine metabolites measured by intrastriatal microdialysis in the rat.

Using a model of intrastriatal microdialysis, we studied the effect of theophylline, an A1 and A2A adenosine receptor antagonist on striatal dopamine (DA) and DA metabolites. Systemic administration of theophylline (10 and 50 mg/kg) significantly reduced striatal extracellular (EC) levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy-phenylacetic acid (HVA). Intrastriatal administration of theophylline (10(-2) M) significantly increased DA and its metabolites (DA1 + 120%; DOPAC, +28%; HVA, +30%). Contradictory effects of systemic and intrastriatal theophylline point to theophylline interactions with different receptors possibly at different locations.

Slow increase of homovanillic acid in cerebrospinal fluid after levodopa administration.

Concentrations of major catabolites of dopamine were followed in the ventricular cerebrospinal fluid (CSF) in five patients undergoing intracranial pressure monitoring for chronic hydrocephalus. Determinations were made every 2 h following the administration of carbidopa/levodopa 25/250 mg (one Sinemet capsule) given 8 h apart. The rise of homovanillic acid (HVA) concentrations was slow and progressive, reaching the level of statistical significance (p < or = 0.01) only 8 h after the second administration of Sinemet. The rise in 3,4-dihydroxyphenylacetic acid (DOPAC) was faster than the rise in HVA, with the peak value detected 4 h after the first administration of Sinemet. These data are interpreted as a confirmation, in humans, of a slow pool of exogenous levodopa, previously demonstrated in animal studies.

Effect of pergolide on endogenous and exogenous L-DOPA metabolism in the rat striatum: a microdialysis study.

We used a model of intrastriatal microdialysis in freely moving rats to study the effect of pergolide, a mixed D1/D2 dopamine (DA) receptor agonist with predominant D2 action in vivo, on the biotransformation of endogenous and exogenous L-DOPA. Levels of L-DOPA, DA, DOPAC, HVA and 5-HIAA were measured by high performance liquid chromatography. Pergolide (50 micrograms/kg, i.p.) caused a 47%, 65% and 70% decrease in basal striatal extracellular (EC) levels of DOPAC, HVA and DA, respectively. L-DOPA (100 mg/kg, i.p.), injected 2 hours after carbidopa, produced significant increase in EC levels of L-DOPA, DOPAC, HVA and DA in rats with and without local perfusion of 10(-4) M pergolide. The DOPAC peak value was lower and was reached 60 minutes later in the group with pergolide. This study demonstrated inhibitory effects of pergolide on endogenous DA release and influence of pergolide on exogenous L-DOPA biotransformation.

Variations of homovanillic acid levels in ventricular cerebrospinal fluid.

We studied the nycterohemeral variations of homovanillic acid (HVA) in ventricular cerebrospinal fluid (CSF) in 24 patients undergoing monitoring of intracranial pressure as part of the normotensive hydrocephalus (NTH) work-up. CSF samples were obtained every 4 h in each patient. The mean individual values of HVA in the ventricular CSF ranged from 133 to 421 ng/ml, and they could not be correlated to any clinical feature. The intraindividual levels of HVA were stable throughout 24 hours, with a variation coefficient inferior to 10% in 63% of cases, and inferior to 20% in all the patients.