Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine

Abstract

The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine , increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3-4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1-1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D2 antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.

Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists

“…Thirdly, it seems unlikely that D-CPPene, a competitive NMDA receptor antagonist, acts on nicotinic receptors in the way reported for channelblockers such as mecamylamine or dizocilpine. Finally, as cited above, dizocilpine attenuates adaptive changes to other psychostimulants, opioids and alcohol, substances that do not interact potently with nicotinic receptors (Karler et al, 1989;Wolf & Khanza, 1991;Kuribara et al, 1992). It seems reasonable to conclude that an antagonist effect at NMDA receptors is more likely than nicotinic blockade to be the mechanism by which dizocilpine and D-CPPene influenced responses to nicotine.…”

“…There have been recent reports that pretreatment with dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, weakens or prevents the development of adaptations to diverse drugs including CNS stimulants such as amphetamine, methamphetamine and cocaine (Karler et al, 1989;Kuribara et al, 1992;Wolf & Khansa, 1991;Schenk et al, 1993), opioids such as morphine (Trujillo & Akil, 1990;Ben-Eliyahu et al, 1992) and alcohol (Morriset et al, 1990 receptors may play a role in the adaptive responses to nicotine since, when rats are exposed chronically to dizocilpine, as well as to nicotine, the usual sensitization reaction to the locomotor stimulant effect of nicotine fails to develop (Shoaib & Stolerman, 1992b). These data have been interpreted as evidence that activation of NMDA receptors may be a necessary step in the development of sensitization to nicotine.…”

The Repeated Administration of Ketamine Induces an Enhancement of Its Stimulant Action in Mice

“…It is not clear whether such a mechanism con tributes to the production of the ketamine-induced reverse tolerance as demonstrated in our study. Phencycli dine (13) and MK-801 (14), which are similar to ketamine in behavioral and NMDA antagonistic properties (4), are reported to produce the reverse tolerance to their ambula tion-increasing effect after the repeated administration, but not a cross-sensitization to amphetamines. Ketamine sensitized mice also do not display the cross-sensitization to methamphetamine (Y. Uchihashi, unpublished data).…”

“…Ketamine sensitized mice also do not display the cross-sensitization to methamphetamine (Y. Uchihashi, unpublished data). These results suggest that the reverse tolerance to keta mine is produced through a different dopaminergic mechanism from that of amphetamines, probably via an agonistic action on sigma receptors and/or an antagonis tic action on NMDA receptors (13,14). Livingston and Waterman (9) demonstrated that the tolerance to the hypnotic action of ketamine is associated with an increased hepatic metabolism in rats.…”

Inhibition of Cocaine Sensitization by MK-801, a Noncompetitive N-Methyl-D-Aspartate (NMDA) Receptor Antagonist: Evaluation by Ambulatory Activity in Mice

“…In our previous study (13), the coadministration of MK-801 with methamphetamine potentiated the ambulation-increasing effect. However, a comparatively higher dose of MK-801 (1 mg/kg) rather inhibited the development of sensitization to methamphetamine.…”