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NEUROPHARMACOLOGY

Dopaminergic Agonists and Muscarinic Antagonists Improve Lateralization in Hemiparkinsonian Rats in a Novel Exploratory Y-Maze

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan

Parkinson's disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. Its primary clinical symptoms are akinesia, tremor, and rigidity, which usually start from one side, resembling the lateralization in hemiparkinsonian rats having 6-hydroxydopamine-induced unilateral lesion of the medial forebrain bundle. A novel exploratory Y-maze was designed to detect the lateralization of hemiparkinsonian rats in terms of biased turns in the maze. Dopamine agonists levodopa (L-3,4-dihydroxyphenylalanine, 10-30 mg/kg) and apomorphine (0.1-0.3 mg/kg), but not methamphetamine (0.5-2 mg/kg), improved the lateralization in the rat model. However, high doses of the dopamine agonists, 30 and 0.3 mg/kg, respectively, caused small movements in the arms that seemed to parallel the increase in counts per turn in the Y-maze. Interestingly, the muscarinic antagonists trihexyphenidyl and scopolamine improved lateralization moderately, while increasing total turns, an index of locomotive activity. (-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.3 mg/kg), an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, increased total counts, but did not alleviate the lateralization. The 2-adrenoceptor antagonist idazoxan (1 and 10 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 and 3 mg/kg), a non-NMDA glutamate receptor antagonist, did not affect any of the indices. These findings suggest that the clinical action of drugs on unbalanced movement in PD could be predicted by measuring their effects on lateralization of the 6-hydroxydopamine-lesioned rat model in this exploratory Y-maze.

Address correspondence to: Dr. Makoto Nakagawa, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. E-mail: m-nakagawa{at}hhc.eisai.co.jp