A comparison of various antidepressant drugs demonstrates rapid desensitisation 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.
Boots Pharmaceuticals Research Department, Nottingham, UK.
D J
DJ
Heal
M R
MR
Prow
J
J
Gosden
G P
GP
Luscombe
W R
WR
Buckett
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology*; D004597:Electroshock; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009184:Mydriatics / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D003503:Cyclobutanes; D008996:Monoamine Oxidase Inhibitors; D009184:Mydriatics; D003000:Clonidine; C058254:sibutramine