Inhibition of Central Monoamine Oxidase by Imidazoline₂ Site‐Selective Ligands

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

“…It follows that one possible explanation for the ipsiversive rotational behaviour seen here with 2-BFI and BU224 is that these I 2 -site ligands may also act to release dopamine in the striatum of the intact hemisphere. That I 2 -site ligands may act as 'dopamine releasers' has been suggested previously (Sastre-Coll et al, 2001) and is backed up by the in vivo microdialysis studies of Hudson et al (1999), which showed that acute administration of similar doses of 2-BFI and BU224 as used here (20 mg kg À1 ) increased extrasynaptic levels of dopamine in the striatum by 0.5-and 2.5-fold above baseline, respectively. That this N. MacInnes & S. Duty I 2 -site-specific ligands in 6-OHDA-lesioned rats increase in striatal dopamine levels is small compared to the 10-fold increase above baseline that would be achieved by 5 mg kg À1 amphetamine (Lamensdorf et al, 1999) is consistent with the level of rotations achieved with 2-BFI and BU224 being small compared to that produced by amphetamine.…”

“…However, there is extensive evidence that imidazoline I 2 -binding sites exist on monoamine oxidase (MAO), at a location distinct from the catalytic site (Alemany et al, 1995;Raddatz et al, 1997;Remaury et al, 2000). In vitro, many imidazolines, including 2-BFI and BU224, reversibly inhibit MAO-A with a similar potency to that of the reversible MAO-A inhibitor moclobemide (IC 50 : 2-BFI, 16.572.7 mM; BU224, 4.870.2 mM; moclobemide, 3673.6 mM; Lalies et al, 1999). These imidazolines also similarly inhibit MAO-B, although with less potency than the selective reversible MAO-B inhibitor, lazabemide (IC 50 : 2-BFI, 27.972.2 mM; BU224, 44.876.6 mM (Lalies et al, 1999); lazabemide, 0.03 mM (Da Prada et al, 1987)) and in vivo studies indicate that moclobemide, lazabemide and deprenyl show substitution for 2-BFI in an two-lever drug-discrimination paradigm (MacInnes & Handley, 2002).…”

“…In vitro, many imidazolines, including 2-BFI and BU224, reversibly inhibit MAO-A with a similar potency to that of the reversible MAO-A inhibitor moclobemide (IC 50 : 2-BFI, 16.572.7 mM; BU224, 4.870.2 mM; moclobemide, 3673.6 mM; Lalies et al, 1999). These imidazolines also similarly inhibit MAO-B, although with less potency than the selective reversible MAO-B inhibitor, lazabemide (IC 50 : 2-BFI, 27.972.2 mM; BU224, 44.876.6 mM (Lalies et al, 1999); lazabemide, 0.03 mM (Da Prada et al, 1987)) and in vivo studies indicate that moclobemide, lazabemide and deprenyl show substitution for 2-BFI in an two-lever drug-discrimination paradigm (MacInnes & Handley, 2002). However, there appears to be little correlation between these agents' affinity for I 2 sites and their inhibition of MAO.…”

Presynaptic I1-Imidazoline Receptors Reduce GABAergic Synaptic Transmission in Striatal Medium Spiny Neurons

“…The endogenous ligands may reach both I 1 -and I 2 -imidazoline receptors in the striatum. Activation of I 2 -imidazoline receptors inhibits monoamine oxidase (Carpéné et al, 1995;Ozaita et al, 1997;Lalies et al, 1999) and elicits dopamine release (Sastre-Coll et al, 2001), both of which can result in an increase of extracellular dopamine. Hence, it is plausible that the endogenous ligands facilitate the striatal direct output pathway via both I 1 -imidazoline receptormediated disinhibition and I 2 -imidazoline receptor-mediated increase in dopamine.…”

“…It has been reported that I 1 -imidazoline receptors are subcellularly located on the plasma membrane (Piletz and Sletten, 1993;Ernsberger and Shen, 1997). In contrast, some populations of I 2 -imidazoline receptors are located intracellularly on the outer membrane of mitochondria and inhibit monoamine oxidase activity (Carpéné et al, 1995;Ozaita et al, 1997;Lalies et al, 1999). I 3 -imidazoline receptors have been shown to act peripherally in the regulation of ATP-sensitive K ϩ channels coupled with insulin secretion (Chan et al, 1994;Olmos et al, 1994;Zaitsev et al, 1999) and centrally in the modulation of firing activity of locus ceruleus neurons (Ugedo et al, 1998) and spinal reflexes (Kino et al, 2005).…”