Opioid- and phencyclidine-like discriminative effects of ditolylguanidine, a selective sigma ligand

The sigma binding site in brain has affinity for psychotomimetic opioids, phencyclidine (PCP) and antipsychotic drugs, and is a separate entity from the PCP receptor. In order to demonstrate a behavioral correlate of sigma binding, rats were trained to discriminate between s.c. injections of saline and 3.0 mg/kg of ditolylguanidine (DTG), a selective and high affinity sigma ligand, and tested for generalization to novel drugs. The rats generalized dose dependently and completely or almost completely to PCP and related drugs and to mu, kappa and sigma opioid agonists. A separate group of rats trained to discriminate saline from 2.0 mg/kg of PCP generalized completely to DTG, confirming the commonalities in the discriminative effects of these drugs. DTG-like discriminative effects of opioid enantiomers showed no consistent stereoselectivity. Discriminative effects of the DTG training dose were neither mimicked by haloperidol and (-)-butaclamol, which have high affinity for the sigma site, or by the opioid antagonist naltrexone. Order of potency in producing DTG-like discriminative effects did not correlate with published reports of relative drug affinity for the sigma site or the PCP receptor. Although the discriminative effects of DTG have commonalities with those of several types of opioid and PCP-like drugs, their pharmacologic characteristics are different from the pharmacologic characteristics of opioid and PCP receptors as well as from those of the sigma binding site.