Discontinuation of chronic clonidine treatment: Evidence for facilitated brain noradrenergic neurotransmission

Summary Clonidine, 0.1 mg/kg i.p., or saline was administered to mice twice daily for 12 days. After withdrawal of the drug (14–18.5 h after the last injection), the accumulation of Dopa during 30 min after inhibition of central aromatic amino acid decarboxylase by NSD 1015 (3-hydroxy-benzyl hydrazine, 150 mg/kg i.p.) was significantly increased in the noradrenaline (NA)-rich, but dopamine (DA)-poor, brain stem but not in the DA-rich, but NA-poor corpus striatum. An increased Dopa accumulation was also found in the limbic system and, probably, in the hemispheres. The central accumulation of 5-hydroxytryptophan (5-HTP) was significantly increased in the limbic system. Clonidine, 0.1 mg/kg i.p., administered to mice during the withdrawal phase caused reduction of the accumulation of Dopa and 5-HTP (during 30 min after NSD 1015, 150 mg/kg i.p.) in all brain regions studied to approximately the same levels, as when given to saline-pretreated controls. The disappearance rates of brain NA and DA after synthesis inhibition (-methyl-p-tyrosine methylester HCl 250 mg/kg i.p., 4 h) were probably not altered by clonidine withdrawal.The locomotor stimulation by the central catecholamine receptor agonists apomorphine plus clonidine (1.5 mg/kg i.p. both) after reserpine (10 mg/kg, 4 h) pretreatment was significantly enhanced in clonidine withdrawal mice. However, the motor stimulation by apomorphine (1.5 mg/kg i.p.) alone after reserpine pretreatment was not affected. The spontaneous motor activity was not significantly altered by the withdrawal of clonidine.The data show that brain NA and 5-HT systems are affected by clonidine withdrawal in the opposite direction to that seen after acute administration of low doses of the drug, when they are inhibited. Since postsynaptic central -adrenoceptors, which are stimulated by high but not by low doses of clonidine, showed an enhanced response to high doses of clonidine following discontinuation of a chronic low dose regimen, supersensitivity due to functional noradrenergic denervation might be implicated.