The role of 5-HT1A autoreceptors and α1-adrenoceptors in the modulation of 5-HT release—III. Clozapine and the novel putative antipsychotic S 16924

Bengtsson, Henrik; Kullberg, Anders; Millan, Mark J.; Stephan, Holger

doi:10.1016/s0028-3908(98)00017-3

Cited by 15 publications

(6 citation statements)

References 26 publications

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“…The basal 5-HT levels in the samples collected from the Ringer solution-perfused rats were about 5-6 times lower (6.3 fmol/20 Al) than those measured in the rats perfused with Ringer/1 AM citalopram (36.1 fmol/20 Al) at the same experimental conditions, which is in agreement with previous data (Bengtsson et al, 1998). The reduction of hippocampal 5-HT induced by (R,S)-8-OH-DPAT was attenuated at 20 and 40 min by the presence of 1 AM citalopram in the Ringer solution when compared to the Ringer-only perfused group, as shown in Fig.…”

Section: Discussionsupporting

confidence: 92%

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

Yoshitake

Kehr

2004

Life Sciences

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Section: Discussionsupporting

confidence: 92%

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

Yoshitake

Kehr

2004

Life Sciences

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“…A moderate affinity was however found at α 1 -adrenoceptors, although they were weaker ligands than the reference compound, prazosin, by at least 1 order of magnitude (Table ). Microdialysis studies with compounds that exhibit a dual activity at α 1 and 5-HT 1A receptors have shown that α 1 -adrenoceptor-mediated enhancement in 5-HT release is counteracted by simultaneous activation of somatodendritic 5-HT 1A receptors. , Yet, it is known that the role of α 1 -adrenoceptors in the control of extracellular 5-HT levels is shadowed when drugs, such as BMY 7378 and S 16924, which are also active at presynaptic 5-HT 1A receptors, are given systemically. , Probably, this would be also the case with compounds 12f and 28a , b . It is well-known, on the other hand, that the better safety profile of SSRIs over TCAs is due to the lack of anticholinergic and cardiovascular side effects, derived from the blockade of muscarinic and α 1 -adrenergic receptors, respectively .…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…Microdialysis studies with compounds that exhibit a dual activity at R 1 and 5-HT 1A receptors have shown that R 1 -adrenoceptor-mediated enhancement in 5-HT release is counteracted by simultaneous activation of somatodendritic 5-HT 1A receptors. 37,38 Yet, it is known that the role of R 1 -adrenoceptors in the control of extracellular 5-HT levels is shadowed when drugs, such as BMY 7378 and S 16924, which are also active at presynaptic 5-HT 1A receptors, are given systemically. 38,39 Probably, this would be also the case with compounds 12f and 28a,b.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives, with Dual Action at 5-HT_1ASerotonin Receptors and Serotonin Transporter, as a New Class of Antidepressants

et al. 2000

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In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.

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“…However, because 5‐HT 1A receptor‐mediated inhibition of raphé cell firing dominates over α 1 receptor‐mediated stimulation of raphé cells (Gartside et al . 1997; Bengtsson et al . 1998), fluoxetine administration suppresses raphé cell firing in normal animals, an effect that is reversed by 5‐HT 1A antagonist administration (Gartside et al .…”

Section: Discussionmentioning

confidence: 99%

5‐HT_1A receptor mutant mice exhibit enhanced tonic, stress‐induced and fluoxetine‐induced serotonergic neurotransmission

Parsons

Kerr

Tecott

2001

Journal of Neurochemistry

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Mutant mice that lack serotonin 1A receptors exhibit enhanced anxiety-related behaviors, a phenotype that is hypothesized to result from impaired autoinhibitory control of midbrain serotonergic neuronal ®ring. Here we examined the impact of serotonin 1A receptor deletion on forebrain serotonin neurotransmission using in vivo microdialysis in the frontal cortex and ventral hippocampus of serotonin 1A receptor mutant and wild-type mice. Baseline dialysate serotonin levels were signi®cantly elevated in mutant animals as compared with wild-types both in frontal cortex (mutant 0.44^0.05 nM; wild-type 0.28^0.03 nM) and hippocampus (mutant 0.46^0.07 nM; wild-type 0.27^0.04 nM). A stressor known to elicit enhanced anxiety-like behaviors in serotonin 1A receptor mutants increased dialysate 5-HT levels in the frontal cortex of mutant mice by 144% while producing no alteration in cortical 5-HT in wild-type mice. There was no phenotypic difference in the effect of this stressor on serotonin levels in the hippocampus. Fluoxetine produced signi®cantly greater increases in dialysate 5-HT content in serotonin 1A receptor mutants as compared with wild-types, with two-and three-fold greater responses being observed in the hippocampus and frontal cortex, respectively. This phenotypic effect was mimicked in wild-types by pretreatment with the serotonin Brain serotonin (5-HT) system function has been implicated in the pathophysiology and treatment of a wide variety of neuropsychiatric disorders (Graeff et al. 1996). A heterogeneous family of at least 14 distinct receptor subtypes mediates the effects of serotonin in the central nervous system. Among these, 5-HT 1A receptors have received particular attention as a possible target for the treatment of affective disorders such as anxiety and depression (Briner and Dodel 1998;Apter and Allen 1999).5-HT 1A receptors have a nanomolar af®nity for 5-HT and when activated these receptors inhibit adenylate cyclase formation through a G protein-linked mechanism (Hoyer et al. 1994). Central 5-HT 1A receptors are located both preand postsynaptically. Presynaptic 5-HT 1A receptors are localized on serotonergic cell bodies in the dorsal and median raphe Â nuclei (DRN and MRN, respectively) and provide strong inhibitory control over the activity of these neurons (Blier and Montigny 1987;Sprouse and Aghajanian 1987). Serotonin neurons of the DRN and MRN provide the majority of forebrain serotonergic afferents, and thus presynaptic 5-HT 1A receptors located in these structures may play a pivotal role in the regulation of central 5-HT function. Accordingly, 5-HT 1A autoreceptors have been

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The role of 5-HT1A autoreceptors and α1-adrenoceptors in the modulation of 5-HT release—III. Clozapine and the novel putative antipsychotic S 16924

Cited by 15 publications

References 26 publications

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives, with Dual Action at 5-HT_1ASerotonin Receptors and Serotonin Transporter, as a New Class of Antidepressants

5‐HT_1A receptor mutant mice exhibit enhanced tonic, stress‐induced and fluoxetine‐induced serotonergic neurotransmission

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The role of 5-HT1A autoreceptors and α1-adrenoceptors in the modulation of 5-HT release—III. Clozapine and the novel putative antipsychotic S 16924

Cited by 15 publications

References 26 publications

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives, with Dual Action at 5-HT1ASerotonin Receptors and Serotonin Transporter, as a New Class of Antidepressants

5‐HT1A receptor mutant mice exhibit enhanced tonic, stress‐induced and fluoxetine‐induced serotonergic neurotransmission

Contact Info

Product

Resources

About

New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives, with Dual Action at 5-HT_1ASerotonin Receptors and Serotonin Transporter, as a New Class of Antidepressants

5‐HT_1A receptor mutant mice exhibit enhanced tonic, stress‐induced and fluoxetine‐induced serotonergic neurotransmission