title: Stimulatory effects of clonidine, cirazoline and rilmenidine on locus coeruleus noradrenergic neurones: possible involvement of imidazoline-preferring receptors.
abstract: Clonidine and related drugs not only interact with alpha 2-adrenoceptors but also recognise non-adrenoceptor sites in the brain. The involvement of these imidazoline-preferring receptors in the regulation of the activity of locus coeruleus noradrenergic neurones (NA-LC) was investigated after inactivation of alpha 2-adrenoceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). In EEDQ-pretreated rats (6 mg/kg, i.p., 6 h), the characteristic inhibitory effect of low doses of clonidine on these neurones was abolished and a paradoxical, dose-dependent increase in firing rate was observed at higher doses (640-5120 micrograms/kg, i.v.) (ED50 = 702 micrograms/kg, Emax = 83%, n = 14). Guanfacine (0.3-20 mg/kg) did not modify neuronal activity but antagonised the stimulatory effect of clonidine. Cirazoline (80-640 micrograms/kg) and rilmenidine (0.3-10 mg/kg) also stimulated neuronal activity (ED50 = 192 micrograms/kg, Emax = 102%, n = 5; ED50 = 1563 micrograms/kg, Emax = 70%, n = 1-5, respectively) by an alpha 2-adrenoceptor-independent mechanism. The results suggest that these drugs can modulate the activity of locus coeruleus noradrenergic neurones through the activation of I1-imidazoline-preferring receptors.
authors.affiliation: Departamento de Farmacología, Universidad del País Vasco, Leioa, Bizkaia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Pineda
authors.forename: L
authors.initials: L
authors.lastname: Ugedo
authors.forename: J A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D011955:Receptors, Drug / Q000502:physiology*; D000077769:Rilmenidine
chemical_list: D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D054755:Imidazoline Receptors; D010080:Oxazoles; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D003000:Clonidine; D000077769:Rilmenidine; C014282:cirazoline; D009638:Norepinephrine