Chronic clonidine treatment and its termination: Effects of penile erection and ejaculation in the dog

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 μg/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.