title: Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic alpha 2-adrenoceptors in the brain.
abstract: Since brain alpha 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 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.
authors.affiliation: Research Department, Boots Company, Nottingham, U.K.
authors.forename: D J
authors.initials: DJ
authors.lastname: Heal
authors.forename: M R
authors.initials: MR
authors.lastname: Prow
authors.forename: W R
authors.initials: WR
authors.lastname: Buckett
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009184:Mydriatics; D009498:Neurotoxins / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects
chemical_list: D001596:Benzylamines; D015306:Biogenic Monoamines; D009184:Mydriatics; D009498:Neurotoxins; D011942:Receptors, Adrenergic, alpha; D008694:Methamphetamine; D008734:Methoxyhydroxyphenylglycol; D003000:Clonidine; C012102:DSP 4