[3H]Alnespirone: A novel specific radioligand of 5-HT1A receptors in the rat brain

doi:10.1016/S0014-2999(97)01288-0

European Journal of Pharmacology

Volume 337, Issues 2–3, 22 October 1997, Pages 297-308

https://doi.org/10.1016/S0014-2999(97)01288-0 Get rights and content

Abstract

Determination of the optimal assay conditions for the specific binding of a tritiated derivative of the novel potential anxiolytic drug alnespirone (S-20499, (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro-(4,5)-decane-7,9-dione) allowed the demonstration that this radioligand bound with a high affinity (K_d=0.36 nM) to a homogeneous class of sites in rat hippocampal membranes. The pharmacological properties of [ $^{3} H$ ]alnespirone specific binding sites matched exactly (r=0.95) those of 5-HT_1A receptors identified with [ $^{3} H$ ]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as radioligand. Furthermore, membrane binding experiments and autoradiographic labeling of tissue sections showed that the regional distribution of [ $^{3} H$ ]alnespirone specific binding sites in the rat brain and spinal cord superimposed over that of 5-HT_1A receptors specifically labeled by [ $^{3} H$ ]8-OH-DPAT. However, the differential sensitivity of [ $^{3} H$ ]alnespirone and [ $^{3} H$ ]8-OH-DPAT specific binding to various physicochemical effectors (temperature, pH, Mn²⁺, N-ethyl-maleimide) supports the idea that these two agonist radioligands did not recognize 5-HT_1A receptors exactly in the same way. These differences probably account for the reported inability of alnespirone, in contrast to 8-OH-DPAT, to induce some 5-HT_1A receptor-mediated behavioural effects in rats.

Introduction

Among the numerous serotonin (5-hydroxytryptamine, 5-HT) receptors identified to date (Hoyer et al., 1994), the 5-HT_1A receptor subtype has been the matter of extensive studies since the discovery that the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the central nervous system (CNS) are essentially mediated through 5-HT_1A receptor stimulation (Hjörth et al., 1982; Gozlan et al., 1983). The development of several agonist radioligands and, more recently, of the selective antagonist radioligand [ $^{3} H$ ]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide ([ $^{3} H$ ]WAY 100635, Gozlan et al., 1995; Khawaja, 1995) allowed the autoradiographic mapping of 5-HT_1A receptors in the CNS of various species. Although [ $^{3} H$ ]WAY 100635 was found to bind to approx. 60% more sites then [ $^{3} H$ ]8-OH-DPAT, both [ $^{3} H$ ]WAY 100635- and [ $^{3} H$ ]8-OH-DPAT-specific binding sites exhibit exactly the same distribution pattern, typical of 5-HT_1A receptors, with a marked enrichment in limbic areas such as the hippocampus, the septum, the frontal and entorhinal cortices and the amygdala (Marcinkiewicz et al., 1984; Pazos and Palacios, 1985; Gozlan et al., 1995). In addition, 5-HT_1A receptor binding sites are also abundant in the raphe nuclei where they are located on the cell bodies and dendrites of serotoninergic neurones (Vergé et al., 1986; Sotelo et al., 1990).

In different areas of the brain, 5-HT_1A receptor agonists stimulate the 5-HT_1A receptors with various intrinsic activities. Thus, anxiolytic-like effects of 8-OH-DPAT and azapirones, such as ipsapirone, gepirone and buspirone, have been ascribed to the selective stimulation of somatodendritic 5-HT_1A autoreceptors within the anterior raphe nuclei (Jolas et al., 1995). On the other hand, the antidepressant-like effects of the same drugs apparently involve the selective stimulation of 5-HT_1A receptors located in postsynaptic areas with respect to serotoninergic projections, such as the septum (Martin et al., 1990). Indeed, important differences have been noted between the respective pharmacological, biochemical and regulatory properties of 5-HT_1A receptors depending on their location in the anterior raphe nuclei or postsynaptic target areas of serotoninergic neurones, which led some authors to postulate the existence of 5-HT_1A receptor subtypes (Blier et al., 1993; Clarke et al., 1996). Different subtypes would be expressed in the raphe nuclei and the hippocampus for instance, thereby explaining why spiperone and (−)-pindolol efficiently block the effects of 5-HT_1A receptor agonists in the former but not the latter area (Blier et al., 1993; Romero et al., 1996).

