Precipitation by Yohimbine of the Withdrawal Syndromes of Clonidine, Guanfacine, and Methyldopa in the Spontaneously Hypertensive Rat

In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.