Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine.
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(-1) i.p. from saline vehicle in two-lever operant-chambers, 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 beta-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dose-dependent substitution for 2-BFI. 4. Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the sigma(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 effects with those of I(2)-site ligands.
MacInnes
Nicholas
N
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK.
Handley
Sheila L
SL
D000376:Agmatine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002243:Carbolines / Q000378:metabolism* / Q000494:pharmacology; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D007050:Ibogaine / Q000378:metabolism* / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology; D054755:Imidazoline Receptors; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000378:metabolism*
D001572:Benzofurans; D002243:Carbolines; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D011955:Receptors, Drug; D007050:Ibogaine; D000376:Agmatine; C103723:2-(2-benzofuranyl)-2-imidazoline