Effect of tropatepine, an anticholinergic drug, on regional cerebral blood flow in patients with Parkinson's disease.
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Biomedical subjects
Publications and source records attributed to O Rascol.
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The effects of muscarinic agonists (McN-A-343, pilocarpine, oxotremorine-M, carbachol) and antagonists (pirenzepine, gallamine) applied by iontophoresis were studied on several neuronal populations in the central nervous system of rats anesthetized with urethane. Septohippocampal neurons and neurons from hippocampus, subiculum and somatic sensory cortex were studied. Oxotremorine-M and carbachol had (almost exclusively) potent excitatory effects whereas pilocarpine had some and McN-A-343 had almost exclusively inhibitory effects on the 4 populations of neurons studied. Pirenzepine blocked more easily the effects of pilocarpine and McN-A-343 than those of oxotremorine-M or carbachol. These results suggest (i) that many central neurons may bear different functional muscarinic receptors and (ii) that the various agonists studied might act through (at least partially) different mechanisms.
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We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefit in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.
The effects of nicardipine, a dihydropyridine calcium channel blocker, on adrenal medulla were investigated in chloralose-anesthetized dogs. For analysis of the adrenal medullary function, adrenal venous catecholamine rates were determined. Intravenous administration of nicardipine (50 micrograms/kg) induced a marked increase in both adrenal catecholamine rates and heart rate and a simultaneous decrease in blood pressure. This effect on epinephrine and norepinephrine release is probably explained by the involvement of baroreflex mechanisms. After acute splanchnicectomy, nicardipine (50 and 100 micrograms/kg i.v.) failed to modify catecholamine secretion rates from the denervated adrenal medulla during electrical stimulation of the splanchnic nerve at low (2 Hz) and high (5 Hz) frequencies. In conclusion, these results suggest that in vivo a functional dihydropyridine-sensitive calcium channel is not required for calcium entry mechanisms into dog chromaffin cells. Moreover, adrenal medulla is not involved in the antihypertensive action of nicardipine.
We measured regional cerebral blood flow (CBF) with single photon emission computed tomography and Xenon 133 in 8 patients with Parkinson's disease (stages I or II) before and after acute oral administration of 10 mg bromocriptine. Moreover, Columbia University Rating scale and neuropsychological tests were assessed before and after drug administration. Bromocriptine induced a significant (p less than 0.01) increase in CBF (+ 12 p. 100) in all the regions studied unrelated to pCO2 variations. The Columbia motor scale score decreased (by 16 p. 100) whereas those on the neuropsychological tests did not vary. There was no relationship between the improvement in motor performance and the increase in CBF. The results suggest that the effect of bromocriptine on CBF is not mediated by an action on the major dopaminergic pathways in the brain but rather by a direct effect on dopaminergic receptors located on cerebral vessels.
The excitability of the axonal terminals of medial septal neurons projecting to the dentate gyrus has been studied in the anesthetized rat under various experimental conditions: spontaneous or drug-induced variations in neuronal soma discharge rate, conditioning stimulation of afferent pathways (perforant path, commissural pathway, fimbria-fornix). It has been observed that terminals excitability is inversely correlated to the level of neuronal ongoing activity. These effects were observed on virtually all septal neurons projecting to the dentate gyrus. Since about one half of the septohippocampal neurons are likely to be cholinergic, it follows that such a phenomenon is not transmitter specific.
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The action of several dopamine agonists on blood pressure was investigated. In dogs, apomorphine induced a decrease in blood pressure and an increase in heart rate. These effects were suppressed by intravenous haloperidol or phentolamine. Intravenous but not intracisternal domperidone suppressed the hypotensive responses elicited by intravenous or intracisternal apomorphine. Furthermore, the hypotensive effect of bromocriptine or apomorphine was abolished in adrenal demedullated dogs. Apomorphine and bromocriptine decreased adrenal catecholamine levels. In men, the acute hypotensive property of apomorphine (but not the long term effect of bromocriptine) was suppressed by pretreatment with domperidone. In hypertensive Parkinsonians, bromocriptine reduced blood pressure, induced an increase in inulin clearance, a decrease in plasma creatinine concentration and in renal vascular resistances. These results suggest that dopamine agonists (like apomorphine or bromocriptine) reduce blood pressure through both a decrease in sympathetic tone and an improvement in renal function. However, the mechanism of the acute and long term hypotensive effects could be different only involving peripheral mechanisms after acute administration and both peripheral and central structure under chronic treatment. In addition, preliminary results suggesting the potential interest of dopamine antagonists in the management of orthostatic hypotension are discussed.
