MK-801 and related compounds in monkeys: discriminative stimulus effects and effects on a conditional discrimination.
C. France, J. Moerschbaecher, James H Woods
Journal of Pharmacology and Experimental Therapeutics May 1, 1991 DOI: 10.1016/s0022-3565(25)24770-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study (drug discrimination and operant behavioral pharmacology in monkeys) Peer reviewed |
|---|---|
| Population | Monkeys (separate groups for drug discrimination and for a multiple schedule of repeated acquisition and performance of conditional discriminations) |
| Interventions | (+)-MK-801 (-)-MK-801 dexoxadrol dextrorphan phencyclidine (PCP) ketamine (+)-N-allylnormetazocine dextromethorphan CGS 19755 |
| Dose | 0.032 mg/kg of (+)-MK-801 (training dose in discrimination); other doses not specified |
| Key findings | Dexoxadrol fully substituted for the (+)-MK-801 discriminative stimulus in all monkeys, while dextrorphan and phencyclidine substituted in only two of three; ketamine, (+)-N-allylnormetazocine, dextromethorphan, and CGS 19755 did not substitute. PCP, dextrorphan, dextromethorphan, and both MK-801 enantiomers decreased lever pressing and increased errors in acquisition and performance components, with acquisition errors at lower doses. (+)-MK-801 was 10 times more potent than (-)-MK-801. The authors suggest PCP-like drugs are not a homogeneous class for discriminative stimulus effects. |
Abstract
MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate] and related compounds were studied in monkeys discriminating between 0.032 mg/kg of (+)-MK-801 and saline and in a separate group of monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. In the drug discrimination study, small doses of (+)-MK-801 occasioned saline-lever responding whereas larger doses occasioned responding on the MK-801 lever. Dexoxadrol substituted completely (greater than or equal to 90%) for the MK-801 discriminative stimulus in all subjects whereas dextrorphan and phencyclidine (PCP) substituted in only two of three subjects. Neither ketamine, (+)-N-allylnormetazocine, dextromethorphan nor the competitive excitatory amino acid antagonist CGS 19755 [cis-4-phosphonomethyl-2-piperidine-carboxylic acid] substituted for MK-801 in any of the monkeys. PCP, dextrorphan, dextromethorphan, (+)- and (-)-MK-801 decreased rates of lever pressing and increased errors in both components of the multiple acquisition, performance schedule. For each compound errors were increased in the acquisition component with doses smaller than doses required to increase errors in the performance component. In both procedures (+)-MK-801 was 10 times more potent than (-)-MK-801, although qualitatively similar results were obtained with the two enantiomers. PCP-like drugs have many effects in common, including their effects on learning and performance; however, with regard to discriminative stimulus effects this does not appear to be a homogenous pharmacological class, suggesting that change in excitatory amino acid-mediated neurotransmission might not be the only mechanism by which MK-801 and related compounds exert behavioral effects in nonhuman primates.