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.

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.

“…The compound is MK-801 {(+)-5- (Fig. 1), a substance previously reported to possess an unusual spectrum of pharmacological activities as a potent anticonvulsant that exhibits both anxiolytic and sympathomimetic properties (9)(10)(11).…”

Characteristics of the Ambulation-Increasing Effect of the Noncompetitive NMDA Antagonist MK-801 in Mice: Assessment by the Coadministration with Central-Acting Drugs.

“…It has been reported that MK-801 shows anticonvulsant action (2), neuroprotective ac tion (3), an antiparkinson property (4), and anticonflict action (5,6). Furthermore, Clineschmidt et al (7) demonstrated that MK 801 increased the ambulatory activity of mice and produced an ipsilateral turning in the rat with unilateral nigrostriatal lesion, indicating that MK-801 possesses agonistic action on cen tral dopaminergic systems through an accelera tion of the dopaminergic transmission.…”

Does the pentylenetetrazole (PTZ) cue reflect PTZ‐induced kindling or PTZ‐induced anxiogenesis?

“…Both of these substances have been reported to exert anxiolytic effects in animal models [Stephens et al, 1986;Clineschmidt et al, 19821, but both compounds are better known for their anticonvulsant and muscle-relaxant properties [Clineschmidt et al, 1982;Meldrum and Chapman, 1986;Turski et al, 19851. In this experiment, both substances exerted strong sedative effects and could not be tested at higher doses on the cue.…”