Selective 5-HT1B agonists identify the 5-HT autoreceptor in lumbar spinal cord of rat

The purpose of the present study was to characterize the 5-HT autoreceptor in the lumbar spinal cord of the rat. The effect of selective 5-HT1A and 5-HT1B agonists on K+-evoked release of [3H]5-HT and the binding of [3H]5-HT were examined. The 5-HT1B compounds, mCPP and quipazine were more potent than exogenous 5-HT at decreasing K+-evoked release of [3H]5-HT in slices of spinal cord. The pEC40 values of 5-HT agonists tested, determined from release assays, significantly correlated with the relative affinities (pKD's) of these compounds for the binding of [3H]5-HT to the 5-HT1B receptor subtype in the presence of 2 microM 8-OHDPAT, as determined from radioligand binding studies (r = 0.98, P = 0.003). Conversely, the potencies of the 5-HT1A agonists 5-MeODMT and 8-OHDPAT, at the 5-HT autoreceptor, were negatively correlated (r = -0.77, P less than 0.10) with their potencies at displacing [3H]5-HT from the 5-HT1A subsite (binding of [3H]5-HT in the presence of 1 microM mCPP). Thus, the 5-HT autoreceptor in spinal cord appears to bear a significant pharmacological similarity to the 5-HT1B binding site. Further testing of the present results requires the development of new 5-HT1 agonists which are selective (1000-fold difference) for the 5-HT1A and 5-HT1B subsites.