The stimulatory effect of clonidine through imidazoline receptors on locus coeruleus noradrenergic neurones is mediated by excitatory amino acids and modulated by serotonin.
Clonidine and other imidazoline/oxazoline drugs, such as cirazoline and rilmenidine, have been shown to stimulate the activity of noradrenergic neurones in the locus coeruleus (NA-LC) by an alpha 2-adrenoceptor-independent mechanism through the activation of I-imidazoline receptors. The endogenous modulation of the stimulatory effect of clonidine on NA-LC neurones was further 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), clonidine caused a rapid and dose-dependent (320-5120 micrograms/kg, i.v.) increase in the firing rate of NA-LC neurones (ED50 = 809 micrograms/kg, Emax = 90%). The stimulatory effect of clonidine on NA-LC neurones was completely blocked by pretreatment of rats with the excitatory amino acid receptor antagonist kynurenic acid (1-3 mumol in 10-30 microliters, i.c.v., 2-5 min before clonidine). In contrast, the stimulatory effect of clonidine on NA-LC neurones was potentiated by pretreatment with reserpine (5 mg/kg, s.c., 18 h) (Emax increased by 63%). Pretreatment with alpha-methyl-p-tyrosine (250 mg/kg, i.p., 24 h) did not alter the stimulatory effect of clonidine, but pretreatment with p-chloro-phenylalanine (400 mg/kg, i.p., 24 h) markedly enhanced the stimulatory effect of clonidine on NA-LC neurones (Emax increased by 139%). The present results indicate that the imidazoline receptor-mediated stimulatory effect of clonidine on NA-LC neurones is an indirect effect dependent on an excitatory amino acid pathway and modulated by an inhibitory serotonin mechanism.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000502:physiology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D054755:Imidazoline Receptors; D007736:Kynurenic Acid / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000166:cytology* / Q000187:drug effects; D013565:Sympatholytics / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D054755:Imidazoline Receptors; D008781:Methyltyrosines; D011804:Quinolines; D011955:Receptors, Drug; D013565:Sympatholytics; D012701:Serotonin; C000470:EEDQ; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D007736:Kynurenic Acid; D003000:Clonidine