Treatment of parkinsonism with N-n-propyl norapomorphine and levodopa (with or without carbidopa).

The effects of the concomitant administration of N-n-propyl norapomorphine (NPA) and levodopa, with and without carbidopa, were studied in 12 patients with unsatisfactory symptom control. Double-blind evaluation of the effects of NPA with suboptimal doses of levodopa or levodopa plus carbidopa (Sinemet) showed a mean overall improvement of 44% (20% to 74%) in nine patients and improvement of the "on-off" effect in five. Dyskinesia diminished in some patients after diminution of basal medication. In three patients, plasma dopa and growth hormone patterns did not differ substantially with and without NPA. The magnitude and timing of the therapeutic and side effects did not correlate with the pattern of growth hormone secretion, which suggests that this hormone might not be instrumental in the induction of these effects. N-n-propyl norapomorphine is a useful adjunct in the long-term management of patients with unsatisfactory response to levodopa.

Morphine sulfate stimulates the adenylate cyclase in mouse caudate nuclei.

The effect of several concentrations of morphine on the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing): EC 4.6.1.1.] was measured in homogenates of caudate nuclei of mice. Morphine stimulated the enzyme at 500 micron and inhibited slightly at 5 micron. Morphine stimulation was blocked by naloxone. Depending on its dose, morphine also increased or decreased the stimulating effect of dopamine on the dopamine-sensitive adenylate cyclase activity of caudate homogenate. Like dopamine, morphine'e effect on the adenylate cyclase activity was increased or decreased, respectively, by pretreating the animals with poly(I).poly(C) or with chloramphenicol. Thus, both dopamine and morphine appear to act on the same receptor. This "new" receptor differs from the one described by Snyder et al. and others, who demonstrated only binding affinity and no enzymatic activity. These data indicate that certain functions of the opiates might be mediated through the dopamine-sensitive adenylate cyclase of the caudate nuclei, which are the dopamine receptors in the brain.

Cyproheptadine in levodopa-induced dyskinesia in parkinsonism.

The neuroendocrine properties and the beneficial effects of cyproheptadine in tardive dyskinesia led to the testing of this drug in levodopa-induced dyskinesia. Cyproheptadine administered to 6 parkinsonian patients in doses of up to 42 mg/day was of no significant benefit in either dyskinesia or symptom control. Improvement in appetite was reported by 3 patients. These observations suggested that different mechanisms may be responsible in the pathogenesis of phenothiazine and amine-induced dyskinesia. The failure to control levodopa-induced dyskinesia selectively with serotonin agonists and antagonists and the accentuation of the dyskinesia in the presence of anticholinergic agents further suggest that substances that increase directly central cholinergic activity may be effective in the control of levodopa-induced dyskinesia.

Antagonism by piperidine of levodopa effects in Parkinson disease.

The nicotinic cholinergic amine piperidine diminished both the dyskinesia and the symptomatic control in some patients with Parkinson disease receiving levodopa. Since the piperdine configuration is contained in the molecules of the apomorphine and N-propylnoraporphine, it might be responsible for the antagonism of these drugs to some effects of levodopa in Parkinson disease and for the palliation by apomorphine of some dopamine-mediated symptoms in other extrapyramidal disorders.

An adenylate cyclase of brain reflects propensity for breast cancer in mice.

High propensity for breast cancer in mice was associated with low dopamine-stimulated adenylate cyclase activity in the brain, low spontaneous motorization, and low motor responses to injections of the catecholamine precursor, L-dopa.

L-3,4-dihydroxyphenylalanine-induced hypersensitivity simulating features of denervation.

The manner in which dyskinesia and intermittency of neurological control had emerged late in the therapy of Parkinsonism with L-3,4-dihydroxyphenylalanine (levodopa) had suggested to us that this drug can imprint on the brain a chemical memory of its passage. The majority of authors ascribed these events to denervation hypersensitivity caused by the nigral and other lesions of the disease. By feeding levodopa to mice, however, we induced a state that simulated denervations hypersensitivity, including hyperreaction to single injections of levodopa and increased dopamine-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity in homogenates of caudate nuclei. These phenomena were not caused by actual denervation, because the hypersensitivity declined and disappeared some weeks after the dietary levodopa was stopped.

Levodopa, fertility, and longevity.

High concentrations of the dopaminergic drug levodopa (L-dopa, L-3,4-dihydroxphenylalanine) administered to mice in their diet affected fertility to a moderate degree and prolonged the mean life-span by a maximum of 50 percent.

Quantitative correlation of dopamine-dependent adenylate cyclase with responses to levodopa in various mice.

