Memantine and dizocilpine differ in acute and chronic interactions with morphine

Abstract

Memantine (MEM) is a NMDA channel blocker that binds to dizocilpine (DZ) sites, is well tolerated, and has positive cognitive effects. Because published studies suggest NMDA antagonists prevent development of tolerance to effects of morphine (MS) or other psychoactive drugs by altering learning, we sought to compare effects of MEM to those of the more frequently studied DZ. To examine effects of DZ or MEM on discriminative stimulus effects of MS, Sprague‐Dawley rats were trained to discriminate 3.2 mg/kg MS and saline under fixed ratio 15 schedules of food delivery. Potency and maximal stimulus or rate‐altering effects of cumulative doses of MS were examined 30 min after pretreatment with DZ or MEM, or after chronic co‐treatment of DZ or MEM with 10 mg/kg MS, b.i.d., for 7 days. Effects of DZ or MEM on MS antinociception were examined in a 55°C water tail withdrawal assay with drug treatments parallel to those in discrimination studies. Acutely, 0.032 mg/kg DZ potentiated the MS cue by 1.6 fold, and 0.10 mg/kg potentiated MS antinociception by 2 fold; 10 mg/kg MEM attenuated both effects. Neither chronic DZ nor MEM blocked development of tolerance to the MS cue. In contrast, co‐treatment with 0.1 mg/kg DZ blocked tolerance to MS antinociception, whereas 7.5 to 10 mg/kg MEM produced non‐significant blockade. Thus, MEM differs from DZ in ability to modify stimulus and antinociceptive effects of MS. Supported by USPHS grant DA03796.