INTERACTION OF SIGMA-COMPOUNDS WITH RECEPTOR-STIMULATED PHOSPHOINOSITIDE METABOLISM IN THE RAT-BRAIN

Abstract: σ‐Receptors are nonopioid, nondopaminergic receptors that bind with high affinity several antipsychotic drugs and appear to be involved in regulation of posture and movement. The second messenger system coupled to these receptors is still unknown. Recently, an inhibitory effect of various σ‐compounds on carbachol‐stimulated phosphoinositide metabolism has been reported. We have investigated the effect of six σ‐compounds on carbachol‐ and norepinephrine‐stimulated 3H‐inositol phosphate accumulation in rat cerebral cortex slices. All compounds tested had a dose‐dependent inhibitory effect on both systems, although their order of potency differed between neurotransmitters. Pentazocine and 1,3‐di‐o‐tolylguanidine were the most potent inhibitors of carbachol‐stimulated phosphoinositide turnover (IC50= 31.5 and 45.7 μM, respectively), while haloperidol showed the greatest potency on the norepinephrine‐coupled system (IC50= 3.5 μM). In the presence of IC50 concentrations of these inhibitors, the dose‐response curves for the agonists were shifted to the right and the EC50 values were significantly increased. σ‐Compounds also inhibited the binding of [3H]quinuclidinyl benzilate to muscarinic receptors and of [3H]prazosin to α1‐adrenoceptors in cortical membranes. In the presence of IC50 concentration (11 μM) of 1,3‐di‐o‐tolylguanidine, no differences were found in the maximal number of muscarinic binding sites, whereas the dissociation constant increased approximately fivefold, indicating a decrease of the radioligand's affinity for the receptor. These results indicate that σ‐compounds, at micromolar concentrations, inhibit muscarinic and α1‐adrenergic receptor‐coupled phosphoinositide metabolism, probably through an interaction with the neurotransmitter recognition sites. Copyright © 1990, Wiley Blackwell. All rights reserved