2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I2 binding sites and very low aflinity for α2-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I2 sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α2-adrenoceptor/I 2 site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α 2-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α 2-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.
Abercrombie E.D., Keller R.W., Zigmond M.J. (1988) Characterisation of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioural studies. Neuroscience27: 897-904
2.
Alemany R., Olmos G., Garcia-Sevilla J.A. (1995) The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors. Br J Pharmacol114: 837-845
3.
Ator N.A., Griffiths R.R. (1989) Asymmetrical cross-generalisation in drug discrimination with lorazepam and pentobarbital training conditions. Drug Dev Res16: 355-364
4.
Brown J., Handley S.L. (1980) Effects on the pinna reflex of drugs acting as a-adrenoceptors. J Pharm Pharmacol32: 436-437
5.
Burkard W.P., Bonetti E.P., Da Prada M., Martin J.R., Polc P., Schaffner R., Scherschlidt R., Hefti F., Muller R K M, Wyss P-C., Haefely W. (1989) Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther248: 391-399
6.
Butcher S.P., Fairbrother I.S., Kelly J.S., Arbuthnott G.W. (1990) Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J Neurochem55: 981-988
7.
Carpéné C., Collon P., Remaury A., Cordi A., Hudson A., Nutt D.J., Lafontan M. (1995) Inhibition of amine oxidase activity by derivatives recognising I2-imidazoline sites (NAIBS). J Pharmacol Exp Ther272: 681-688
8.
Colzi A., d-Agostini F., Kettler R., Borroni E., Da Prada M. (1990) Effect of selective and reversible MAO inhibitors on dopamine outflow in rat striatum: a microdialysis study. J Neural Transm Suppl32. 79-84
9.
Dennis T., L'Heureux R., Carter C., Scatton B. (1987) Presynaptic α2-adrenoceptors play a major role in the effects of idazoxan on cortical noradrenaline release (as measured by in vivo dialysis) in the rat. J Pharmacol Exp Ther241: 642-649
10.
Emmett-Oglesby M.W., Spencer D.G., Arnoult D.E. (1982) A TRS-80 based system for the control of behavioural experiments. Pharmacol Biochem Behav17.584-587
11.
Ernsberger P. (1992) Heterogeneity of imidazoline binding sites: proposed I1 and I2 subtypes. Fund Clin Pharmacol6: 55S
12.
Ernsberger P., Meeley M.P., Mann J.J., Reis D.J. (1987) Clonidine binds to imidazoline binding sites as well as α2-adrenoceptors in the ventrolateral medulla. Eur J Pharmacol134:1-13
13.
Ernsberger P., Guiliano R., Willette N., Granata R.N., Reis D.J. (1988) Hypotensive action of clonidine analogues correlates with binding affinity at imidazoline and noradrenergic α2-receptors in the rostral ventrolateral medulla. J Hypertension6: S554-S557
14.
Halliday C.A., Jones B.J., Skingle M., Walsh D.M., Wise H., Tyers M.B. (1991) The pharmacology of fluparoxan: a selective α 2adrenoceptor antagonist. Br J Pharmacol102: 887-895
15.
Jackson H.C., Nutt D.J. (1995) Imidazoline receptors and ingestion. In Cooper S J, Clifton P G (eds), Drug receptor subtypes and ingestive behaviour. Academic Press, London, pp. 278-283
16.
Jackson H.C., Griffin I.J., Nutt D.J. (1991) The effects of idazoxan and other α2-adrenoceptor antagonists on food and water intake in the rat. Br J Pharmacol104: 258-262
17.
Jordan S. (1993) Behavioural and neurochemical correlates of drugs acting at imidazoline and α2-adrenoceptor binding sites. PhD Thesis, Aston University, UK
18.
Jordan S., Jackson H.C., Nutt D.J., Handley S.L. (1993) Central α2-adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm. Psychopharmacology110: 209-212
19.
Jordan S., Jackson H.C., Nutt D.J., Handley S.L. (1995) Discriminative stimulus properties of ethoxyidazoxan . J Psychopharmacol9: 228-233
20.
Lanier B., Raddatz R., Bakthavachalam V., Coupry I., Neumeyer J.L., Lanier S.M. (1995) Structural and ligand recognition properties of imidazoline binding proteins in tissues of rat and rabbit. Mol Pharmacol48: 703-710
21.
