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R I Westphalen

Publications and source records attributed to R I Westphalen.

6 recordsLinked to original sources
PubMed2000

Dopamine uptake blockers nullify methamphetamine-induced decrease in dopamine uptake and plasma membrane potential in rat striatal synaptosomes.

Rat striatal synaptosomes showed a reduced capacity to generate a membrane potential after being exposed to methamphetamine (METH) for 1 h. As a consequence, the dopamine (DA) synaptosomes were impeded in their electrogenic-dependent reuptake of dopamine. The capacity for METH-exposed nerve terminals to generate a membrane potential may contribute to the ability of METH to destroy dopaminergic neurons. DA uptake inhibitors (DAUIs) were found to counteract the METH-induced decrease in synaptosomal [3H]DA Vmax by stablizing METH-induced reductions in PMP. Because DAUIs showed the same effects as a Na+-channel blocker, DAUIs may prevent METH-induced destruction of dopaminergic neurons by raising plasma membrane potential.

Animals↗
PubMed1994

Excitotoxic mechanisms in the pathogenesis of dementia.

Alzheimer disease and related dementias, in common with most major neurological diseases, are characterized by localized brain damage. An abundance of senile plaques and neurofibrillary tangles in certain brain areas is pathognomic of the disease: of the two, the density of tangles may correlate more closely with disease severity ante mortem. Clinical manifestation of the disease also results from a locally severe loss of neurones. This might be caused by over-stimulation by excitant amino acid transmitters such as glutamate, which would promote cell death. Mechanisms which might give rise to the localization of Alzheimer pathogenesis include hypersensitivity to damage because a cell carries a particular sub-set of post-synaptic receptors; local variations in the efficiency of excitatory amino acid transport; and, possibly, local exacerbation of toxicity by substances such as beta-amyloid. Elucidation of such mechanisms could lead to new pharmacotherapies of dementia.

Alzheimer Disease↗
PubMed1993

The regeneration of d,l-fenfluramine-destroyed serotonergic nerve terminals.

The regeneration of serotonergic nerve terminals subsequent to their destruction by high-dose fenfluramine administration was examined. Treating rats with fenfluramine (80 mg/kg over 2 days) destroyed 80% of serotonergic nerve terminals, indicated by reduced maximal [3H]paroxetine binding to 5-hydroxytryptamine (5-HT) uptake sites on synaptic membranes (Bmax) and maximal [14C]5-HT uptake rate into synaptosomes (Vmax). 25 weeks later, these indices of serotonergic nerve terminals had returned to 72% of control. Maximal synaptosomal loading (alpha) with [14C]5-HT also recovered (to 79% of control), reflecting an increased number of serotonergic synaptosomes. This suggests that the rebound in 5-HT uptake site density found after fenfluramine illustrates the regeneration of 5-HT-containing nerve endings.

Animals↗
PubMedDate not supplied

The nature of d,l-fenfluramine-induced 5-HT reuptake transporter loss in rats.

The administration of the anorexigenic drug d,l-fenfluramine (Ponderax) to laboratory animals results in a dose-dependent reduction in presynaptically located serotonergic reuptake transporter protein. This long-term effect may represent an altered mechanism of synthesis of the transporter (downregulation). Alternatively, fenfluramine may destroy the serotonergic terminals on which 5-HT transporters are located. To distinguish between these two alternatives, we applied an assay of neurotransmitter-specific nerve endings (alpha) to brain tissue from two animal models of reduced 5-HT transporter density. In Model 1, serotonergic nerve terminals were destroyed (rats received 5,7-dihydroxytryptamine [5,7-DHT] intracisternally); in Model 2, there was a loss of 5-HT transporter per se on otherwise intact serotonergic nerve terminals. The manner in which alpha declined as transporter density was decreased (reducing Vmax values) in animal Models 1 and 2 was found to be significantly different. In rats treated with fenfluramine, the association between 5-HT transporter density and alpha was the same as in the neurotoxic model.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

New evidence for a loss of serotonergic nerve terminals in rats treated with d,l-fenfluramine.

Fenfluramine has been classified as a neurotoxin because animals treated with this anorectic lose 5-HT uptake sites located on serotonergic nerve terminals. However, there are two possible bases for this finding: either uptake sites are lost because the terminals themselves have been destroyed (neurotoxicity); or uptake sites are lost from otherwise intact terminals. To distinguish between these possibilities, we established an animal model in which male Wistar rats were injected (intraperitoneally) with an irreversible 5-HT uptake site antagonist (EEDQ). Since their 5-HT sites were inhibited (blocked) non-competitively, by this agent, such animals had effectively lost 5-HT uptake sites from intact serotonergic terminals. Synaptosomes prepared from such animals showed the predicted reduction in the Bmax of [3H]paroxetine binding to the 5-HT uptake site, and a reduction in the Vmax of [14C]5-HT uptake. However, they showed no significant reduction in maximal [14C]5-HT loading (alpha) compared with synaptosome from sham-injected controls. In contrast, fenfluramine-treated animals showed reduced [3H]paroxetine binding, reduced maximal [14C]5-HT uptake and significantly (P < 0.02) reduced synaptosomal [14C]5-HT loading. Therefore, the results suggest that fenfluramine does indeed cause the destruction of serotonergic nerve terminals.

Animals↗