THE NOVEL 5-HT(1A)-RECEPTOR ANTAGONIST, SDZ 216-525, DECREASES 5-HT RELEASE IN RAT HIPPOCAMPUS IN-VIVO

1 Recent evidence suggests that the novel compound SDZ 216-525 is a se lective and possibly silent 5-HT1A receptor antagonist. Here we have e xamined the action of SDZ 216-525 on central 5-HT1A autoreceptor funct ion. The experiments involved measurement of drug effects on extracell ular 5-HT in the ventral hippocampus of the chloral hydrate anaestheti zed 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 valu e is 20-30 times greater than ED50 values previously obtained for 8-hy droxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and NAN-190. In compar ison, 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 SD Z 216-525 (1 mg kg-1, s.c.) on 5-HT was blocked by the 5-HT1/beta-adre noceptor antagonist, (-)-pindolol (8 mg kg-1, s.c.) but not by a combi nation of the beta1- and beta2-selective adrenoceptor antagonists meto prolol and ICI 118,551 (4 mg kg-1, each). 4 Although in several experi mental models SDZ 216-525 has high affinity, selectivity and lacks int rinsic activity at the 5-HT1A receptor, our experiments show that the drug decreases extracellular 5-HT in ventral hippocampus of the chlora l hydrate anaesthetized rat via a pindolol-sensitive mechanism. We con clude that either SDZ 216-525 promotes (with low potency in vivo) 5-HT 1A receptor/G-protein interactions, or that the 5-HT1A autoreceptor is a 5-HT1A receptor subtype different from the postsynaptic 5-HT1A rece ptor.