Locomotor effects of imidazoline I2‐site‐specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6‐hydroxydopamine lesion of the nigrostriatal pathway

• Published in: British journal of pharmacology 2004-12, Vol.143 (8), p.952-959
• Main Authors: MacInnes, Nicholas, Duty, Susan
• Format: Article
• Language: English
• Subjects: 2‐BFI; Animals; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Corpus Striatum - physiology; deprenyl; Dose-Response Relationship, Drug; Imidazoles - pharmacology; imidazoline I2 site; Imidazoline Receptors; in vivo; lazabemide; Ligands; Male; Medical sciences; moclobemide; monoamine oxidase; Monoamine Oxidase Inhibitors - pharmacology; Motor Activity - drug effects; Motor Activity - physiology; Neural Pathways - drug effects; Neural Pathways - enzymology; Neural Pathways - physiology; Oxidopamine; Parkinson's disease; Pharmacology. Drug treatments; rat; Rats; Rats, Sprague-Dawley; Receptors, Drug - physiology; Substantia Nigra - drug effects; Substantia Nigra - enzymology; Substantia Nigra - physiology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706019

The present study examined the ability of the selective imidazoline I2‐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 μg 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 I2‐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 I2‐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