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

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Abstract
MK‐801 at doses < 100 μg/kg given orally induced an ipsilaterally directed 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 μg/kg of MK‐801 were reduced by pretreatment with haloperidol (ED50 = 0.068 mg/kg IP), clozapine (ED50 = 3.35 mg/kg IP), or prazosin (ED50 = 0.15 mg/kg SC). MK‐801‐induced turning was also inhibited by pretreatment with α‐methyl‐p‐tyrosine (α‐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 α‐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 α‐MPT‐pretreated mice, while the actions of the other three compounds were not singnificantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mg/kg 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.