Robert E. Barrett

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.

The developing neostriatum of the rabbit: Correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels, and [3H]dopamine uptake

Abstract A correlation has been made between the sequential variation of fluorescent profiles during early fetal development and the maturation of growth cones into more differentiated axons with synapses ‘en passage’. The initial ingrowth of fluorescent axons enters the ventromedial putamen, probably in the angle formed by the external capsule, anterior commissure, and internal capsule. Later in fetal life, a second ingrowth of axons running adjacent to the internal capsule enters both the caudate nucleus and putamen. Circumscribed islands of fluorescence which are visible in late fetal and early postnatal stages, may indicate an anatomical and functional organization not previously recognized. The attainment of maximum endogenous dopamine levels in the rabbit lags behind the maturation of the uptake system and the development of the mature number of vesicle-filled processes and synaptic profiles. The maturation of the uptake process and the development of adult numbers of vesicle-filled axonal profiles, on the other hand, appear to correlate quantitatively with one another. The latter observation and the linear character of the fluorescent profiles tend to support the notion that axons having synapses ‘en passage’ and vesicles along their length may correspond to the dopamine-containing axons.

POLYAMINE METABOLISM IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

The complexity of the nervous system tissue relative to other tissues of the organism is such that it is in some respects less suitable for biochemical study; however, because of its unique character, the study of the nervous system may provide some special insight into both the metabolism and function of the polyamines. The neuron is not only one of the most actively biosynthesizing cells in the animal body, but it also, along with its supporting cells, provides the means for communication, learning and memory. In 1924, Dudley and coworkers isolated spermine from bovine brain; this was the first indication that the polyamines were present in the nervous system.l Subsequently, Hamalainen determined the spermine content of some discrete areas of the humain brain.? With the development of improved analytical procedures, employing ion exchange chromatography, Rosenthal and Tabor established the presence of both spermidine and spermine in the rat brain.3 This was followed by a report by Kewitz, in 1959, of the occurrence of putrescine and spermidine in pig brain.4 Subsequently, it was reported that S-adenosylmethionine, a precursor of both spermidine and spermine was present in, and synthesized by, the rat brain.5 The first information on the distribution of the polyamines in discrete regions of the nervous system was the result of a study of the rabbit brain by Shimizu and associates in 1964.G These investigators also noted marked differences in the polyamine concentration in gray and white matter of human brain cortex. More recently, putrescine has also been isolated from the human brain.7 Although the polyamines and their metabolic precursors are present in relatively large amounts in the central nervous system (CNS), quantitatively the polyamines are the major amine constituents, there is no definite knowledge of their biological function. Our studies are directed toward clarification of polyamine metabolism and function in the nervous system.

6,7-Dihydroxytetrahydroisoquinoline: Uptake and Storage by Peripheral Sympathetic Nerve of the Rat

6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline is a pharmacologically active alkaloid that can be formed by condensation of dopamine with formaldehyde. We used fluorescence microscopy to study in vitro the uptake and storage of this compound by sympathetic nerves of the rat iris. Rats were treated with reserpine or with the methyl ester of α-methyl-p-tyrosine in order to deplete the endogenous catecholamine stores. Accumulation of the alkaloid was about onetenth that of norepinephrine. Uptake was completely blocked by 10-5M desmethylimipramine. These results offer some explanation for the sympathomimetric properties of the alkaloid. Similar results can be expected for similar tetrahydroisoquinolines that may be formed in vivo from endogenous catecholamines during ingestion of alcoholic beverages.

Tetrahydroisoquinoline alkaloids: Uptake and release by adrenergic nerves in vivo

Abstract Mice or rats were depleted of endogenous norepinephrine by treatment with reserpine or α-methyl-p-tyrosine methyl ester. Subsequently, two tetrahydroisoquinoline alkaloids, namely 6,7-dihydroxytetrahydroisoquinoline (a dopamine derivative) and 4,6,7-trihydroxytetrahydroisoquinoline (a norepinephrine derivative) were injected i.v. and their presence in the mouse iris was studied by fluorescence microscopy. Both alkaloids were taken up and accumulated by the reserpinized adrenergic nerve plexus. Uptake was blocked by desmethylimipramine. In rats pretreated with α-methyl-p-tyrosine, stimulation of the preganglionic fibers to the superior cervical ganglion caused depletion of 6,7-dihydroxytetrahydroisoquinoline that had been previously taken up into nerve terminals in the iris. Stimulated release of this alkaloid resulted in contraction of the iris, retraction of the upper eyelid and protrusion of the eyeball. These combined results showed that the catecholamine-derived tetrahydroisoquinoline alkaloids possess the properties of false adrenergic neurotransmitters. Of additional interest, desmethylimipramine alone, without stimulation of the sympathetic trunk, evoked near maximal eyelid retraction in rats loaded with 6,7-dihydroxytetrahydroisoquinoline. If formed in vivo from circulating acetaldehyde or formaldehyde (during ingestion of ethanol or methanol, respectively), catecholamine-derived tetrahydroisoquinolines could play a role in altering adrenergic function.

