A COMPARISON OF VARIOUS ANTIDEPRESSANT DRUGS DEMONSTRATES RAPID DESENSITIZATION OF ALPHA-2-ADRENOCEPTORS EXCLUSIVELY BY SIBUTRAMINE HYDROCHLORIDE

The functional status of presynaptic and postsynaptic alpha-2-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate alpha-2-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the alpha-2-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS, 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic alpha-2-adrenoceptors. ECS down-regulated postsynaptic alpha-2-adrenoceptors when given for 3 days, but required 5 days to desensitise both alpha-2-adrenoceptor populations.