Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test

Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors demonstrated an anxiolytic-like effect in the four-plate test (FPT). (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; a 5-HT2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the alpha-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the alpha2-adrenoceptor agonists abolished the anxiolytic-like effect of antidepressants.

The aim of the present study was to evaluate the role of noradrenergic system on the regulation of 5-HT2 receptors implicated in the DOI anxiolytic-like activity in the FPT.

First, the effect of noradrenergic and serotonergic lesions on DOI anxiolytic-like activity was studied in the FPT. Second, the effect of co-administration of alpha-adrenoceptor ligands and DOI was evaluated in the same test.

The noradrenergic and serotonergic lesions had no effect on DOI (1 mg/kg) anti-punishment activity in the FPT. Adrafinil 0.25 and 4 mg/kg (an alpha1-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an alpha1-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an alpha2-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two alpha2-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific alpha2A-adrenoceptor agonist) completely abolished DOI-induced increase in punished passages.

These results indicate that the DOI seems to act on the 5-HT2 receptors post-synaptically located. The effect of DOI is regulated by the alpha2-adrenoceptors.