?2-Adrenoceptor antagonists potentiate the anticonflict and the rotarod impairing effects of benzodiazepines

Abstract

Putative interactions between the specific alpha 2-adrenoceptor antagonist idazoxan and benzodiazepines (BDZs) were examined in two different rat conflict models; Vogel's drinking conflict test (VT) and Montgomery's conflict test (MT) (the elevated +-maze). In the MT, idazoxan (0.031 mg/kg) produced anxiogenic-like effects, which were counteracted both by the triazolo-BDZ alprazolam (APZ; 0.2 mg/kg) and the conventional BDZ diazepam (DIZ; 0.2 mg/kg). In fact, the anxiolytic-like effects of APZ were significantly potentiated when co-administering idazoxan. A tendency to such a phenomenon was seen also in rats treated with DIZ and idazoxan. In the VT, the anxiolytic-like effects both of APZ (1.0 mg/kg) and DIZ (4.0 mg/kg) were significantly enhanced when co-administering idazoxan (1.0 mg/kg) in a dose not affecting the behavior per se. Similar potentiating phenomena by behaviorally inert doses of alpha 2-adrenoceptor antagonists (idazoxan 1.0 mg/kg; yohimbine 2.0 mg/kg) were seen with regard to the ataxic/sedative effects of the BDZs (APZ 0.25 mg/kg; DIZ 1.5 mg/kg). The present results provide further support for the notion that the anxiolytic-like effects of BDZs are not related to attenuation of Locus Coeruleus activity. In addition, it is suggested that the potentiation caused by the alpha 2-adrenoceptor antagonist is mediated via a noradrenaline induced increase in signal-to-noise ratio in target neurons of the brain noradrenergic system.

?1- and ?-adrenoceptor stimulation potentiate the anticonflict effect of a benzodiazepine

“…The present results are in concert with our earlier findings of a potentiative effect of the specific %-adrenoceptor antagonist idazoxan on BDZ induced anticonflict effects (S6derpalm and Engel, 1989). It therefore seems likely that it is the a2-adrenoceptor antagonistic properties of idazoxan and yohimbine that accounts for the potentiation observed.…”

“…It was previously suggested that potentiative effects of %-adrenoceptor antagonists on the anticonflict activity of BDZs are mediated through blockade of a2-adrenoceptors located on NA neurons, so-called autoreceptors (S6derpalm and Engel, 1989). Blockade of such receptors increases the electrical activity of neurons originating in the principal NA nucleus of the brain, the Locus Ceruleus (LC) (see e.g.…”

“…In fact, when concomitantly administering idazoxan, the anticonflict effects of the BDZs were potentiated both in Montgomery's conflict test and in Vogel's conflict test. It was suggested that the potentiation observed was due to enhanced NA neurotransmission (for discussion see S6derpalm and Engel, 1989).…”

A re‐evaluation of the role of α2‐adrenoceptors in the anxiogenic effects of yohimbine, using the selective antagonist delequamine in the rat

“…For example, imiloxan and piperoxan are apparently anxiogenic in the elevated X-maze (Handley & Mithani, 1984) and this latter agent is anxiogenic in the fear-potentiated startle test (Davis et al, 1979). On the other hand, whereas idazoxan has been reported by some authors (Handley & Mithani, 1984;Soderpalm & Engel, 1989) to be anxiogenic in the elevated X-maze test, others have found it to be without effect in this test (File, 1987;Moser, 1989). Similarly, 1-pyrimidyl piperazine, a metabolite of buspirone with a2-adrenoceptor antagonist properties, is not anxiogenic in this test (Moser, 1989), nor is the selective a2-adrenoceptor antagonist, atipamezole (Kauppila et al, 1991).…”

Characterization of the Binding and Comparison of the Distribution of Benzodiazepine Receptors Labeled with [3H]Diazepam and [3H]Alprazolam

“…Other pharmacokinetic or pharmacodynamic properties must distinguish these two benzodiazepines. [Neuropsychopharmacology 8:305-314, 1993J in the treatment of panic disorder (Feighner et Eriksson et al, 1986;Kostowski et al, 1986;Soderpalm and Engel 1989) lap of [3Hlalprazolam onto other sites, a receptor au toradiographic approach (Kuhar et al 1985) was used in the present study. Previous investigations, aimed at analyzing the distribution of benzodiazepine receptors in the CNS, have principally involved the use of pHlflunitrazepam as the ligand of choice Kuhar 1979, 1980).…”