Behavioral characterization of sigma site compounds.

Abstract

There are currently no well characterized sigma functional assays. Until such an assay is developed, the sigma site cannot be considered a true receptor, since by definition receptors must express functional consequences of binding. The present experiments represent an effort to develop an assay for sigma effects in rat observation procedures and pigeon drug discrimination experiments. In the rat observation procedures, analysis of the behaviors elicited by several putative sigma drugs did not reveal a clear sigma mediated syndrome. Instead, the behavioral properties of these compounds could generally be related to their effects at other receptor systems, e.g., dopaminergic, serotonergic, or PCP receptors. The syndrome engendered by di-ortho-tolyl-guanidine (DTG), however, could not be related to actions at other sites, nor could sideways walking (SW) produced by (+)3-(3-hydroxyphenyl)-N-(propylpiperidine) ((+)3-PPP). These two drugs were chosen for analysis in drug interaction studies. In these experiments, (+)3-PPP-induced SW could not be linked to a sigma mechanism. Certain behavioral effects of DTG were attenuated by some (e.g., d-pentazocine, MR 2035) but not all (e.g., haloperidol) sigma compounds, although the doses of haloperidol studied were below its ED$\\sb{50}$ value for displacing sigma sites in vivo. The ability of (+)3-PPP to induce SW and DTG to engender its behavioral effects might be mediated through similar functional mechanisms, since pirenperone decreased SW and some of the behaviors elicited by DTG, and subchronic administration of DTG produced reductions in all DTG induced behaviors and in SW produced by (+)3-PPP. Pigeons trained to discriminate MR 2035 from saline did not provide irrefutable evidence for a sigma mediated interoceptive stimulus. Some sigma compounds substituted for MR 2035 (e.g., d-pentazocine, DTG), while others did not (e.g., (+)SKF 10,047, (+)3-PPP). The present experiments do not provide an unequivocal sigma functional assay. This does not mean that behavioral paradigms will not be useful in determining the functional interaction of drugs with the sigma site; however, the observation and drug discrimination procedures described above cannot be used for this purpose.