Evidence for noradrenergic involvement in mediating the FG 7142 discriminative stimulus

Abstract

Rats were trained to discriminate the stimulus properties of the benzodiazepine receptor partial inverse agonist β-carboline-3-carboxylate acid methyl amide (FG 7142) (5.0 mg/kg) or the α 2-adrenergic receptor antagonist 17α-hydroxyyohimban-16α-carboxylic acid methyl ester (yohimbine) (3.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. These compounds have in common a β-carboline structure and anxiogenic behavioral profiles. The yohimbine discriminative stimulus was mimicked by the α 2-adrenergic receptor antagonist idazoxan and antagonized by the α 2-adrenergic receptor agonist clonidine, indicating that the yohimbine stimulus was mediated through the α 2-adrenergic receptor. THe anxiogenic β-carbolines FG 7142, 1,2,3,4,-tetrahydro-β-carboline (THBC), and norharmane, the anxiogenic/convulsant agent pentylenetetrazole (PTZ), and two physiological stressors failed to mimic the yohimbine discriminative stimulus. In contrast, both yohimbine and idazoxan dose responsively mimicked the anxiogenic FG 7142 stimulus. The present results demonstrate that an asymmetrical generalization exists between the discriminative stimuli produced by yohimbine and FG 7142. Furthermore, these data suggest that yohimbine can produce a multicomponent discriminative stimulus, part of which may be anxiogenic in nature. The ability of α 2-adrenergic receptor antagonists to mimic the FG 7142 cue suggests that activation of the noradrenergic system may underlie cues produced by benzodiazepine receptor inverse agonists.