Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI.
The functional significance of imidazoline I2 binding sites is unknown but microdialysis studies have indicated that the administration of I2-site ligands leads to an increase in extracellular levels of monoamines. The specific I2-site ligand 2-(-2-benzofuranyl)-2-imidazoline (2-BFI) generates a cue in drug discrimination, thereby indicating functional consequences of I2-site ligand binding. In the present work, we explored the ability of selective noradrenergic and serotonergic ligands to substitute for 2-BFI. Hooded Lister rats were trained in two-lever operant chambers with condensed milk reward to distinguish 2-BFI (7 mg/kg) from saline vehicle, by pressing the correct lever to a predetermined success criterion. Training sessions were then interspersed with sessions in which animals were administered test substances and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. Several agents exhibited significant partial substitution for 2-BFI: The monoamine-releasing agents D-amphetamine and fenfluramine dose-dependently substituted for 2-BFI, while norepinephrine (desipramine, reboxetine) and serotonin (clomipramine, citalopram) reuptake inhibitors substituted at one or more doses. Further investigation using specific receptor agonists and antagonists indicated a possible role for activation of alpha1-adrenoceptors but failed to support involvement of alpha2-adenoceptor, beta-adrenoceptor or 5-HT1A receptor activation. These results support the concept that the 2-BFI cue may contain both noradrenergic and serotonergic components.
MacInnes
Nicholas
N
Pharmaceutical Sciences Research Institute, Aston University, Birmingham, B4 7ET, UK. nicholas.macinnes@kcl.ac.uk
Handley
Sheila L
SL
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054755:Imidazoline Receptors; D008297:Male; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D018765:Dopamine Uptake Inhibitors; D007093:Imidazoles; D054755:Imidazoline Receptors; D009638:Norepinephrine; D011955:Receptors, Drug; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C103723:2-(2-benzofuranyl)-2-imidazoline