EFFECT OF ACUTE AND REPEATED ADMINISTRATION OF 5-HT1A RECEPTOR AGONISTS ON 5-HT RELEASE IN RAT-BRAIN IN-VIVO

1. Electrophysiological measurements of 5-HT neuronal activity report that repeated administration of 5-HT1A receptor agonists leads to dese nsitization of the 5-HT1A autoreceptor but this has not yet been detec ted in measurements of brain 5-HT synthesis or metabolism. Here we hav e determined the effect of repeated administration of 5-HT1A receptor agonists on brain 5-HT release using microdialysis. 2. Acute administr ation of the 5-HT1A receptor agonists buspirone (0.1 - 5 mg/kg s.c.) a nd ipsapirone (0.03 - 3 mg/kg s.c.) caused a dose-dependent decrease i n 5-HT output in ventral hippocampus of the chloral hydrate anaestheti zed rat. 3. The 5-HT response to buspirone (0.1 and 0.5 mg/kg s.c.) an d ipsapirone (0.3 mg/kg s.c.) was significantly inhibited by pre-treat ment with the 5-HT1/beta-adrenoceptor antagonist pindolol (8 - 16 mg/k g s.c.). The 5-HT response to buspirone (0.1 mg/kg s.c.) and ipsapiron e (0.3 mg/kg sc.) was not blocked by pretreatment with a combination o f the beta1 and beta2-adrenoceptor antagonists metoprolol and ICI 118, 551 (4 mg/kg s.c.). 4. The effect of an acute challenge of buspirone ( 0.5 mg/kg s.c.) on 5-HT output in ventral hippocampus was not attenuat ed in rats treated twice daily for 14 days with 0.5 or 5 mg/kg s.c. bu spirone compared to saline-injected controls. Similarly, the decrease in 5-HT induced by an acute challenge of ipsapirone (0.5 mg/kg s.c.) w as not attenuated in rats treated twice daily for 14 days with 5 mg/kg s.c. ipsapirone. 5. In further experiments it was shown that the decr ease in 5-HT induced in both ventral hippocampus and striatum by an ac ute challenge of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.02 5 mg/kg s.c.), was not attenuated in rats treated twice daily for 14 d ays with 1 mg/kg s.c. 8-OH-DPAT. 6. Basal levels of 5-HT in hippocampa l and striatal microdialysates of animals treated repeatedly with the 5-HT1A receptor agonists were not consistently altered relative to tre atment controls. 7. In agreement with earlier studies measuring region al brain 5-HT synthesis and metabolism, the present microdialysis meas urements of 5-HT release indicate that the inhibitory effect of 5-HT1A receptor agonists on presynaptic 5-HT function is maintained in rats treated repeatedly with the same drugs.