Involvement of 5-HT1C-receptors in drug-induced penile erections in rats

Drug-induced penile erections (PE) were initially suggested to be 5-HT1B receptor mediated. However, since the discovery of the 5-HT1C receptor a number of compounds, considered to be 5-HT1B selective, appear to bind more strongly to the 5-HT1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22–2.2 mg/kg), TFMPP (0.46–1.0 mg/kg) and MK 212 (0.1–1.0 mg/kg). The 5-HT agonist DOI (0.022–0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT2 antagonists it did. These compounds have in common a strong affinity for the 5-HT1C receptor. mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED50s were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT1C receptor versus the 5-HT2 receptor. Spiperone (0.1–1.0 mg/kg) and GR 38032F (1–10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED50s were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0–10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT1C receptor and are functionally inhibited by activation of 5-HT1A or 5-HT2 receptors.