Medial septal-nucleus of the diagonal band of Broca area (MS-nDBB) neurons, identified by their antidromic response to the electrical stimulation of the fimbria and/or hippocampus, were studied in the rat under various conditions of anesthesia. These septo-hippocampal neurons (SHNs) were classified into 4 groups on the basis of: (i) their antidromic latency; and (ii) the presence or absence of a rhythmically bursting pattern of spontaneous discharge. The rhythmically bursting activity (43.5% of the SHNs) was highly dependent on the anesthetic conditions. The groups of SHNs differed in their mean conduction velocity and rate of spontaneous activity. In contrast, irrespective of their classification in a particular group, the large majority of the SHNs could be excited by the iontophoretic application of cholinergic agonists. Beside the SHNs, two other populations of MS-nDBB neurons could be identified by electrical antidromic stimulation: neurons projecting to the amygdala (Am) and neurons projecting through the medial forebrain bundle (MFB). Half of the MS-nDBB neurons projecting to Am were also antidromically driven from the fimbria. The axonal branch projecting to Am had a slower conduction velocity than that projecting to hippocampus. In contrast MS-nDBB neurons projecting through the MFB were never antidromically driven from the fimbria, although they received orthodromic inputs. They had a slower conduction velocity than the other groups of MS-nDBB neurons.
The electrophysiological properties of septo-hippocampal (SHNs) and basalo-cortical neurons (BCNs) identified by antidromic stimulation were compared in rats anesthetized with urethane. SHNs and BCNs had comparable conduction velocities (about 2-3 m/s) and relatively high spontaneous firing rates (about 20 impulses/s). In contrast, they differed in their pattern of spontaneous discharge as studied by generating inter-spike interval histograms. Many BCNs had a regular pattern of discharge. Among SHNs, about 40% had a spontaneous rhythmically bursting pattern of discharge, whereas the remaining 60% had a more or less irregular pattern. These results suggest that SHNs represent a more heterogeneous neuronal population than BCNs, and that central cholinergic neurons involved in different systems might also have different properties.
Neurons located in the ventromedial globus pallidus (nucleus basalis) and substantia innominata, that were antidromically driven by electrical stimulation of the frontoparietal cortex, were recorded in the urethane anesthetized rat. The basalocortical neurons (BCNs) were antidromically driven with latencies of 1.1-13.5 ms, giving conduction velocities of 0.6-6.8 m/s. Many BCNs had regular patterns of spontaneous discharge (mean spontaneous activity: 20 impulses/s). Most BCNs were not responsive to non-noxious peripheral somatic stimulation. BCNs were readily excited by the iontophoretic application of glutamate and strongly inhibited by GABA. Eighty-five percent of the BCNs could be excited by acetylcholine. They could also be excited by cholinergic agonists. Muscarinic agonists excited a higher proportion of BCNs than nicotinic agonists. Excitatory responses to acetylcholine, carbachol and muscarinic agonists were abolished by atropine.
The putative cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), was injected bilaterally into the cerebral ventricles of male rats. The properties of the medial septum-nucleus of the diagonal band of Broca's area (MS-nDBB) neurons were studied 4 to 6 or 19 to 23 days following injections. The spontaneous activity of those neurons was higher in the injected animals, but their responses to glutamate and cholinergic agonists were not modified. The proportion of orthodromic responses elicited by fimbria-fornix stimulation in MS-nDBB neurons was unchanged. In contrast, the proportion of septohippocampal neurons (SHNs) identified by the antidromic stimulation of the fimbria-fornix was smaller in pretreated animals and their mean antidromic latency was shorter. These results suggest that intracerebroventricular administration of the neurotoxin AF64A is followed by changes in the properties of MS-nDBB neurons and specifically by the disappearance of a subpopulation of SHNs.
The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.
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The septo-hippocampal terminals were electrically stimulated at the level of the gyrus dentatus in urethane anesthetized rats and antidromic responses were recorded in the medial septum. The excitability of the terminals was assessed by the threshold of terminal antidromic activation. An increase in the discharge frequency of the septal neurons following a microiontophoretic application of glutamate to their soma induced an increase in the antidromic activation threshold, i.e. a decrease in excitability of the terminals. An application of GABA which inhibited septal neuronal activity, induced a decrease in the antidromic activation threshold, i.e. an increase in the terminal excitability of septo-hippocampal neurons. These results are discussed in the light of the presynaptic autoreceptor hypothesis.