5-HT_1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists

Abstract

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4–5] décane-7,9 dione), is a high affinity full 5-HT_1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10⁻⁸ M affinity for D₂ dopamine (DA) receptors, 100 fold lower than for 5-HT_1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 µg/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT_1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT_1A receptor antagonist tertatolol (2–5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT_1A agonist property opposes to that of D₂ dopamine receptor stimulation with regard to yawning and penile erections.