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Journal of Neuroscience, Vol 15, 117-134, Copyright © 1995 by Society for Neuroscience
Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability
BJ Vilner, BR de Costa and WD Bowen
Unit on Receptor Biochemistry and Pharmacology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
The morphological effects of several neuroleptics as well as other novel
and prototypic sigma ligands were examined by addition to cultures of C6
glioma cells. Sigma ligands caused loss of processes, assumption of
spherical shape, and cessation of cell division. The time course and
magnitude of this effect were dependent on the concentration of sigma
ligand. Continued exposure to sigma compounds ultimately resulted in cell
death. However, the morphological effect was reversible when sigma ligand
was removed shortly after rounding. The potency of compounds to produce
these effects generally correlated with binding affinity at sigma receptors
of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a
concentration of 100 microM, haloperidol, reduced haloperidol,
fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and
SH344 produced significant effects in 3-6 hr of exposure. Other compounds,
such as trifluperidol, thioridazine, and (-)-butaclamol, produced
significant effects by 24 hr of exposure. Despite the requirement of
micromolar concentrations of ligand (some compounds were effective at 30
microM), the effect showed a remarkable specificity for compounds
exhibiting sigma receptor binding affinity. Neuroleptics lacking potent
sigma affinity [e.g., (-)- sulpiride, (+)-butaclamol, and clozapine] and
other compounds that lack significant sigma affinity but that are agonists
or antagonists at dopamine, serotonin, adrenergic, glutamate,
phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were
without effect on cellular morphology at concentrations up to 300 microM
over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and
Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity
were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG),
(+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP],
(+)-pentazocine, (+)- cyclazocine, and other sigma-active benzomorphans and
morphinans appeared inactive in up to 72 hr of culture. However, these
compounds interacted synergistically with a subeffective dose of BD737 (30
microM) to produce effects usually in 6 hr or less. Also, the pH of the
culture medium had a profound effect on the activity of sigma compounds.
Increasing the pH from the normal range of 7.2-7.4 to pH 8.3- 8.5 shifted
the dose curves (30, 100, 300 microM) for all sigma compounds to the left.
Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects
in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)
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