Comparison of pharmacodynamic effects of the non-competitive NMDA receptor antagonists MK-801 and ketamine in pigs

Abstract

The non-competitive NMDA receptor antagonists MK-801 and ketamine were injected into pigs via chronically implanted intravenous catheters, and the animals were observed closely for alterations in general behaviour, heart rate, respiration and body temperature. MK-801 produced head shakes, stereotypies, ‘psychotic’ behaviour (e.g., hyperexcitation and screaming), and ketamine-like anesthetic effects in pigs at doses of 0.1–1.6 mg/kg. Almost the same behavioural pattern of effects was observed after i.v. injection of ketamine, 15 mg/kg. Furthermore, both drugs reduced heart rate and increased respiration rate and body temperature. The most marked differences between MK-801 and ketamine were that MK-801 had a much longer duration of action and the catalepsy produced by MK-801 was much more pronounced. When animals were first anesthetized with pentobarbital, MK-801 did not alter the cardiovascular functions. In pigs genetically susceptible to induction of malignant hyperthermia by volatile anesthetics, MK-801 did not produce signs characteristics of fulminant malignant hyperthermia. The data show that MK-801 produces psychomotor and anesthetic effects that are almost indistinguishable from those observed after traditional dissociative anesthetics, such as phencyclidine and ketamine. With respect to the behavioural similarities between MK-801 and phencyclidine or ketamine, it seems unlikely that MK-801 will be useful clinically as an anticonvulsant or anxiolytic drug, but the data indicate that the drug may be suited as a long-acting dissociative anesthetic.