Among drugs which exhibit differential actions at 5-HT_1A receptors in the raphe nuclei on one hand and postsynaptic target areas of serotoninergic neurones on the other hand, the potent agonist alnespirone (S-20499, (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro-(4,5)-decane-7,9-dione) has been the matter of special interest (Porsolt et al., 1992; Kidd et al., 1993). As expected of its agonist action at somatodendritic 5-HT_1A autoreceptors in the dorsal raphe nucleus, alnespirone produced a marked inhibition of the firing of serotoninergic neurones, and a decrease in 5-HT release and turnover in their projection areas (Kidd et al., 1993). Furthermore, relevant behavioural paradigms clearly demonstrated that alnespirone exhibits anxiolytic-like properties through its stimulatory effect at 5-HT_1A autoreceptors (Griebel et al., 1992; Barrett et al., 1994; Curle et al., 1994). However, in contrast to other 5-HT_1A receptor agonists such as 8-OH-DPAT, alnespirone does not cause the `5-HT syndrome' which normally results from the stimulation of postsynaptic 5-HT_1A receptors (Scott et al., 1994). Furthermore, alnespirone was shown to neither mimic nor attenuate the forepaw treading due to 5-HT_1A receptor stimulation in reserpine-pretreated rats (Scott et al., 1994), therefore suggesting that this drug does not interact with the postsynaptic 5-HT_1A receptors responsible for this behavioural effect.

Because of its differential actions at 5-HT_1A receptors in the raphe nuclei versus postsynaptic target areas of serotoninergic projections, alnespirone should be especially useful for investigating further the respective properties of pre (i.e., somatodendritic)- and post-synaptic 5-HT_1A receptors. On this basis, [ $^{3} H$ ]alnespirone was synthesized and used as a radioligand for the characterization of the pharmacological properties and regional distribution of corresponding specific binding sites in comparison with 5-HT_1A receptors identified with [ $^{3} H$ ]8-OH-DPAT as the prototypical radioligand (Marcinkiewicz et al., 1984; Hall et al., 1985).

Section snippets

Animals

Experiments were performed on adult male Sprague-Dawley rats (three months old, 250–300 g body weight, Centre d'Elevage R. Janvier, Le Genest-St. Isle, France). They were kept under controlled environmental conditions (12 h light–dark cycle, 21±1°C, 60% relative humidity, food and water ad libitum) for at least 7 days before being used for the experiments.

All the procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance

Effect of temperature

As shown in Fig. 1, the specific binding of both radioligands increased as a function of temperature between 4°C and 20–25°C. A decrease in the specific binding was then observed at higher temperatures, and this effect was more pronounced with [ $^{3} H$ ]8-OH-DPAT (−78% at 40°C compared to 20°C) than with [ $^{3} H$ ]alnespirone (−34% at 40°C compared to 20°C). Subsequent assays were performed at 25°C to ensure optimal binding of [ $^{3} H$ ]alnespirone. Under this condition, the non-specific binding amounted to less

Discussion

The present study shows that [ $^{3} H$ ]alnespirone binds with high affinity to a homogeneous population of specific sites in the rat brain. Extensive characterization of these sites indicates that they correspond to 5-HT_1A receptors previously identified using the selective agonist radioligand [ $^{3} H$ ]8-OH-DPAT (Gozlan et al., 1983; Hall et al., 1985).

