Stuart R. Snider

Analysis of the clinical problems in parkinsonism and the complications of long‐term levodopa therapy

We evaluated the current status of 131 patients with idiopathic parkinsonism who were receiving levodopa therapy. The residual parkinsonian symptoms and signs were tabulated, as were the adverse effects from medication. Response to therapy was correlated with duration of the disease and with duration of treatment. Patients with on-off or wearing-off effects were likely to have been treated for 4 years or longer. Patients treated with levodopa for 4 to 8 years were significantly more impaired with parkinsonism than patients treated for 0 to 3 years, even when patients were matched for total duration of disease. These data suggest that the deterioration of responsiveness after several years of levodopa therapy may be due to the therapy itself. Our findings support the concept that utilization of levodopa therapy should be delayed until a patient becomes significantly impaired in occupational or social situations.

Primary sensory symptoms in parkinsonism

Forty-three of 101 outpatients with parkinsonism reported that they regularly experienced primary sensory symptoms, i.e., spontaneous abnormal sensations not caused by somatic disease. This is in contrast to similar symptoms reported by only 8 percent of a control population. The most striking and severe symptom was burning of the trunk and proximal extremities, occurring in 11 patients. Twenty-nine patients reported spontaneous pain; a variety of other paresthesialike sensations, e.g., tingling, numbness, and formication, occurred in 32 patients. These subjective sensory phenomena were not associated with sensory loss or autonomic or motor signs. In 20 percent of affected individuals (9 percent of the total), sensory symptoms preceded the onset of the movement disorder, causing difficulty in diagnosis. It is concluded that at least some sensory symptoms originate within the nervous system as a manifestation of the disease process and are not secondary effects of the motor disorder.

Correlation of behavioural inhibition or excitation produced by bromocriptine with changes in brain catecholamine turnover

The dopamine agonist, bromocriptine, produced either inhibition or stimulation of motor behaviour in rats depending upon the dose and time after administration. Stimulation of motor activity occurred only with high doses after a 1–2 h delay. Both inhibition and stimulation were associated with decreased turnover of dopamine in the brain. Release of noradrenaline in brain and noradrenaline plus adrenaline in adrenal varied with motor activity. It is suggested that low doses of bromocriptine inhibit behaviour by activating an inhibitory presynaptic receptor, resulting in reduced synthesis and release of dopamine, whilst high doses cause behavioural excitation by activating the post‐synaptic dopamine receptor.

The role of bromocriptine in the treatment of parkinsonism.

Fifty-three patients with parkinsonism, either with intractable symptoms despite optimum-dosage levodopa therapy or with adverse effects from levodopa limiting its usefulness, were treated with bromocriptine, with gradually increasing doses until benefit or adverse effect was encountered. All were initially maintained on optimal levodopa therapy. Improvement was seen in 26 patients, of whom 19 (36 percent of the total 53 patients) had sustained improvement. Effective doses of bromocriptine ranged from 5 to 90 mg per day. Improvement occurred in all categories of clinical problems, including patients who lost some benefit from chronic levodopa therapy as well as those with adverse effects from levodopa. A high incidence (70 percent) of adverse effects of bromocriptine limited the usefulness of this drug. Since one cannot predict which patients might benefit from bromocriptine, this drug is worth a trial in patients not doing well on levodopa therapy if other means to improve their condition are not successful.

Normalization of brain serotonin by L‐tryptophan in levodopa‐treated rats

To test possible biochemical mechanisms by which L-tryptophan may reverse mental side effects of levodopa therapy in parkinsonism we administered levodopa, 250 mg per kilogram intraperitoneally, alone and with L-tryptophan, 500 mg per kilogram intraperitoneally, to rats pretreated with the peripheral dopa decarboxylase inhibitor, carbidopa (25 mg per kilogram). Rats were decapitated 0.5, 1, and 2 hours following amino acid injection and brain levels of amino acids, amines, and acid metabolites were determined. As expected, levodopa alone reduced tryptophan and serotonin and increased dopa and dopamine at the 1 and 2 hour intervals. Concurrent administration of L-tryptophan did not significantly alter the increased dopa and dopamine but did restore serotonin levels to within normal range at all time points. If similar events occur in parkinsonian patients, normalization of brain serotonin and not competitive reduction of brain dopa and dopamine may be the basis for the improvement in mental status.

