Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells |
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Authors: | Cobos Enrique J del Pozo Esperanza Baeyens José M |
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Affiliation: | Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain |
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Abstract: | We evaluated the effect of haloperidol (HP) and its metabolites on [3H](+)-pentazocine binding to σ1 receptors in SH-SY5Y human neuroblastoma cells and guinea pig brain P1, P2 and P3 subcellular fractions. Three days after a single i.p. injection in guinea pigs of HP (but not of other σ1 antagonists or (−)-sulpiride), [3H](+)-pentazocine binding to brain membranes was markedly decreased. Recovery of σ1 receptor density to steady state after HP-induced inactivation required more than 30 days. HP-metabolite II (reduced HP, 4-(4-chlorophenyl)-α-(4-fluorophenyl)-4-hydroxy-1-piperidinebutanol), but not HP-metabolite I (4-(4-chlorophenyl)-4-hydroxypiperidine), irreversibly blocked σ1 receptors in guinea pig brain homogenate and P2 fraction in vitro . We found similar results in SH-SY5Y cells, which suggests that this process may also take place in humans. HP irreversibly inactivated σ1 receptors when it was incubated with brain homogenate and SH-SY5Y cells, but not when incubated with P2 fraction membranes, which suggests that HP is metabolized to inactivate σ1 receptors. Menadione, an inhibitor of the ketone reductase activity that leads to the production of HP-metabolite II, completely prevented HP-induced inactivation of σ1 receptors in brain homogenates. These results suggest that HP may irreversibly inactivate σ1 receptors in guinea pig and human cells, probably after metabolism to reduced HP. |
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Keywords: | [3H](+)-pentazocine binding guinea pig brain haloperidol metabolism receptor turnover SH-SY5Y human neuroblastoma cells sigma-1 receptors |
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