The self-administration of MK-801 can depend upon drug-reinforcement history, and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys.
The proposed noncompetitive N-methyl-D-aspartate antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] has therapeutic potential as an anticonvulsant and neuroprotectant. Previous research has demonstrated that MK-801 shares many of the biochemical and pharmacological actions of the abused drug phencyclidine (PCP). The purpose of the present study was to determine whether rhesus monkeys would self-administer i.v. MK-801 and to determine whether MK-801 has discriminative stimulus properties similar to those of PCP. Four Rhesus monkeys were trained to press response levers according to fixed-ratio 10 schedules of reinforcement for infusions of cocaine (33 micrograms/kg/injection) or PCP (10 micrograms/kg/injection). Various doses of MK-801 were evaluated during substitution tests to determine whether they would maintain lever pressing. None of the four rhesus monkeys tested self-administered MK-801 when it was offered to them after a recent history of cocaine self-administration. Three of the four monkeys, however, did self-administer MK-801 when provided a history of PCP self-administration. All four rhesus monkeys given drug discrimination training with 80 micrograms/kg PCP and tested with MK-801 generalized from the PCP stimulus in a dose-dependent manner. MK-801 was about 2 to 3 times more potent and had a longer duration of action than PCP. Overall, these results provide further evidence in a primate species of similarities in the behavioral effects of MK-801 and PCP, and suggest that MK-801 may have abuse potential of the PCP type.
Beardsley
P M
PM
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
Hayes
B A
BA
Balster
R L
RL
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003986:Dibenzocycloheptenes / Q000008:administration & dosage*; D004193:Discrimination Learning / Q000187:drug effects*; D016291:Dizocilpine Maleate; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D012646:Self Administration
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D016291:Dizocilpine Maleate; D003042:Cocaine; D010622:Phencyclidine