Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic α2-adrenoceptors in the brain

Abstract

Since brain α 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1–3000 μg/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED 50 values were: 120 μg/kg for hypoactivity (95% confidence limits 103–140 μg/kg), 54 μg/kg for mydriasis (95% confidence limits 40–74 μg/kg) and 18 μg/kg for MHPG reduction (95% confidence limits 8–36 μg/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose depedently produce mydriasis, but not hypoactivity, after peripheral (0.1–5 mg/kg i.p.) or central (0.5–10 gmg i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 μg idazoxan or yohimbine, but not 2.5 μg prazosin or pindolol, showing this effect was mediated by central α 2-adrenoceptors. Methamphetamine (1–10 μg i.c.v.) potentiated the mydriasis induced by clonidine (50 μg/kg i.p.) suggesting this was a postsynaptic α 2-adrenoceptor response. By contrast, methamphetamine (1–10 μg i.c.v.) dose dependently reversed clonidine (100 μg/kg i.p.) hypoactivity indicating this response was mediated by presynaptic α 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. × 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 μg.kg i.p.) and markedly attenuated clonidine (100 μg/kg i.p.) hypoactivity.