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(−)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain

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Summary

The potential 5-HT1A antagonist properties of the ß-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (±) Tertatolol bound with high affinity (Ki = 38 nM) to 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal membranes. The (−)stereoisomer (Ki = 18 nM) was about 50-fold more potent than the (+)stereoisomer (Ki = 864 nM) to inhibit the specific binding of [3H]-8-OHDPAT. As expected of a 5-HT1A antagonist, (−)tertatolol prevented in a concentration-dependent manner (Ki = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (−)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-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; Ki ∼ 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID50 ∼ 0.40 mg/kg i.v.), (−)tertatolol prevented the inhibitory effects of the 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (−)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus) - and post (in the hippocampus) - synaptic 5-HT1A receptors in the rat brain.

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Abbreviations

ACSF:

artificial cerebrospinal fluid

BMY-7378:

8-[2-[4(2-methoxy-phenyl)-1-piperazinyl]ethyl]-8-azaspiro-[4,5]-decane-7,9dione

DRN:

dorsal raphe nucleus

5-HIAA:

5-hydroxyindole acetic acid

5-HT:

5-hydroxytryptamine (serotonin)

5-HTP:

5-hydroxytryptophan

MDL 73005 EF:

8-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)-methylamino]ethyl]-8-azaspiro-[4,5]-decane-7,9-dione, methyl sulfonate

NAN-190:

1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine

8-OH-DPAT:

8-hydroxy-2-(di-n-propylamino) tetralin

(S)-UH-301:

(S)-5-fluoro-8-hydroxy-2-(dipropylamino) tetralin

WAY-100,135:

N-tert-butyl-3,4-(2-methoxyphenyl)-piperazin-1-yl-2-phenylpropanamide

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Authors and Affiliations

  1. INSERM U288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêrière, 91, boulevard de l'Hôpital, F-75634, Paris Cedex 13, France

    T. Jolas, S. Haj-Dahmane, L. Lanfumey, C. M. Fattaccini, E. J. Kidd, J. Adrien, H. Gozlan & M. Hamon

  2. Institut de Recherches Internationales SERVIER, I.R.I.S., 6, place des Pléïades, F-92415, Courbevoie Cedex, France

    B. Guardiola-Lemaitre

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  1. T. Jolas
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  2. S. Haj-Dahmane
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  3. L. Lanfumey
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  4. C. M. Fattaccini
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  6. J. Adrien
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  9. M. Hamon
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Correspondence to T. Jolas at the above address

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Jolas, T., Haj-Dahmane, S., Lanfumey, L. et al. (−)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 347, 453–463 (1993). https://doi.org/10.1007/BF00166735

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