5-HT1A-receptor over-expressing mice: Genotype and sex dependent responses to antidepressants in the forced swim-test

NEUROPHARMACOLOGY

卷:61

Article

Guenther, Lydia²  Rothe, Julia¹  Rex, Andre^3,4  Voigt, Joerg-Peter⁵  Millan, Mark J.⁶  Fink, Heidrun¹  Bert, Bettina¹ 

[1] Free Univ Berlin, Inst Pharmacol & Toxicol, Sch Vet Med, D-14195 Berlin, Germany

[2] Univ Klinikum TU Dresden, AG Neurobiol, Psychiat Clin, D-01307 Dresden, Germany

[3] Charite, Dept Expt Neurol, D-10117 Berlin, Germany

[4] Charite, Ctr Stroke Res CSB, D-10117 Berlin, Germany

[5] Univ Nottingham, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England

[6] Inst Rech Servier, Dept Psychopharmacol, F-78290 Paris, France

关键词: 5-HT1A-receptor;    Buspirone;    Citalopram;    Depression;    Forced swim;    Over-expression;    Postsynaptic;    Reboxetine;    S 15535;   

DOI  :  10.1016/j.neuropharm.2011.03.004

来源: Elsevier

【 摘 要 】

Deficiencies in serotonergic neurotransmission are involved in the pathophysiology of depression. Due to its modulatory effect on serotonin (5-HT) release, the 5-HT1A-receptor is thought to play a decisive role in the therapy of this mood disorder. However, it is not fully understood how antidepressant effects are mediated by pre- and postsynaptic receptor sites. In this study we examined the impact of postsynaptic 5-HT1A-receptor over-expression in corticolimbic areas of male and female mice on the performance in the forced swim-test (FST). Furthermore, we investigated their response to the serotonin selective reuptake inhibitor (SSRI) citalopram in comparison to the selective noradrenaline reuptake inhibitor reboxetine, as well as the partial 5-HT1A-receptor agonists, buspirone and S 15535. Additionally, these drugs were evaluated in the open field-test in order to observe effects on motor activity. The density of 5-HTm-receptors in discrete corticolimbic regions was determined in detail by quantitative autoradiography with [H-3]8-OH-DPAT to investigate genotype as well as sex dependent differences in the expression pattern. [H-3]8-OH-DPAT binding differed depending on sex with female mice of both genotypes displaying higher receptor binding in distinct brain areas. In the FST untreated male but not female over-expressing (OE) mice showed an antidepressant-like behaviour compared to wild-type (WT) mice. Citalopram yielded an antidepressant effect without influencing locomotor activity in OE mice but not in WT mice. Reboxetine had no antidepressant-like effect in OE mice, but sex-dependently in WT mice. The two partial agonists, buspirone and S 15535 produced no antidepressant-like activity in both genotypes and sexes, but aberrant motor effects. The antidepressant-like phenotype of male transgenic mice accounts for an involvement of postsynaptic 5-HT1A-receptors in the FST behaviour. In addition, the selective over-expression of postsynaptic 5-HT1A-receptors in mice contributes to the antidepressant response to citalopram in the FST. Although further pharmacological analysis is required, the data provide novel support for a role of postsynaptic 5-HT1A-receptors in the effects of SSRIs. This article is part of a Special Issue entitled 'Serotonin: The New Wave'. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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