We obtained 12 groups of mice with widely different neurological responses to levodopa by selecting them from different strains and submitting some of them to pretreatments. We scored the symptoms evoked by a standardized dose of levodopa in one subgroup from each group. We tested another subgroup for activation of an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by a standardized dose of dopamine added to homogenates of the caudate nuclei of the brains of these mice. Both sets of tests were performed randomly. When the accruing two sets of data were plotted against each other there emerged a straight line which fitted the data with a coefficient of correlation of 0.97 (P less than 0.0001). The dopamine-dependent activity of the adenylate cyclase of the brain was thus shown to be a determinant of the neurological responses of intact animals to a dopaminergic drug.

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

In contrast to antipsychosis drugs which inhibit the dopamine-activated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of caudate nucleus, dopaminergic drugs for treatment of Parkinson's disease stimulate this cyclase. Stimulants and inhibitors of cholinergic neurons inhibited this adenylate cyclase activity competitively and specifically. Thus, the mechanism by which dopaminergic medications ameliorate the effects of Parkinson's disease includes activation of the dopamine-sensitive adenylate cyclase. Excessive activation might be present during the psychotic episodes seen in patients with parkinsonism who are overtreated. The enzymatic effects of the drugs that affect cholinergic mechanisms seem to be generally in keeping with the pharmacological reciprocity between psychoses and extrapyramidal function, except for the anticholinergic ones which inhibited this cyclase although they can be hallucinogenic.

Treatment of Parkinson's disease with aporphines. Possible role of growth hormone.

To avoid the main drawbacks of prolonged treatment with levodopa (involuntary movements and the "on-off" phenomenon), we administered apomorphine by mouth to 14 patients with Parkinson's disease. This treatment caused azotemia, which we circumvented by switching to N-propylnoraporpine, whose nephrotoxic dose (80 mg six times per day) was larger than its therapeutic dose (10 to 15 mg six times per day). Slowly increasing doses induced significant improvement (P less than 0.005) in all 24 patients studied, transitory mental aberrations in seven, and release of growth hormone in three patients tested. In patients previously on prolonged levodopa administration, the dyskinesia and "on-off" phenomenon were almost identical with N-propylnoraporphine, but both drawbacks were reduced or abolished in six patients by coadministration of alpha-methyldopa hydrazine plus levodopa. This coadministration seemed to abolish tachyphylaxis. We conclude that N-propylnoraporphine is very useful in the treatment of Parkinson's disease.

Modification of the actions of some neuroactive drugs by growth hormone.

The flat serum growth hormone (GH) patterns of untreated parkinsonian patients develop diurnal rises during treatment with levodopa. This chronic exposure to excesses of GH might lead to the eventual emergence of the "on-off" phenomenon, which would indicate a need for animal experiments. Pretreatment of mice with GH increased (1) cerebral dopa and dopamine concentrations in levodopa-treated mice, (2) cerebral accumulation of injected tritiated apomorphine and tritiated thymidine, and (3) behavioral responses to levodopa, L-m-tyrosine, apomorphine hydrochloride, and oxotremorine.

Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines.

The hydrochlorides of molecular segments of apomorphine [2-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline, 2-(3'4'-dihydroxybenzyl)piperidine, and 1,2,3,4-tetrahydroisoquinoline with their respective N-methyl and N-n-propyl homologs] and N,N-dialkylated dopamine compounds were synthesized and studied for (1) LD50 in intact mice; (2) stereotypy in intact mice; (3) curving of the body in unilaterally caudectomized mice; (4) rotation in 6-hydroxydopamine-lesioned rats, and (5) activation of adenylate cyclase in homogenates of mouse caudate nuclei. Instead of dopaminergic effects 1-(3',4'-dihydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline showed cholinergic ones. These effects were blocked in atropine-pretreated animals. Of the N,N-dialkylated dopamine compounds synthesized, the N-n-propyl-N-n-butyldopamine ranked in all tests as the strongest dopamine-receptor agonist and N-methyl-N-n-propyldopamine as the weakest. In contrast, N,N-dimethyldopamine and 1-(3,4-dihydroxyphenylethyl)piperidine showed no dopaminergic effects. The effectiveness of the dopaminergic agonists depended on the length of the N-alkyl substituents suggesting interactions with hydrophobic regions of the receptor site.

Control of tissue manganese: initial absence and sudden emergence of excretion in the neonatal mouse.

All adult animals and humans tested up to this time have controlled their tissue manganese concentrations by controlling primarily the rate of the metal's excretion. In sharp contrast, neonatal mice did not excrete manganese for the first 17-18 days of life, although absorption of the natural 55Mn as well as distribution, tissue accumulation, and mitochondrial accumulation of the radioactive 54Mn were vigorous. This suggested as initially avid accumulation of this essential micronutrient, supplied in scarce traces in mouse milk (54 ng/ml) by mothers consuming very much higher dietary concentrations (55,000 ng/g). The tissue accumulation was demonstrated analytically and was particularly impressive in the brain, which can be susceptible to both manganese poisoning and deficiency.