Central Mechanisms Regulating Penile Erection in Conscious Rats:The Dopaminergic Systems Related to the Proerectile Effect of Apomorphine

摘要

Apomorophine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders.The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically.Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (K_i) of 101,32,26,2.6,and 10 nM for D_1,D_2,D_3,D_4,and D_5,respectively.When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.),apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 mumol/kg s.c.and 3 nmol/rat i.c.v.,respectively.Apomorphne was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30-100 nmol/rat i.t.).Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p.and i.c.v) but not by domperidone (a peripherally acting dopaminergic receptor antagonist).In this model using conscious rats,penile erection was significantly induced by quinpirole (D_2-D_3-D_4 receptor agonist),but not by R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF38393) and R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzapine (SKF81297) (D_1 receptor agonists),or a D_2 receptor agonist R-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine (PNU-95666E).The role of D_4 receptors in penile erection was demonstrated using selective D_4 receptor agonists [(4-phenylpiperazinyl)-methyl]benzamide (PD168077) and 5-fluoro-2-{[4-(2-pyridinyl)-1-piperazinyl]methyl}-1H-indole (CP226269),whether administered systemically (s.c.) or locally in the brain (i.c.v.).The ability of apomorphine to activate D_3 receptors in relation to its proerectile activity remains to be elucidated by use of selective subtype agonists.These results suggest that the proerectile action of apomorphine in rats is mediated at supraspinal levels and that this effect is not mimicked by a D_2 receptor agonist but associated with activation of D_4 receptors.