As expected from the labeling of the same receptor population, the regional distribution of high affinity [ $^{3} H$ ]alnespirone specific binding sites matched

Acknowledgements

This research has been supported by grants from INSERM, DRET (Contract No. 95/142) and IRIS. The excellent technical and secretarial assistance of C.M. Fattaccini and C. Sais, respectively, is gratefully acknowledged. We are grateful to the Institut de Recherches Internationales Servier and the Service des Molécules Marquées of CEA for their generous gifts of [ $^{3} H$ ]alnespirone and [ $^{3} H$ ]8-OH-DPAT, respectively. The generous gifts of drugs by pharmaceutical companies (Bristol-Myers Squibb, Esteve,

References (38)

M.B Emerit et al.
Physical evidence of the coupling of solubilized 5-HT_1A binding sites with G regulatory proteins
Biochem. Pharmacol.
(1990)
H Gozlan et al.
The selective 5-HT_1A antagonist radioligand [ $^{3} H$ ]WAY 100635 labels both G-protein-coupled and free 5-HT_1A receptors in rat brain membranes
Eur. J. Pharmacol.
(1995)
X Khawaja
Quantitative autoradiographic characterisation of the binding of [ $^{3} H$ ]WAY-100635, a selective 5-HT_1A receptor antagonist
Brain Res.
(1995)
O.H Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
M Marcinkiewicz et al.
Autoradiographic evidence for the heterogeneity of 5-HT₁ sites in the rat brain
Brain Res.
(1984)
P Martin et al.
Antidepressant-like action of 8-OH-DPAT, a 5-HT_1A agonist, in the learned helplessness paradigm: Evidence for a postsynaptic mechanism
Behav. Brain Res.
(1990)
J.G Mulheron et al.
Human 5-HT_1A receptor expressed in insect cells activates endogenous Go-like G-protein(s)
J. Biol. Chem.
(1994)
A Pazos et al.
Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors
Brain Res.
(1985)
F Radja et al.
Autoradiography of serotonin receptor subtypes in the central nervous system
Neurochem. Int.
(1991)
L Romero et al.
Effect of pindolol on the function of pre- and postsynaptic 5-HT_1A receptors: In vivo microdialysis and electrophysiological studies in the rat brain
Neuropsychopharmacology
(1996)

J.E Barrett et al.

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT_1A agonist, S 20244 and its enantiomers (+)S 20499 and (−)S 20500

Psychopharmacology

(1994)

P Blier et al.

Differential properties of presynaptic and postsynaptic 5-hydroxytryptamine_1A receptors in the dorsal raphe and hippocampus: I Effect of spiperone

J. Pharmacol. Exp. Ther.

(1993)

Y.C Cheng et al.

Relationship between the inhibition constant K_i and the concentration of inhibitor which causes 50% inhibition (IC₅₀) of an enzymatic reaction

Biochem. Pharmacol.

(1973)

W.P Clarke et al.

Lack of 5-hydroxytryptamine_1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats

J. Pharmacol. Exp. Ther.

(1996)

F.C Colpaert et al.

S14506: A novel, potent, high-efficacy 5-HT_1A agonist and potential anxiolytic agent

Drug. Dev. Res.

(1992)

R.F Cox et al.

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT_1A agonists

Synapse

(1993)

P.F Curle et al.

Anxiolytic properties of (+)S 20499, a novel serotonin 5-HT_1A full agonist, in the elevated plus-maze and social interaction tests

Drug Dev. Res.

(1994)

J Glowinski et al.

Regional studies of catecholamines in the rat brain. I. Disposition of $^{3} H$ -norepinephrine, $^{3} H$ -dopamine and $^{3} H$ -dopa in various regions of the brain

J. Neurochem.

(1966)

H Gozlan et al.

Identification of presynaptic serotonin autoreceptors using a new ligand: $^{3} H$ -PAT

Nature

(1983)

