Characterization of the discriminable stimulus produced by 2‐BFI: effects of imidazoline I₂‐site ligands, MAOIs, β‐carbolines, agmatine and ibogaine

Abstract

1 The molecular nature and functions of the I 2 subtype of imidazoline binding sites are unknown but evidence suggests an association with monoamine oxidase (MAO). Rats can distinguish the selective imidazoline I 2 -site ligand 2-BFI from vehicle in drug discrimination, indicating functional consequences of occupation of these sites. We have used drug discrimination to investigate the nature of the discriminable stimulus, especially in relation to MAO inhibition. 2 Following training to distinguish 2-BFI 7 mg kg 71 i.p. from saline vehicle in two-lever operantchambers, male Hooded Lister rats underwent sessions where test substances were given instead and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. 3 2-BFI; its cogeners BU216, BU224, BU226 and LSL60101; the reversible MAO-A inhibitors moclobemide and RO41-1049; the b-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dosedependent substitution for 2-BFI. 4 Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the s 2 -site ligand SKF10,047 and the I 2A -site ligand, amiloride, failed to substitute. The irreversible inhibitor of MAO, deprenyl, substituted for 2-BFI while clorgyline did not. 5 These results suggest imidazoline I 2 site ligands produce a common discriminable stimulus that appears associated with reversible inhibition of MAO-A rather than MAO-B, possibly through increases in extracellular concentration of one or more monoamines. Ibogaine exhibits a commonality in its subjective e ects with those of I 2 -site 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

“…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.…”

“…Based on our previous studies (MacInnes & Handley, 2002), single-drug experiments were conducted every other day, while L-DOPA combination studies were conducted on Mondays and Thursdays. Different doses, including vehicle control, were distributed across sessions and rats in pseudorandom order except for deprenyl, which, because it is an irreversible inhibitor, was given as the last dose to group 2.…”

“…All drugs were dissolved in 0.9% physiological saline, except for moclobemide which was made up in deionised water, and administered i.p in a dose volume of 2 ml kg À1 . Doses of I 2 -specific ligands and reversible MAO inhibitors were based on those that were effective in previous N. MacInnes & S. Duty I 2 -site-specific ligands in 6-OHDA-lesioned rats drug discrimination studies (MacInnes & Handley, 2002) and that retained full solubility in saline. The dose of deprenyl (20 mg kg…”

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

“…Similarly, agmatine, BU224 and clonidine had also been reported to attenuate many behavioural characteristics of morphine abstinence syndrome [115]. In drug-discrimination models, harmane along with selective I 2 -BS compounds were shown to potently and dose-dependently substitute for 2-BFI in the twolever operant chamber model [116]. Moreover, harmane was also reported to substitute BU224 in drug discrimination studies [117].…”

Behavioral effects of the imidazoline I2 receptor ligand BU99006 in rats

“…For example, both 2-BFI and BU224 increase rotational behaviors in rats with nigrostriatal lesions (MacInnes and Duty, 2004). In drug discrimination studies, both idazoxan and BU224 produce responding predominantly on the 2-BFI-associated lever in rats (Jordan et al, 1996; MacInnes and Handley, 2002). Thus, idazoxan and BU224 appear to be agonists in some assays and antagonists in other assays, suggesting that these drugs have lower efficacy at I 2 receptors as compared to other ligands.…”