1. Recent evidence suggests that the novel compound SDZ 216-525 is a selective and possibly silent 5-HT1A receptor antagonist. Here we have examined the action of SDZ 216-525 on central 5-HT1A autoreceptor function. The experiments involved measurement of drug effects on extracellular 5-HT in the ventral hippocampus of the chloral hydrate anaesthetized rat by use of microdialysis. 2. Acute injection of SDZ 216-525 (0.1, 0.3, 1.0 and 3 mg kg-1, s.c.) caused a dose-related decrease in 5-HT output with an estimated ED50 of at least 0.3 mg kg-1. This ED50 value is 20-30 times greater than ED50 values previously obtained for 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and NAN-190. In comparison, SDZ 216-525 is reported to have slightly higher affinity for the 5-HT1A site than 8-OH-DPAT and NAN-190. 3. The inhibitory effect of SDZ 216-525 (1 mg kg-1, s.c.) on 5-HT was blocked by the 5-HT1/beta-adrenoceptor antagonist, (-)-pindolol (8 mg kg-1, s.c.) but not by a combination of the beta 1- and beta 2-selective adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg kg-1, each). 4. Although in several experimental models SDZ 216-525 has high affinity, selectivity and lacks intrinsic activity at the 5-HT1A receptor, our experiments show that the drug decreases extracellular 5-HT in ventral hippocampus of the chloral hydrate anaesthetized rat via a pindolol-sensitive mechanism. We conclude that either SDZ 216-525 promotes (with low potency in vivo) 5-HT1A receptor/G-protein interactions, or that the 5-HTlA autoreceptor is a 5-HT1A receptor subtype different from the postsynaptic 5-HT1A receptor.