Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists.

In rats trained to recognize the drug dizocilpine, various NMDA receptor antagonists were tested for their ability to produce similar effects. The dissociative anesthetics dizocilpine, phencyclidine, and ketamine fully substituted for dizocilpine without slowing response rates. Dexoxadrol also fully substituted but reduced response rates by 35%. Memantine, a low-affinity antagonist, fully substituted but only at doses that reduced response rates by 68%. Other low-affinity antagonists showed partial or no substitution, often at rate-reducing doses. The findings indicate that low-affinity NMDA antagonists produce discriminative stimulus effects distinct from those of dissociative anesthetics, with only the more potent low-affinity drugs showing substantial substitution, and then only at doses that impair behavior.

Study at a glance

Abstract

The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (+/-)-5-aminocarbonyl-10,11-dihydro -5H-dibenzo-[a,d]cyclohepten-5,10-imine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low-affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.