On the mode of action of clonidine: Relationship between effects on behaviour and cyclic nucleotide content in mouse brain

Abstract

Low doses of clonidine (0.1 mg/kg) caused sedation in mice and decreased cyclic GMP content in the cerebellum, but not in the medial forebrain. High doses of clonidine (10.0 mg/kg) caused only a moderate and transient fall in cerebellar cyclic GMP content, the values returning to controls or above after 30 min, when behavioural excitation occurred. Phentolamine potentiated and prolonged the moderate reduction in cerebellar cyclic GMP content of the high dose of clonidine, at the same time counteracting the clonidine-induced behavioural effects. In reserpinized mice, the high dose of clonidine caused a marked rise of cyclic GMP content in both areas of the brain and produced massive behavioural excitation. These results indicate that high doses of clonidine stimulate central α-adrenergic receptors. The decrease in cyclic GMP content elicited by clonidine was prevented or even converted into an increase by pretreatment of the mice with cholinolytics. An increase in locomotor activity and intensified tremor was observed under these conditions. Clonidine antagonized the elevation of cyclic GMP content and the behavioural manifestations elicited by direct or indirect dopaminergic stimulation. These data suggest cholinomimetic properties of the drug. A direct cholinomimetic action can, however, not be attributed to the drug, since stimulators of central muscarinic receptors such as arecoline and oxotremorine increased cyclic GMP content in both areas of the brain.