MK-801-INDUCED HYPERLOCOMOTION - DIFFERENTIAL-EFFECTS OF M100907, SDZPSD-958 AND RACLOPRIDE

The influence of three selective monoamine receptor antagonists on spo ntaneous locomotion and on the hyperlocomotion induced by the un-compe titive N-methyl-D-aspaaate (NMDA) receptor antagonist 1-dihydro-5H-dib enzo-[a,d]-cyclohepten-5,,10-imine hydrogen maleate (MK-801; dizocilpi ne) was investigated. The selective and potent 5-hydroxytryptamine (5- HT)(2A) receptor antagonist a(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl )ethyl)] (MDL100,907; M100907) displayed a clearcut selectivity far re duction of MK-801-induced as compared to spontaneous locomotion, in th at the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) block ed and even totally abolished by the highest dose, while the latter wa s only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. T he selective dopamine D-1 receptor antagonist 2-methyl-phenyl)-1-methy l-benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a sligh t preference for the latter; spontaneous locomotion was dose-dependent ly diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopami ne D-2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-eth yl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.3 3, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomot ion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several com binations of different doses of the 5-HT2A receptor antagonist and the dopamine D-1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M10 0907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely admin istered MK-801 is a valid model of at least some aspects of schizophre nia, these results indicate that the 5-HT2A receptor antagonist M10090 7 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine r eceptor antagonists, will be less prone to induce psychomotor side-eff ects. Ongoing clinical studies will hopefully give the answers in the near future. (C) 1997 Elsevier Science B.V.