Locomotor effects of imidazoline I-2-site-specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway

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Abstract

1 The present study examined the ability of the selective imidazoline I-2-site ligands 2-(-2-benzofuranyl)-2-imidazoline (2-BFI) and 2-[4,5-dihydroimidaz-2-yl]-quinoline (BU224) and selected monoamine oxidase (MAO) inhibitors to evoke locomotor activity in rats bearing a lesion of the nigrostriatal pathway. 2 Male Sprague-Dawley rats were injected with 12.5 mug 6-hydroxydopamine (6-OHDA) into the right median forebrain bundle to induce a unilateral lesion of the nigrostriatal tract. After 6 weeks, test drugs were administered either alone or in combination with L-DOPA (L-3,4-dihydroxyphenylamine) and the circling behaviour of animals was monitored as an index of anti-Parkinsonian activity. 3 Intraperitoneal (i.p.) administration of the irreversible MAO-B inhibitor deprenyl (20 mg kg(-1)) or the imidazoline I-2-site ligands BU224 (14 mg kg(-1)) and 2-BFI (7 and 14 mg kg(-1)) produced significant increases in ipsiversive rotations compared to vehicle controls totaling, at the highest respective doses tested, 521+/-120, 131+/-37 and 92.5+/-16.3 net contraversive rotations in 30 (deprenyl) or 60 (BU224 and 2-BFI) min. In contrast, the reversible MAO-A inhibitor moclobemide (2.5-10 mg kg(-1)) and the reversible MAO-B inhibitor lazabemide (2.5-10 mg kg-1) failed to instigate significant rotational behaviour compared to vehicle. 4 Coadministration of lazabemide (10 mg kg(-1)), moclobemide (10 mg kg(-1)) or 2-BFI (14 mg kg(-1)) with L-DOPA (20 mg kg(-1)) significantly increased either the duration or total number of contraversive rotations emitted over the testing period in comparison to L-DOPA alone. 5 These data suggest that I-2-specific ligands have dual effects in the 6-OHDA-lesioned rat model of Parkinson's disease; a first effect associated with an increase in activity in the intact hemisphere, probably via an increase in striatal dopamine content, and a secondary action which, through the previously documented inhibition of MAO-A and/or MAO-B, increases the availability of dopamine produced by L-DOPA.
Original languageEnglish
Pages (from-to)952 - 959
Number of pages8
JournalBritish Journal of Pharmacology
Volume143
Issue number8
DOIs
Publication statusPublished - Dec 2004

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