Withdrawal syndrome upon cessation of chronic clonidine treatment in rats

Clinical reports indicate that cessation of treatment with the antihypertensive agent clonidine is associated with a withdrawal syndrome which may include a hypertensive overshoot of critical proportions. We have attempted to produce an animal model of this syndrome in rats. Rats were treated with clonidine in the drinking water (5 microgram/ml; total dose 300-500 microgram/kg/day) which produced a significant (approx. 20%) decrease in heart rate and blood pressure. Within 24 h of cessation of treatment a significantly greater (approximately 100 beats/min) heart rate was seen in treated animals than in control animals when measurements were made in conscious animals. No hypertensive overshoot was observed. Cessation of treatment was associated with an increase in sympatho-adrenal tone as shown by a trans-synaptic induction of adrenal tyrosine hydroxylase activity. Adrenal denervation prevented the rise in adrenal tyrosine hydroxylase seen after cessation of treatment. Administration of clonidine to pregnant rats (10th day until term) did not alter the development of adrenal tyrosine hydroxylase in the offspring. The data indicate that a withdrawal syndrome is produced upon cessation of chronic clonidine treatment.