Effects of antidepressant drugs and electroconvulsive shock on pre- and postsynaptic alpha 2-adrenoceptor function in the brain: rapid down-regulation by sibutramine hydrochloride.
Clonidine (0.1 mg/kg IP)-induced hypoactivity and mydriasis responses were respectively used as functional indices of pre- and postsynaptic alpha 2-adrenoceptors in mouse brain. A single injection of various antidepressant drugs had no effect on either response when measured 24 h later. However, 14 days' treatment with sibutramine HCl (3 mg/kg IP), dothiepin (50 mg/kg IP), amitriptyline (10 mg/kg IP), desipramine (10 mg/kg IP) or tranylcypromine (10 mg/kg IP) markedly attenuated both clonidine-induced hypoactivity and mydriasis. Repeated administration of zimeldine (10 mg/kg IP), mianserin (10 mg/kg IP) or clenbuterol (5 mg/kg IP) had no effect on either response. Subchronic treatment with sibutramine HCl (3 mg/kg IP; 3 days) also attenuated pre- and postsynaptic alpha 2-adrenoceptor function. Five ECS (200 V, 2 s) spread over 10 days, but not a single shock, reduced the hypoactivity and mydriasis responses to clonidine. Together, the results indicate that pre- and postsynaptic alpha 2-adrenoceptor function is attenuated by repeated treatment with those antidepressants which acutely increase synaptic levels of noradrenaline. These adrenergic receptor populations are also desensitized by ECS, although this effect is probably mediated via a different mechanism. Finally, the rapid down-regulation observed with sibutramine HCl is not confined to beta-adrenoceptors alone, because pre- and postsynaptic alpha 2-adrenoceptor function is also attenuated by 3 days of treatment with this novel antidepressant drug.
Heal
D J
DJ
Boots Pharmaceuticals Research Department, Nottingham, UK.
Prow
M R
MR
Buckett
W R
WR
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004597:Electroshock; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D015878:Mydriasis / Q000188:drug therapy; D009184:Mydriatics; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*
D000928:Antidepressive Agents; D001679:Biogenic Amines; D003503:Cyclobutanes; D009184:Mydriatics; D011942:Receptors, Adrenergic, alpha; D003000:Clonidine; C058254:sibutramine