Behavioral evidence for the role of noradrenaline in the putative anxiogenic actions of the inverse benzodiazepine receptor agonist methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate.

The role of noradrenaline in the anxiogenic action of the inverse benzodiazepine receptor agonist methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM) was assessed in a drug discrimination procedure using yohimbine as the stimulus cue and a conflict procedure using a conditioned behavioral suppression paradigm in rats. The yohimbine cue was antagonized by clonidine (0.03-0.5 mg/kg) and diazepam (0.1-10.0 mg/kg). DMCM (0.1-0.7 mg/kg) only partially substituted for the yohimbine stimulus cue. However, DMCM, in a smaller dose (0.1 mg/kg), significantly shifted the dose-effect curve of the yohimbine cue to the left. This potentiating effect of DMCM on the yohimbine cue was antagonized by Ro 15-1788, a benzodiazepine receptor antagonist, and by the type I benzodiazepine receptor agonist CL218,872. In the conditioned behavioral suppression paradigm, both clonidine (0.03 mg/kg) and diazepam (3 mg/kg) had an anticonflict effect by increasing responses in the conditioned fear period, whereas DMCM (0.1, 0.5 mg/kg) decreased the responses of rats in the conditioned fear period. This proconflict effect of DMCM was antagonized by muscimol (0.5 mg/kg), a type A gamma-aminobutyric acid receptor agonist, Ro 15-1788 (3 mg/kg) and clonidine (0.01 mg/kg). Our results suggest that the depressive effect of DMCM on the function of the gamma-aminobutyric acid-benzodiazepine receptor complex may cause increased noradrenergic activity, which may, in turn, be one of the anxiogenic mechanisms in DMCM.