Locomotor effects of imidazoline I2-site-specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway.
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 microg 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.
Macinnes
Nicholas
N
Wolfson Centre for Age-Related Diseases, G20 Wolfson Wing, Hodgkin Building, Guy's Campus, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, UK.
Duty
Susan
S
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D008024:Ligands; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology
C105826:BU 224; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D011955:Receptors, Drug; C487767:imidazoline receptor 2; D016627:Oxidopamine