Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI

Pharmacol Biochem Behav. 2003 May;75(2):427-33. doi: 10.1016/s0091-3057(03)00136-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Benzofurans / antagonists & inhibitors
  • Benzofurans / pharmacology*
  • Conditioning, Operant / drug effects
  • Cues
  • Discrimination, Psychological / drug effects*
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Imidazoles / antagonists & inhibitors
  • Imidazoles / pharmacology*
  • Imidazoline Receptors
  • Male
  • Norepinephrine / physiology*
  • Rats
  • Receptors, Drug / drug effects*
  • Serotonin / physiology*
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Adrenergic Uptake Inhibitors
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Benzofurans
  • Dopamine Uptake Inhibitors
  • Imidazoles
  • Imidazoline Receptors
  • Receptors, Drug
  • Serotonin Uptake Inhibitors
  • Serotonin
  • 2-(2-benzofuranyl)-2-imidazoline
  • Norepinephrine