Behavioral evidence for modulation by sigma ligands of (+)MK-801-induced hyperlocomotion in monoamine-depleted mice.
The selective non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine maleate ((+)MK-801) led to a dose-dependent increase in locomotor activity in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine (alpha-MT). A selective and potent sigma receptor "antagonist" NE-100 (N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride), which did not per se affect spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. Sulpiride, a dopamine D2 receptor antagonist, and clozapine, a dopamine D4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. The sigma receptor "agonists" (+)N-allynormetazocine [(+)SKF10,047], (+)pentazocine and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP], which did not per se affect spontaneous locomotor activity, did dose-dependently enhance the hyperlocomotion induced by (+)MK-801. The enhancement of (+)MK-801-induced the hyperlocomotion by (+)SKF10,047, (+)pentazocine and (+)3-PPP was completely blocked by NE-100. The enhancement of (+)MK-801-induced hyperlocomotion by (+)pentazocine was not affected by treatment with sulpiride and clozapine. As sigma ligands can markedly attenuate NMDA antagonist-induced behavior, the major physiological role of sigma receptors in vivo might be to modulate functions of the NMDA receptor ion channel complex.
Okuyama
S
S
First Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, Saitama, Japan.
Imagawa
Y
Y
Tomisawa
K
K
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D011437:Propylamines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017480:Receptors, sigma / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D019805:alpha-Methyltyrosine
D000840:Anisoles; D015306:Biogenic Monoamines; D002395:Catecholamines; D018691:Excitatory Amino Acid Antagonists; D008781:Methyltyrosines; D011437:Propylamines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D019805:alpha-Methyltyrosine; D016291:Dizocilpine Maleate; D013469:Sulpiride; D012110:Reserpine; D003024:Clozapine