PHENCYCLIDINE-LIKE DISCRIMINATIVE STIMULUS EFFECTS OF POLYAMINE MODULATORS OF N-METHYL-D-ASPARTATE RECEPTOR ACTIVITY IN RATS

Excessive N-methyl-D-aspartate (NMDA) receptor activation has been imp licated in many acute and chronic neuropathologies. NMDA antagonists m ight prove to be useful treatments, unfortunately, some can produce ph encyclidine (PCP)-like side effects. The polyamine-site modulators, sp ermine (SPM) and spermidine (SPD), produce dose related biphasic modul ation of NMDA channel currents while another polyamine, arcaine (ARC), produces only negative modulatory effects. The PCP-like effects of th ese compounds were tested in rats trained to discriminate PCP from sal ine in a standard two-lever drug discrimination paradigm under a fixed ratio schedule of food reinforcement. SPM, SPD and ARC occasioned lit tle, if any, responding on the PCP-associated lever, even at response rate suppressing doses. The results provide further evidence that diff erences exist between the discriminative stimulus effects produced by drugs active at different sites on the NMDA receptor and suggest that the polyamine modulatory site should be a good target for development of NMDA antagonist medications with a reduced propensity for PCP-like acute behavioral effects. (C) 1998 Elsevier Science Ireland Ltd. All r ights reserved.