Clonidine withdrawal: Activation of brain noradrenergic neurons with specifically reduced α2-receptor sensitivity

Abstract

The firing rate of brain norepinephrine (NE) neurons in locus coeruleus (LC) was studied by means of single cell recording techniques in rats during, and after cessation of, chronic clonidine treatment (100–500 μg/kg/day, 14 days). In addition, the sensitivity of α 2- and oplate receptros, respectively, on the LC neurons was assessed utilizing microiontophoretic methodology. Whereas the average basal firing rate of LC neurons, randomly encountered throughout the nucleus was reduced during ongoing treatment, it was largely increased in a dose-related manner after discontinuation of treatment (maximum activation, 60 per cent above control base-line, obtained about 30 h after withdrawal). After chronic clonidine treatment the LC neurons displayed a reduced responsiveness to the inhibitory effect of systemic or microiontophoretic administration of clonidine but not to the inhibitory effect of morphine. Since the activity of LC neurons seems to be controlled by inhibitory noradrenergic axon collaterals via α 2-receptors on the soma of the cells, a reduced sensitivity at these α 2-receptor sites may be causally related to the LC activation in clonidine withdrawal. Clinically, sudden discontinuation of chronic clonidine treatment can be associated with a withdrawal reaction, which resembles the morphine abstinence syndrome and includes both signs of sympathetic overactivity such as tachycardia and hypertension and mental symptoms like anxiety. Previous experimental and clinical data indicate that activation of brain NE neurons such as those in the LC may be causally related to the morphine abstinence reaction. The present results suggest a similar mechanism underlying the clonidine withdrawal reaction.