ABSTRACT-Characteristics of the ambulation-increasing effect of MK-801, a non competitive NMDA antagonist, were assessed through the coadministration of MK 801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methampheta mine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopol amine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) pro duced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increas ing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.03 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by a-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-bio pterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl) adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.). These re sults indicate the MR-801 increases the mouse's ambulatory activity through stimula tion of the dopaminergic system which is strongly affected by a calcium-dependent mechanism.The noncompetitive NMDA antagonist MK 801, (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine (1), has been re ceiving much attention in behavioral pharma cology as a tool for assessing the role of the central neurotransmission systems of the NMDA-component.It has been reported that MK-801 shows anticonvulsant action (2), neuroprotective ac tion (3), an antiparkinson property (4), and anticonflict action (5, 6). Furthermore, Clineschmidt et al. (7) demonstrated that MK

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.

ABSTRACT-Alterationsof cocaine effects, which were induced by prior repeated 5-time administration of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (i.p.) alone or in combination with cocaine (s.c.) at 3-to 4-day intervals, were investigated by means of ambulatory activity in mice. The repeated administration of either cocaine (10 and 20 mg/kg) alone or MK-801 (0.3 mg/kg) alone progressively enhanced each drug's effect. The enhanced effects of cocaine and MK-801 were estimated to be 1.8-2.2 times and about 1.4 times, respectively, as great as those at the 1st administration. Although the coadministration of MK-801 with cocaine produced a significant enhancement in the ambulation-increasing effect, the comparatively higher doses of MK-801 (0.3 and 1 mg/kg) acted not only to reduce cocaine sensitivity but also to inhibit the development of cocaine sensitization. Thus, the mice that had been given MK-801 (0.3 and 1 mg/kg) alone 5 times showed lower sensitivities to cocaine (20 mg/kg) than the mice given saline alone. The mice coadministered MK-801 (0.3 and 1 mg/kg) with cocaine (10 and 20 mg/kg) also exhibited lower sensitivities to cocaine (10 and 20 mg/kg) than those given cocaine alone. However, MK-801 could not ameliorate the established sensitization to cocaine. Similar interactions have been demonstrated between MK-801 at 1 mg/kg, but not 0.3 mg/kg, and methamphetamine. The present results indicate that MK-801 can inhibit the development of sensitization to cocaine at a lower dose than that required to inhibit methamphetamine sensitization.

No abstract

Abstract-Behavioral effects of 6R-L-erythro-5,6,7,8-tetra hydrobiopterin (R THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, were investigated by means of ambulatory activity in mice. Single administration of R THBP (50 and 100 mg/kg, s.c.) showed no significant effect on the mouse's ambulatory activity for 5 hr. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was dramatically enhanced and prolonged by the pretreatment with R-THBP (100 mg/kg, s.c.) 0, 2, 6, 12 and 24 hr before, but not 18 or 36 hr before, the methamphetamine administration. However, when combined administration of R-THBP (100 mg/kg, s.c., 2 hr before) with methamphetamine (2 mg/kg, s.c.) was repeated at intervals of 3-4 days, the enhancement by R-THBP of the methamphet amine effect was observed only in the 1st and 2nd administration, but not in the