Li G., Regunathan S., Barrow C.J., Eshraghi J., Cooper R., Reis D.J. (1994) Agmatine, an endogenous clonidine-displacing substance . Science263: 966-969
22.
Mallard N.J., Hudson A.L. (1992) Characterisation and autoradiographical localisation of non-adrenoceptor idazoxan binding sites in the rat brain. Br J Pharmacol106:1019-1027
23.
Mallard N.J., Tyacke R., Hudson A.L. (1991) Comparative binding studies of [3H] idazoxan and [3H] RX821002 in the rat brain. Br J Pharmacol102: 221P
24.
Michel M.C., Insel P.A. (1989) Are there multiple binding sites? Trends Pharmacol Sci10: 342-344
25.
Michel M.C., Ersnberger P. (1992) Keeping an eye on the I site: imidazoline-preferring receptors. Trends Pharmacol Sci13: 369-370
26.
Mongeau R., de Montigny C., Blier P. (1994) Effects of long-term alpha-2 adrenergic antagonists and electroconvulsive treatments on the alpha-2 adrenoceptors modulating serotonin neurotransmission. J Pharmacol Exp Ther269: 1152-1159
27.
Musgrave I.F., Seifert R. (1995) Alpha 2A-adrenoceptors mediate activation of non-selective cation channels via Gi-proteins in human erythroleukaemia (HEL) cells. No evidence for a functional role of imidazoline receptors in modulating calcium . Biochem Pharmacol49:187-196
28.
Nutt D.J., French N., Handley S.L., Hudson A., Husbands S., Jackson H., Jordan S., Lalies M.D., Lewis J., Lione N., Mallard N., Pratt J. (1995) Functional studies of specific imidazoline-2 receptor ligands. In Reis D J, Bousquet P, Parini A (eds), The imidazoline receptor: pharmacology, functions, ligands and relevance to biology and medicine. New York Academy of Science, New York, pp. 125-139
29.
Raiteri M., Maura G., Versace R. (1983) Functional evidence for two stereochemically different α 2-adrenoceptors regulating norepinephrine and serotonin release. J Pharmacol Exp Ther224: 679-684
30.
Reis D.J., Regunathan S., Wang H., Feinstein D.L., Meeley M.P. (1992) Imidazoline receptors in the nervous system. Fund Clin Pharmacol6: 23S-29S
31.
Renouard A., Widdowson P.S., Millan M.J. (1994) Multiple alpha-2 adrenergic subtypes. I. Comparison of [3H]RX821002-labelled rat R alpha-2A adrenergic receptors in cerebral cortex to human alpha-2A adrenergic receptor and other populations of alpha-2 adrenergic subtypes. J Pharmacol Exp Ther270: 946-957
32.
Sastre M., Garcia-SevillaJ A. (1993) Opposite age-dependent changes of α2A -adrenoceptors and non-adrenoceptor [3H]idazoxan binding sites (I2-imidazoline binding sites) in the human brain: strong correlation of I2 with MAO-B sites. J Neurochem61: 881-889
33.
Tesson F., Prip-Buus C., Lemoine A., Pegorier J-P., Parini A. (1991) Subcellular distribution of imidazoline-guanidinium-receptive sites in human and rabbit liver. J Biol Chem266:155-160
34.
Thomas D.N., Holman R.B. (1991) A microdialysis study of the regulation of endogenous noradrenaline release in the rat hippocampus. J Neurochem56:1741-1746
35.
Trendelenberg A.U., Starke K., Limburger N. (1994) Presynaptic alpha 2A-adrenoceptors inhibit release of endogenous dopamine in rabbit caudate nucleus slices. Naunyn Schmiedeberg's Arch Pharmacol350: 473-481
36.
U'Prichard D.C. (1981) 3H-clonidine and 3H-p-aminoclonidine interactions in vitro with central and peripheral alpha 2-adrenergic receptors. Prog Clin Biol Res71: 53-74
37.
Winter J.C., Rabin R.A. (1992) Yohimbine as a serotonergic agent: evidence from receptor binding and drug discrimination. J Pharmacol Exp Ther263: 682-689
38.
Yang X-M., Luo Z-P., Zhou J-H. (1988) Behavioural evidence for the role of noradrenaline in putative anxiolytic and sedative effects of benzodiazepines. Psychopharmacology95: 280-286
