title: 5-HT(1A)-receptor over-expressing mice: genotype and sex dependent responses to antidepressants in the forced swim-test.
abstract: Deficiencies in serotonergic neurotransmission are involved in the pathophysiology of depression. Due to its modulatory effect on serotonin (5-HT) release, the 5-HT(1A)-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-HT(1A)-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-HT(1A)-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-HT(1A)-receptors in discrete corticolimbic regions was determined in detail by quantitative autoradiography with [(3)H]8-OH-DPAT to investigate genotype as well as sex dependent differences in the expression pattern. [(3)H]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-HT(1A)-receptors in the FST behaviour. In addition, the selective over-expression of postsynaptic 5-HT(1A)-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-HT(1A)-receptors in the effects of SSRIs.
authors.affiliation: AG Neurobiology, Clinic for Psychiatry, Universitätsklinikum der TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Günther
authors.forename: Julia
authors.initials: J
authors.lastname: Rothe
authors.forename: André
authors.initials: A
authors.lastname: Rex
authors.forename: Jörg-Peter
authors.initials: JP
authors.lastname: Voigt
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Heidrun
authors.initials: H
authors.lastname: Fink
authors.forename: Bettina
authors.initials: B
authors.lastname: Bert
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000009:adverse effects / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy*; D005260:Female; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009928:Organ Specificity; D000077593:Reboxetine; D044282:Receptor, Serotonin, 5-HT1A / Q000096:biosynthesis* / Q000235:genetics; D058825:Serotonin 5-HT1 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D012727:Sex Characteristics
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D015283:Citalopram; D009025:Morpholines; D009419:Nerve Tissue Proteins; D000077593:Reboxetine; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors