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

Abstract

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 < 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.Greengard and his colleagues discovered a dopamnine-activated adenylate cyclase in homogenates of caudate nuclei (1-3) which appears to be the site of interaction between dopamine and the receptors on the membranes of postsynaptic dopaminergic neurons. The enzyme synthesizes a second messenger, adenosine 3':5'-cyclic monophosphate (cyclic AMP), governing the neuron's response to dopamine.-This enzyme seems to play a behavioral role in animals and man since neuroactive drugs tested against the adenylate cyclase have imitated drug effects seen in animals or man. The dopamine-dependent activity, for example, was selectively inhibited by antipsychosis drugs that block the mental effects of dopamine (4)(5)(6)(7)(8). These drugs, however, can induce pharmacological parkinsonism. Dopaminergic drugs in low concentrations potentiated selectively the enzyme's dopaminedependent activity but higher concentrations caused inhibition (2, 9). Furthermore, mutually antagonistic drugs, the cholinergic and anticholinergic ones, both-inhibited this enzyme (9). The sum of this evidence was only suggestive but did not prove a behavioral function of this enzymatic activity (9). It was useful, therefore, to seek quantitative correlations between (i) selected neurological or behavioral scores in intact animals and (ii) the dopamine-dependent activity of the cyclase in homogenates of brains from corresponding animals. Such a correlation would strengthen the assumption of a behavioral role without precluding a search for further functions (9).We had found earlier that the intensity of neurological responses evoked by standard single doses of levodopa in mice was sex-dependent (10) and was influenced by some genetic factors (11) and some pharmacological pretreatments (12, 13). One could therefore select appropriate groups so that the reactions of the mice in each group to single injections of levodopa would differ from those of the other groups (11-13). One could test Abbreviations: cyclic AMP, adenosine 3':5'-cycic monophosphate; HS, Hale-Stoner strain of Swiss albino mice.

The relationships of aging changes in the basal ganglia to manifestations of Huntington's chorea

“…For example, CBA mice have 25 to 50% fewer nigral DA neurons [57] and striatal D A receptors [62] than some other strains. Strain differences in DA-activated adenyl cyclase [63] indicate genetic influences on number or functions of striatal neurons. Such strain differences permit study of how genetic factors influence the effects of striatal lesions.…”

New dopaminergic and potential anti-Parkinson compounds, N,N-disubstituted .beta.-(3,4-dihydroxyphenyl)ethylamines

“…the hypothalamic hormone that inhibits the release of melanocyte-stimulating hormone from the anterior pituitary gland.3-6 The extra-endocrine effects of 1 were first demonstrated by Plotnikoff et al7 with Everett's Dopa potentiationtest.8 In this test 1 was found to potentiate the behavioral effects of L-3,4-dihydroxyphenylalanine (L-Dopa) in both normal and hypophysectomized mice. Subsequent studies with 1 have also shown that this tripeptide antagonizes the central and peripheral effects of oxotremorine,9,10 reverses the sedative effects of deserpidine,11 potentiates the behavioral effects of apomorphine,12 attenuates puromycin-induced amnesia,13 and facilitates the development of morphine dependence.14 Moreover, a number of preliminary clinical studies have indicated that 1 may be of potential value in the treatment of Parkinson's disease 15,…”