PubMed · 282486
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J A Codd. 1978-10-25. Hyperactive children: problems, issues and approaches.. https://pubmed.ncbi.nlm.nih.gov/282486/
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A role for calcium in p-chloroamphetamine-induced neurotoxicity has been inferred previously from protective effects of dextromethorphan. We found that dextromethorphan reduces rat brain concentrations of 5-hydroxyindoleacetic acid and blocks the acute, non-neurotoxic depletion of brain serotonin by p-chloroamphetamine and by H75/12. Inhibition of the membrane transporter on brain serotonin neurons by dextromethorphan in vivo might explain its protective effect against p-chloroamphetamine neurotoxicity.
The regulation of collagenase gene expression by serotonin and progesterone was investigated in primary cultures of rat uterine smooth muscle cells. Northern blot analysis demonstrates that serotonin (5-hydroxytryptamine (5-HT)), when administered to cells in serotonin-depleted medium, causes 6-8-fold increases in levels of collagenase mRNA. Selective serotonin 5-HT2 receptor agonists were able to mimic the effect of the natural hormone, while the induction by serotonin could be blocked by 5-HT2 receptor antagonists. Addition of phorbol ester (PMA) to 5-HT-depleted cultures fully mimicked the effect of 5-HT on collagenase mRNA induction. Treatment with progesterone analogs caused a decrease in collagenase mRNA, even in the presence of saturating levels of serotonin or PMA. In all experiments, levels of secreted collagenase were observed to correspond to levels of collagenase mRNA. Experiments with cycloheximide demonstrate that serotonin- and PMA-induced increases in collagenase mRNA are dependent on protein synthesis. Furthermore, nuclear run-on analysis shows that mRNA increases are accompanied by increases in initiation of transcripts. These data indicate that transcription of collagenase mRNA in myometrial smooth muscle cells is stimulated by serotonin, possibly via activation of protein kinase C, but is in some way prevented by the negative influence of progesterone.
The sulfhydryl-selective alkylating agent, N-ethylmaleimide (NEM), has been used as a tool to discern whether different binding domains exist on the neuronal serotonin (5-HT) transporter for 5-HT and 5-HT uptake inhibitors (Reith, M. E. A., Allen, D. L., Sershen, H., and Lajtha, A. (1984) J. Neurochem. 43, 249-255; Graham, D., Esnaud, H., Habert, E., and Langer, S. Z. (1989) Biochem. Pharmacol. 38, 3819-3826). However, relatively high concentrations of NEM and long incubation times have been required for inactivation of the transporter-binding site which raises the possibility that NEM is reacting with other nucleophilic groups (Smyth, D. G., Blumenfeld, O. O., and Konigsberg, W. (1964) Biochem. J. 91, 589-595). In the present work, the reactivity and essential nature of sulfhydryl groups associated with substrate/inhibitor binding to the neuronal 5-HT transporter was assessed. [3H]Paroxetine, a potent and selective 5-HT uptake inhibitor, was used to label the 5-HT transporter. The effects of a relatively wide range of sulfhydryl reagents on [3H]paroxetine binding in digitoninsolubilized preparations of rat brain neuronal membranes and the relative abilities of different classes of drugs to protect against NEM-induced inactivation of [3H]paroxetine binding were studied. It was observed that digitonin-solubilized preparations were more sensitive than membrane preparations to the inactivating effects of NEM. The pKa of the reactive group was estimated to be 6.17, in the range expected for a reactive sulfhydryl. Sulfhydryls essential to ligand binding reacted preferentially with hydrophobic compounds (p-hydroxymercuribenzoate = dithiobisnitrobenzoate > methyl methanethiosulfonate > N-phenylmaleimide > N-ethylmaleimide) and were unreactive toward hydrophilic reagents such as iodoacetate and iodoacetamide. 5-HT, 5-HT uptake inhibitors and cocaine protected the digitonin-solubilized transporter from NEM-induced inactivation while the amphetamine-related releasing agents p-chloroamphetamine and fenfluramine were ineffective. The observation that the binding of some, but not all, ligands requires reduced sulfhydryl groups, suggests that differential mechanisms and/or different binding domains do exist for agents which interact at the neuronal 5-HT transporter.