Antidepressants Comparison

Psychopharmacology (1992) 107: 497-502 Psychopharmacology © Springer-Verlag 1992 A comparison of various antidepressant drugs demonstrates rapid desensitisation of 2-adrenoceptors exclusively by sibutramine hydrochloride David J. Heal, Michael R. Prow, Jane Gosden, Graham P. Luscombe, and W. Roger Buckett Boots Pharmaceuticals Research Department, Nottingham NG2 3AA, UK Received September 13, 1991 / Final version November 4, 1991 Abstract. The functional status of presynaptic and postsynaptic a2-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 m g/kg IP). Both responses were attenu ated 24 h after 3 days of injection of sibutramine hydrochloride (3 rag/ kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate a2-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 tP, none of the other 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 ~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 con- clusion, this comparative study using antidepressant treatments with differing pharmacological modes of ac- tion demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic ~2-adrenoceptors. ECS down-regulated postsynaptic ~2-adrenoceptors when given for 3 days, but required 5 days to desensitise both o,2-adrenoceptor populations. Key words: a2-Adrenoceptors - Presynaptic az-adrenoceptors - Postsynaptic a2-adrenoceptors - Cloni- dine-induced behaviours - Sedation - Hypoactivity - Mydriasis - Sibutramine hydrochloride - Electroconvul- sive shock - Antidepressants Offprint requests to: D.J. Heal Clonidine-induced hypoactivity and mydriasis in mice can be respectively used to indicate the functional status of central pre- and postsynaptic ~2-adrenoceptors (Heal et al. 198%, b). Recently, Heal et al. (1991a) have shown that both adrenoceptor populations are down-regulated by 10 days of treatment with either antidepressant drugs which enhance central noradrenergic function, or electroconvulsive shock (ECS), a model of electroconvulsive therapy (Costain et al. 1979). Sibutramine hydrochloride (BTS 54 524; N-(1-[1- (4-chlorophenyl) cyclobutyl]-3-methylbutyl)-N,N-dimeth- ylamine hydrochloride monohydrate) is a novel mono- amine reuptake inhibitor antidepressant which rapidly down-regulates central ]3-adrenoceptors after low dose administration (Buckett et al. 1988a; Heal et al. 1989c; Martin and Heal unpublished) and in the above study, this drug was similarly found to desensitise pre- and postsynaptic az-adrenoceptors after 3 days (Heal et al. 1991a). However, no direct comparison was conducted between sibutramine and other antidepressants to ascertain whether the ability to rapidly down-regulate c~2-adrenoceptors was universal or whether it was un- usual, or perhaps even exclusive, to sibutramine. We have therefore conducted an investigation to compare the effects on clonidine-induced hypoactivity and mydriasis of subchronic administration of sibutramine and various other antidepressants. Materials and methods Animals and drugs. Adult m ale C57/B1/6Ola mice (Olac) weighing 20-30 g were used. They were housed in groups of ten on a 12 h light/dark cycle (l ights on at 07: 00 hours) a t 21 * C an d 55 % humid- ity. Mice were allowed free access to food and water. Drugs were obtained from the following sources: ctonidine HC1, desipramine HC1, amitriptyline HC1, doxepin HC1, tranylcypromine HC1 (Sigma, Poole); sibutramine HC1 monohydrate (BTS 54 524) (Boots Pharmaceuticals Research Department, Nottingham); amoxapine (Cyanamid, Gosport); nomifensine maleate (RBI, Na- tick); zimeldine (HC1)2 (Astra, S odertalje); fluoxetine HC1 (Lilly, Indianapolis); mianserin HC1 (Organon, Oss); halothane (M ay and Baker, Dagenham). All drugs were dissolved n 0.9 % weight/volume

Antidepressants Comparison

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