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

Autor: Michael Williams, Bradley V. Clineschmidt, J. A. Totaro, Patricia R. Bunting, John J. Witoslawski, Edwin A. Risley
Rok vydání: 1982
Předmět:
Zdroj: Drug Development Research. 2:147-163
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430020205
Popis: 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.
Databáze: OpenAIRE
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