Phencyclidine-like discriminative stimulus effects of polyamine modulators of N-methyl-D-aspartate receptor activity...

Excessive N-methyl-D-aspartate (NMDA) receptor activation has been implicated in many acute and chronic neuropathologies. NMDA antagonists might prove to be useful treatments, unfortunately, some can produce phencyclidine (PCP)-like side effects. The polyamine-site modulators, spermine (SPM) and spermidine (SPD), produce dose related biphasic modulation of NMDA channel currents while another polyamine, arcaine (ARC), produces only negative modulatory effects. The PCP-like effects of these compounds were tested in rats trained to discriminate PCP from saline in a standard two-lever drug discrimination paradigm under a fixed ratio schedule of food reinforcement. SPM, SPD and ARC occasioned little, if any, responding on the PCP-associated lever, even at response rate suppressing doses. The results provide further evidence that differences 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.