THE STIMULATORY EFFECT OF CLONIDINE THROUGH IMIDAZOLINE RECEPTORS ON LOCUS-COERULEUS NORADRENERGIC NEURONS IS MEDIATED BY EXCITATORY AMINO-ACIDS AND MODULATED BY SEROTONIN

Clonidine and other imidazoline/oxazoline drugs, such as cirazoline an d rilmenidine, have been shown to stimulate the activity of noradrener gic neurones in the locus coeruleus (NA-LC) by an alpha(2)-adrenocepto r-independent mechanism through the activation of I-imidazoline recept ors. 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 and dose-dependent (320-5120 mu g/kg, i.v.) in the firing rate of NA- LC neurones (ED(50) = 809 mu g/kg, E(max) = 90%). The stimulatory effe ct of clonidine on NA-LC neurones was completely blocked by pretreatme nt of rats with the excitatory amino acid receptor antagonist kynureni c acid (1-3 mu mol in 10-30 mu l, i.c.v., 2-5 min before clonidine). I n contrast, the stimulatory effect of clonidine on NA-LC neurones was potentiated by pretreatment with reserpine (5 mg/kg, s.c., 18 h) (E(ma x) increased by 63%). Pretreatment with alpha-methyl-p-tyrosine (250 m g/kg, i.p., 24 h) did not alter the stimulatory effect of clonidine, b ut pretreatment with p-chloro-phenylalanine (400 mg/kg, i.p., 24 h) ma rkedly enhanced the stimulatory effect of clonidine on NA-LC neurones (E(max) increased by 139%). The present results indicate that the imid azoline receptor-mediated stimulatory effect of clonidine on NA-LC neu rones is an indirect effect dependent on an excitatory amino acid path way and modulated by an inhibitory serotonin mechanism.