Kinetic and fluorescent histochemical analysis of the serotonin compartments in rat pineal gland

Abstract Kinetic and fluorescent histochemical changes of rat pineal serotonin (5HT) were found after injecting p-chlorophenylalanine methyl ester (PCP), desipramine (DMI), or reserpine, alone or in combination. These changes indicate that the 5HT stores in sympathetic nerves amount to about 26 mμg/pineal which is approximately 30% of the total pineal store. Since this 5HT store almost completely disappears after DMI, a drug which blocks amine transport in neurons, it is concluded that 5HT is synthesized in pinealocytes and is subsequently taken into axons. The turnover rate of 5HT in the pinealocytes was estimated to be about 100 mμg/pineal/hr. The half-life of decline of 5HT stored in axons after PCP treatment is about ten times faster than that of pinealocytes.

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.

Torsion dystonia and spasmodic torticollis—results of treatment with L‐dopa

THE REMARKABLE EFFECTIVENESS of L-dopa in reversing the symptoms of parkinsonism has stirred interest in its therapeutic potential for other diseases of the basal ganglia for which no satisfactory treatment is presently available. As part of a systematic exploration of the spectrum of clinical conditions which might respond to L-dopa, we have treated seven patients with torsion dystonia (dystonia musculorum deformans) and three with spasmodic torticollis. Patients were selected according to the criteria established by Oppenheiml and Herz:2 the occurrence of hyperkinesias and postural distortions in the absence of paresis, atrophy, sensory abnormalities, long-tract signs, sphincter impairment, or mental changes. Patients with dystonic symptoms and other neurological deficits representing instances of the so-called “symptomatic dystonias” were excluded. L-dopa was administered orally in divided doses with graduated small increments from four to six times daily, The final dose achieved ranged from 4 to 7 gm. per day, depending on the tolerance of each patient. Treatment was continued for durations of one to twelve months during which time complete blood counts, urine, blood sugar, blood urea nitrogen, serum transaminase, and serum alkaline phosphatase analyses were monitored every two to six weeks. In only 1 patient (Case 5 ) was additional drug therapy with diazepam continued during treatment with L-dopa. This patient was also treated with S-hydroxytryptophan (5-HTP) for a brief period prior to commencing the L-dopa trial. The patients were carefully observed with the aid of cinematographic documentation for any evidence of a change in the severity of dystonic movements and posture; clear-cut amelioration in the performance of the activities of daily living, for example, sitting, walking, feeding, handwriting, speaking, dressing, etc.; and a recognizable difference in the dystonic state while on L-dopa as compared with a period following its withdrawal. In several instances, placebo control was used in single-blind fashion at various intervals during the treatment periods. For purposes of discussion, it is convenient to divide the patients into 3 groups according to the severity of their dystonic features as follows: [l] a group considered to have mild involvement (Table 1) in whom the dystonic process was of relatively short duration and confined to only one limb or to dystonic activity evident only when the patient attempted to perform skilled activity with the hands such as writing or performing rapid succession or alternating movements; [2] a severely involved group of patients whose disease process had been established for years and who had developed profound disturbances in locomotion, speech, ability to perform skilled activity of the hands, and marked postural abnormalities (Table 1); and [3] a group consisting of pa-

Uptake of catecholamines into serotonergic nerve cells as demonstrated by fluorescence histochemistry

Die histochemische Fluoreszenzmethode wird zum Studium der Nervenzellen des Gehirnstammes der Ratte angewandt. Die erhebliche Zunahme des Dopamins, hervorgerufen durch die Injektion eines peripher wirkenden Dekarboxylase-Hemmstoffes zusammen mitl-DOPA, wird im Gehirn verfolgt und gefunden, dass serotonergische Neuronen imstande sind, Catecholamine aufzunehmen.

Correlation of anatomical and biochemical development of the rabbit neostriatum.

Publisher Summary This chapter focuses on the correlation of anatomical and biochemical development of the rabbit neostriatum. The chapter presents data on (1) the endogenous levels of dopamine in the neostriatum at each stage and the ability of the tissue to take up exogenous dopamine, (2) the time of appearance and pattern of distribution of dopamine fluorescence, (3) the correlation of electron microscopic profiles of developing and mature synapses with changing fluorescent patterns, and (4) the formation of dense material within axonal vesicles of tissue slices of neostriatum after incubation in 5- or 6-hydroxydopamine. Dopamine has been recognized in recent years as one of the neuromodulators in the nervous system. It captured the attention of many investigators because of its role in the extrapyramidal motor system. The origin of dopamine in the neostriatum was uncertain until fluorescence microscopy studies demonstrated dopamine-containing neurons in the substantia nigra, which send axons to the caudate nucleus and putamen to form the nigroneostriatal tract.