Alteration of 5‐HT 1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography

Ipsapirone, a high‐affinity ligand for the 5‐hydroxytryptamine 1A (5‐HT 1A ) receptor subtype, has been shown to be a full agonist at presynaptic serotonergic sites and a partial agonist at postsynaptic sites. Several recent studies have examined the effects of chronic treatment with ipsapirone or other structurally related pyrimidinylpiperazine compounds, including buspirone and gepirone, on 5‐HT 1A binding sites with mixed results. Since the neural mechanism responsible for the anxiolytic and antidepressant properties of these compounds is currently uncertain, further investigation of this issue appeared warranted. [ 3 H] 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin ([ 3 H] 8‐OHDPAT), a ligand specific for the 5‐HT 1A site, has been used successfully to label these sites using both membrane binding assays and autoradiography. Experiments were performed to determine whether chronic treatment with ipsapirone would differentially affect binding to 5‐HT 1A receptors at different brain sites. Rats were treated twice daily with ipsapirone (10 mg/kg i. p.) for 1 day or for 1, 2, or 3 weeks. Quantitative analyses were done of autoradiograms of in vitro [ 3 H] 8‐OH‐DPAT binding to selected brain regions. Binding in vehicle‐treated rats was highest in the hippocampus, septal nucleus, interpeduncular nucleus, entorhinal cortex, and dorsal raphe nucleus. Following 3 weeks of treatment with ipsapirone, a large decline in binding was measured in the dorsal raphe nucleus. This decline was not seen with ipsapirone treatments for shorter periods. With the 3‐week treatment, there were less robust declines in [ 3 H] 8‐OH‐DPAT binding in the entorhinal cortex and interpeduncular nucleus. Binding in the other brain regions analyzed was unaltered. These results, together with those in the literature, indicate the importance of dose and length of treatment in producing these alterations. The large decline in binding sites in the dorsal raphe is consistent with the view that the anxiolytic and antidepressant properties of ipsapirone are mediated by a downregulation of the somatodendritic 5‐HT 1A autoreceptors. © 1992 Wiley‐Liss, Inc.