NON-AMPHETAMINIC MECHANISM OF STIMULANT LOCOMOTOR EFFECT OF MODAFINILIN MICE

Previously established dose-response curves indicated that modafinil 2 0-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor a ctivity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. T he effects of various agents modifying dopamine transmission were comp ared on the locomotor response to both drugs. The preferential D2 dopa mine receptor antagonist haloperidol 37.5-150 mu g/kg i.p. suppressed the stimulant effect of(+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 ( 7.5-30 mu g/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor a-methyl-pa ra-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/k g dexamphetamine but not that induced by 20 mg/kg modafinil. Associati ng L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 m g/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 m g/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [H-3]dopamine, modafinil 10(-5) M di d not increase the spontaneous [H-3]dopamine release whereas (+)amphet amine, at the same concentration, doubled it. From all these differenc es between the two drugs, it is concluded that the mechanism underlyin g the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.