THE EFFECTS OF SIGMA-LIGANDS ON PROTEIN RELEASE FROM LACRIMAL ACINAR-CELLS - A POTENTIAL AGONIST-ANTAGONIST ASSAY

Sigma (sigma) receptor antagonists have been proposed as leading clini cal candidates for use in various psychotic disorders. Prior to clinic al testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the ps ychosis. For sigma-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activ ity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by t he presumed antagonist a consequence of sigma-receptor activity? Previ ously we have identified sigma-receptors in acinar cells of the main l acrimal gland of the New Zealand white rabbit and have measured protei n release after the addition of various N,N-disubstituted phenylalkyla mine derivatives known to be sigma-ligands by receptor binding studies . Although protein release from acinar cells has been attributed to ei ther muscarinic or alpha-adrenergic stimulation, protein release from sigma-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrati ons of known sigma-ligands and measured protein concentration. A knowl edge of the receptor profile for the disubstituted phenylalkylamines p ermitted experiments to be designed in which various alpha, muscarinic , serotonergic, and dopaminergic antagonists could be added in equimol ar concentrations. Under the conditions of these experiments, statisti cally significant increases in protein release for sigma-ligands could be attributed to stimulation of sigma-receptors. Haloperidol, an appa rent sigma-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known sigma-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively. Of particular interest were the results for BMY14802 and +/- pentazocine, both of which were found to be agonists. Various antipsychotic and antidepressant drugs w ere measured for their agonist/antagonist behavior. Because of multire ceptors present in acini, their agonist or antagonist behavior could n ot be attributed solely to interaction with the sigma-receptor unless specific antagonists were added.