Increased synthesis of adrenomedullary catecholamines induced by caffeine and theophylline

SummaryCaffeine or theophylline, 20 mg/kg i.p., was given to rats. Thirty minutes after the injection of either drug, adrenal dopamine increased 80 and 50%, respectively. This increase was prevented by a C-7 spinal cord transection made 24 h before. In transected animals adrenal dopamine decreased after caffeine; no statistically significant decreases in adrenaline + noradrenaline were observed. It is concluded that caffeine and theophylline activate the tyrosine hydroxylase by a mechanism which depends on a normal or increased nerve impulse flow. In addition, release of adrenal catecholamines may occur both via neurogenic stimulation and directly.

Increase in brain serotonin produced by bromocryptine

Abstract The dopamine agonist, bromocryptine (BrC), 5 mg/kg, was administered intraperitioneally to rats. Br-C-treated and matched control animals were sacrified 1, 2 and 4 h later. Some were pretreated with an inhibitor of l -aromatic amino acid decarboxylase to determine 5-hydroxytryptophan (5-HTP) synthesis rate. An increase in brain serotonin (5-HT) occurred 2 h after BrC and persisted at 4 h. 5-Hydroxyindoleacetic acid was reduced about 35% at 1, 2 and 4 h. Only slight changes in 5-HTP synthesis and tryptophan concentration were seen. It is concluded that BrC reduces 5-HT release in vivo , possibly by direct effects on 5-HT neurons as well as indirectly by effects on dopamine receptors.

EFFECT OF A CATECHOL-O-METHYL TRANSFERASE INHIBITOR, U-0521, WITH LEVODOPA ADMINISTRATION

Abstract The in vivo effect of 3,4-dihydroxy-2-methyl-propriophenone (U-0521) was studied in rats treated with l -Dopa, 250 mg/kg, intraperitoneally. In a time-course study, experimental animals received two doses of U-0521, 250 mg/kg, i.p., 30 min before l -Dopa and along with l -Dopa. Rats were decapitated at intervals of 30–120 min. U-0521-treated animals showed elevated levels of plasma and brain DOPA and of brain dopamine; they also had a reduction of 3- O -methyldopa (OMD) in plasma and brain, and of homovanillic acid (HVA) in brain, compared to rats treated with l -Dopa alone. A dose-response study of U-0521, given 30 min before l -Dopa, showed that there was effective inhibition of plasma and brain OMD accumulation at a dose of U-0521 of 100 mg/kg, i.p., or greater. Brain HVA accumulation was inhibited at a dose of 200 mg/kg, i.p., or greater. U-0521 can effectively block formation of O -methylated metabolites of l -DOPA and dopamine peripherally and centrally after high dosage l -Dopa administration.

Kainic acid: Enduring alterations in cerebellar morphology and in cerebral catecholamine and GABA concentrations after cerebellar injection in the rat

Kainic acid injected locally in the vermian cortex produces a focal lesion with severe cellular loss. Microscopic changes in 3-week-old preparations are given for both central and peripheral segments. Biochemical studies indicate that norepinephrine, dopamine and gamma-aminobutyric acid (gaba) concentrations in the forebrain are consistently higher on the side of the lesion and remain elevated for at least 3 weeks. It is postulated that disinhibition of cerebellar activity traversing the uncrossed pathway from cerebellar nuclei to catecholamine cell bodies was a major mechanism causing increased catecholamine metabolism in the ipsilateral forebrain.

Increase in adrenal dopamine following 6-hydroxydopamine

6-Hydroxydopamine (6-OHDA) does not have the devastating effect on adrenomedullary cells that it has on peripheral adrenergic nerves. There are slight, if any, changes in the levels of rat adrenal catecholamines with a treatment schedule that reduces the content of noradrenaline in sympathetic nerves more than 80 % (Thoenen & Tranzer, 1968). However, 6-OHDA may induce a reflex increase in nerve impulse flow to the adrenals (Mueller, Thoenen & Axelrod, 1969) and thus secondarily affect catecholamine synthesis and release. In this communication, stimulation of adrenal catecholamine synthesis, with an accompanying elevation of dopamine, is shown to occur following the administration of a single intraperitoneal dose of