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.