Differentiation of 8-OH-DPAT and Ipsapirone in Rat Models of 5-HT1A Receptor Function

Because the anxiolytic/antidepressant profile of 5-HT1A receptor ligands may be related to their intrinsic activity at 5-HT1A receptors, we characterized the apparent intrinsic activities of 8-OH-DPAT and ipsapirone in several models reflecting pre- or postsynaptic 5-HT1A receptor activation. Presynaptically, as measured with electrophysiological techniques, 8-OH-DPAT and ipsapirone acted as full agonists; whereas in some behavioral models, which presumably reflect postsynaptic activity (i.e., 5-HT syndrome or circling behavior), as well as in the hippocampal adenylate cyclase assay, ipsapirone but not 8-OH-DPAT had mixed agonist/antagonist properties. In a drug discrimination and body temperature model, however, 8-OH-DPAT and ipsapirone appeared to be full agonists both after systemic administration and local application into the dorsal raphe nucleus and the hippocampus. Similar results have been obtained when 8-OH-DPAT and ipsapirone were applied after lesion of the brain serotonergic system by 5,7-DHT. These results suggest that ipsapirone may act as a full agonist at some post-synaptic 5-HT1A receptors. The experiments confirm earlier suggestions that the apparent intrinsic activity of a 5-HT1A ligand may differ at pre- vs postsynaptic 5-HT1A receptors. In addition, it is suggested that the compound’s intrinsic activity also may differ at various postsynaptic 5-HT1A receptor populations. Whether this finding reflects the occurrence of regio-specific spare receptors and/or the existence of subtypes of 5-HT1A receptors is presently unclear.