(-)TERTATOLOL IS A POTENT ANTAGONIST AT PRESYNAPTIC AND POSTSYNAPTIC SEROTONIN 5-HT(1A) RECEPTORS IN THE RAT-BRAIN

The potential 5-HT1A antagonist properties of the beta-antagonist tert atolol were assessed using biochemical and electrophysiological assays in the rat. (+/-) Tertatolol bound with high affinity (K(i) = 38 nM) to 5-HT1A sites labelled by [H-3]8-OH-DPAT in hippocampal membranes. T he (-)stereoisomer (K(i) = 18 nM) was about 50-fold more potent than t he (+)stereoisomer (K(i) = 864 nM) to inhibit the specific binding of [H-3]-8-OH-DPAT. As expected of a 5-HT1A antagonist, (-)tertatolol pre vented in a concentration-dependent manner (K(i) = 24 nM) the inhibito ry effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activ ity in rat hippocampal homogenates. Furthermore in vivo pretreatment w ith (-)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/kg s.c.) on the accumulation of 5-hydro xytryptophan in various brain areas after the blockade of aromatic L-a mino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in bra instem slices; K(i) approximately 50 nM) and in vivo (in chloral hydra te anaesthetized rats; ID50 approximately 0.40 mg/kg i.v.), (-)tertato lol prevented the inhibitory effects of the 5-HT1A receptor agonists 8 -OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninerg ic neurones within the dorsal raphe nucleus. In about 25% of these neu rones, the basal firing rate was significantly increased by (-)tertato lol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the d orsal raphe nucleus) - and post (in the hippocampus) - synaptic 5-HT1A receptors in the rat brain.