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Irreversible blockade of sigma‐1 receptors by haloperidol and its metabolites in guinea pig brain and SH‐SY5Y human neuroblastoma cells
Author(s) -
Cobos Enrique J.,
Pozo Esperanza del,
Baeyens José M.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04533.x
Subject(s) - receptor , metabolite , guinea pig , in vitro , sh sy5y , biology , pentazocine , biochemistry , chemistry , neuroblastoma , endocrinology , pharmacology , cell culture , genetics , morphine
We evaluated the effect of haloperidol (HP) and its metabolites on [ 3 H](+)‐pentazocine binding to σ 1 receptors in SH‐SY5Y human neuroblastoma cells and guinea pig brain P 1 , P 2 and P 3 subcellular fractions. Three days after a single i.p. injection in guinea pigs of HP (but not of other σ 1 antagonists or (−)‐sulpiride), [ 3 H](+)‐pentazocine binding to brain membranes was markedly decreased. Recovery of σ 1 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 σ 1 receptors in guinea pig brain homogenate and P 2 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 σ 1 receptors when it was incubated with brain homogenate and SH‐SY5Y cells, but not when incubated with P 2 fraction membranes, which suggests that HP is metabolized to inactivate σ 1 receptors. Menadione, an inhibitor of the ketone reductase activity that leads to the production of HP‐metabolite II, completely prevented HP‐induced inactivation of σ 1 receptors in brain homogenates. These results suggest that HP may irreversibly inactivate σ 1 receptors in guinea pig and human cells, probably after metabolism to reduced HP.