Premium
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
Author(s) -
MacInnes Nicholas,
Duty Susan
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706019
Subject(s) - moclobemide , imidazoline receptor , medial forebrain bundle , nigrostriatal pathway , monoamine oxidase b , monoamine oxidase , chemistry , lesion , medicine , endocrinology , hydroxydopamine , oxidopamine , pharmacology , moxonidine , substantia nigra , striatum , dopamine , agonist , biochemistry , dopaminergic , hippocampus , enzyme , antidepressant , receptor , psychiatry
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. Male Sprague–Dawley rats were injected with 12.5 μ g 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. 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. 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. 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.British Journal of Pharmacology (2004) 143 , 952–959. doi: 10.1038/sj.bjp.0706019