Central sympathomimetic activity of (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo [a, d]cyclohepten‐5,10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties

Abstract

MK-801 at doses < 100 pglkg given orally induced an ipsilaterally directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6-hydroxydopamine. (+)-Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose-response lines lying considerably to the right of that for MK-801. Rotations caused by a standard test dose of 50 pglkg of MK-801 were reduced by pretreatment with haloperido1 (EDso = 0.068 mglkg IP), clozapine ( E L = 3.35 rnglkg IP), or prazosin (ED% = 0.15 mglkg SC). MK-801 -induced turning was also inhibited by pretreatment with a-methyl-ptyrosine (a-MPT) and blocked by reserpine.Locomotor activity in mice was increased by MK-801, amfonelic acid, (+)-amphetamine, and methylphenidate. Following administration P.o., MK-801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with a-MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK-801, amfonelic acid and methylphenidate, whereas (+)-amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)-amphetamine was, on the other hand, markedly reduced in a-MPT-pretreated mice, while the actions of the other three compounds were not significantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mglkg SC) examined was an effective antagonist of only MK-801 and (+)-amphetamine. MK-801 has effects in rodents resembling indirect-acting central sympathomimetic substances such as amfonelic acid, ( +)-amphetamine, and methylphenidate. The central sympathomimetic actions of MK-801 are mediated via catecholamine-dependent processes.Results from the drug-interaction studies in mice (locomotor activity) indicate that the precise mechanism of action of MK-801 differs from that of the other three compounds.

Differential Antagonism of the Stimulant Effects of MK-801 and Methamphetamine by Ceruletide: Evaluation by Discrete Shuttle Avoidance Response in Mice.

“…It has been suggested that MK-801 and amphetamines-induced increase in the mouse's ambulatory activity were differentially reduced by reserpine and a -methyl-p-tyrosine, respec tively (2). Such a result also supports the idea …”

“…A noncompetitive NMDA antagonist MK 801, (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]-cyclohepten-5,10-imine (1), increases the ambulatory activity of mice, produces an ipsi lateral turning in the rat with unilateral nigro striatal lesion (2), and reduces the haloperidol induced catalepsy (3), indicating that MK-801 possesses an indirect agonistic action on cen tral dopaminergic systems, as amphetamines do. Dimpfel and Spuler (4) also reported an activation of the dopaminergic transmission by MK-801 in terms of brain field potentials.…”

“…Dimpfel and Spuler (4) also reported an activation of the dopaminergic transmission by MK-801 in terms of brain field potentials. However, Clineschmidt et al (2) also reported that the MK-801 and methamphetamine-in duced increases in the mouse's ambulatory activity were selectively inhibited by reserpine and a-methyl-p-tyrosine, respectively. Such a result indicates that the characteristics of MK 801 differ from those of amphetamines.…”

Characteristics of the Ambulation-Increasing Effect of the Noncompetitive NMDA Antagonist MK-801 in Mice: Assessment by the Coadministration with Central-Acting Drugs.

“…Furthermore, Clineschmidt et al (7) demonstrated that MK 801 increased the ambulatory activity of mice and produced an ipsilateral turning in the rat with unilateral nigrostriatal lesion, indicating that MK-801 possesses agonistic action on cen tral dopaminergic systems through an accelera tion of the dopaminergic transmission. Dimp fel and Spuler (8) also confirmed an MK-801 induced activation of dopaminergic transmis sion by recording the brain field potentials from the frontal cortex, hippocampus, striatum and reticular formation in rats that was similar to those observed after administra tion of amphetamine and L-dopa.…”

“…Dimp fel and Spuler (8) also confirmed an MK-801 induced activation of dopaminergic transmis sion by recording the brain field potentials from the frontal cortex, hippocampus, striatum and reticular formation in rats that was similar to those observed after administra tion of amphetamine and L-dopa. However, Clineschmidt et al (7) demonstrated that the MK-801 and amphetamine-induced increases in the ambulatory activity were differentially modified by a -methyl-p-tyrosine and reser pine. Thus, further study was required to characterize the ambulation-increasing effect of MK-801.…”