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Citation Excerpt :
Consistent with its agonist actions at selective postsynaptic 5-HT1A receptors, alnespirone induces hypothermia (Scott et al., 1994; de Boer et al., 2000) and stimulates the release of ACTH and corticosterone (Levy et al., 1995; own unpublished findings) as has been reported for repinotan, and OHDPAT, buspirone, ipsapirone and eltoprazine as well (Millan et al., 1993; own unpublished observations). However, in contrast to the other 5-HT1A receptor agonists, alnespirone does not seem to interact with the postsynaptic 5-HT1A receptors that are responsible for inducing the 5-HT behavioral syndrome since alnespirone up to high doses does not cause any of the signs and symptoms of this (Scott et al., 1994; Fabre et al., 1997). Consistent with its antagonistic actions at postsynaptic 5-HT1A receptors, S-15535 dose-dependently and completely blocks postsynaptically mediated behavioral physiological responses like spontaneous tail-flicks, flat-body posture, and hypothermia (Millan et al., 1997b; de Boer et al., 2000).
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Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT_1A) receptors, both in receptor binding and in mRNA levels, in the aggressive line [Brain Res 736 (1996) 338]. The aim of this experiment was to study whether similar differences in 5-HT_1A receptors exist in individuals from a random-bred rat strain, varying in aggressiveness. In addition, because little is known about the functional consequences of these receptor differences, a response mediated via postsynaptic 5-HT_1A receptors (i.e., hypothermia) was studied both in the selection lines of mice and in the randomly bred rats. The difference in receptor binding, as demonstrated in mice previously, could not be shown in rats. However, both in rats and mice, the hypothermic response to the 5-HT_1A agonist alnespirone was larger in aggressive individuals. So, in the rat strain as well as in the mouse lines, there is, to a greater or lesser extent, an enhanced sensitivity of postsynaptic 5-HT_1A receptors in aggressive individuals. This could be a compensatory up-regulation induced by a lower basal 5-HT neurotransmission, which is in agreement with the serotonin deficiency hypothesis of aggression.
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2000, Neuropsychopharmacology
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[3H]Alnespirone: A novel specific radioligand of 5-HT1A receptors in the rat brain

Abstract

Introduction

Section snippets

Animals

Effect of temperature

Discussion

Acknowledgements

Biochem. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

J. Biol. Chem.

Brain Res.

Behav. Brain Res.

J. Biol. Chem.

Brain Res.

Neurochem. Int.

Neuropsychopharmacology

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, S 20244 and its enantiomers (+)S 20499 and (−)S 20500

Psychopharmacology

Differential properties of presynaptic and postsynaptic 5-hydroxytryptamine1A receptors in the dorsal raphe and hippocampus: I Effect of spiperone

J. Pharmacol. Exp. Ther.

Relationship between the inhibition constant Ki and the concentration of inhibitor which causes 50% inhibition (IC50) of an enzymatic reaction

Biochem. Pharmacol.

Lack of 5-hydroxytryptamine1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats

J. Pharmacol. Exp. Ther.

S14506: A novel, potent, high-efficacy 5-HT1A agonist and potential anxiolytic agent

Drug. Dev. Res.

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists

Synapse

Anxiolytic properties of (+)S 20499, a novel serotonin 5-HT1A full agonist, in the elevated plus-maze and social interaction tests

Drug Dev. Res.

Regional studies of catecholamines in the rat brain. I. Disposition of 3H-norepinephrine, 3H-dopamine and 3H-dopa in various regions of the brain

J. Neurochem.

Identification of presynaptic serotonin autoreceptors using a new ligand: 3H-PAT

Nature

[ $^{3} H$ ]Alnespirone: A novel specific radioligand of 5-HT_1A receptors in the rat brain

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT_1A agonist, S 20244 and its enantiomers (+)S 20499 and (−)S 20500

Differential properties of presynaptic and postsynaptic 5-hydroxytryptamine_1A receptors in the dorsal raphe and hippocampus: I Effect of spiperone

Relationship between the inhibition constant K_i and the concentration of inhibitor which causes 50% inhibition (IC₅₀) of an enzymatic reaction

Lack of 5-hydroxytryptamine_1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats

S14506: A novel, potent, high-efficacy 5-HT_1A agonist and potential anxiolytic agent

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT_1A agonists

Anxiolytic properties of (+)S 20499, a novel serotonin 5-HT_1A full agonist, in the elevated plus-maze and social interaction tests

Regional studies of catecholamines in the rat brain. I. Disposition of $^{3} H$ -norepinephrine, $^{3} H$ -dopamine and $^{3} H$ -dopa in various regions of the brain

Identification of presynaptic serotonin autoreceptors using a new ligand: $^{3} H$ -PAT