Restoration of shock‐suppressed behavior by treatment with (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties

Abstract

MK‐801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever‐pressing by unaviodable shock and (2) a simple conflict test in water‐deprived animals that were shocked for licking water. The effect of MK‐801 in both procedures was qualitatively similar to the benzodiazepines. Lever‐pressing in the CER test was increased by MK‐801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK‐801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK‐801 was without anticonflict activity when administered 1 hour prior to study.In squirrel monkeys trained in a response‐contingent conflict paradigm, a specific anticonflict effect for MK‐801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK‐801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK‐801.The mode of action for the antipunishment effect of MK‐801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK‐801 and chlordiazepoxide. In vitro, MK‐801 was inactive (IC₅₀ > 2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB‐4101, dihydroalprenolol, QNB, and 2‐chloroadenosine). An increase in ³H‐diazepam binding in vitro in rat brain tissue was detected following acute, but not chronic, treatment in vivo with MK‐801.