The cannabinoid CB1 receptor antagonist SR 141716A induces penile erection by increasing extra-cellular glutamic acid in the paraventricular nucleus of male rats

The cannabinoid CB1 receptor antagonist SR 141716A (0.1, 0.5 and 1 microg) induces penile erection when injected into the paraventricular nucleus of the hypothalamus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of glutamic acid in the paraventricular dialysate obtained by means of intra-cerebral microdialysis. Glutamic acid increase and penile erection did not occur when SR 141716A was given after tetrodotoxin, a voltage-dependent Na(+) channel blocker. Both penile erection and glutamic acid increases were also reduced by the cannabinoid CB1 receptor agonists WIN 55,212-2 or HU 210 given into the paraventricular nucleus before SR 141716A at doses unable to induce penile erection or to modify glutamic acid. In contrast, dizocilpine ((+)MK-801), an antagonist of excitatory amino acid receptors of the N-methyl-d-aspartic acid (NMDA) subtype, given into the paraventricular nucleus reduced penile erection, but was ineffective on the glutamic acid increase induced by the CB1 receptor antagonist. 6-Cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and (+/-)-2-amino-4-phosphono-butanoic acid (AP(4)), antagonists of the excitatory amino acid receptors of the AMPA subtype and of the metabotropic subtype, respectively, were ineffective on both penile erection and glutamic acid increase. SR 141716A responses were also reduced by muscimol, a GABA(A) receptor agonist, but not by baclofen, a GABA(B) receptor agonist, given into the paraventricular nucleus before SR 141716A. The present results show that SR 141716A induces penile erection by activating glutamic acid neurotransmission, which causes in turn the activation of paraventricular oxytocinergic neurons mediating penile erection.