5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants

Richardson-Jones, Jesse W.; Craige, Caryne P.; Guiard, Bruno P.; Stephen, Alisson; Metzger, Kristina B.; Kung, Hank F.; Gardier, Alain M.; Dranovsky, Alex; David, D. J.; Beck, Sheryl G.; Hen, René; Leonardo, E. David

doi:10.1016/j.neuron.2009.12.003

Cited by 395 publications

(436 citation statements)

References 63 publications

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“…Our results also agree with those found recently using conditional knockout mice for presynaptic 5-HT 1A R. 43 Both studies indicate that the selective -yet partialreduction of 5-HT 1A -autoreceptor expression with unchanged postsynaptic 5-HT 1A R expression evokes antidepressant-like behavior and augments SSRI effects.…”

Section: Discussionsupporting

confidence: 93%

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

et al. 2011

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Depression is a major health problem worldwide. Most prescribed antidepressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT 1A -autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders, as monotherapy or in combination with SSRI.3

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Section: Discussionsupporting

confidence: 93%

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

et al. 2011

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“…Our results show that decreases in 5-HT1A autoreceptors during development impact anxiety-related behaviors but not depression-related behaviors. In contrast, decreases in 5-HT1A autoreceptors in adulthood have no effect on anxiety-related behavior and result in lower levels of depression-related behaviors (Bortolozzi et al, 2012;Richardson-Jones et al, 2010). Thus, the temporal-and region-specific aspects of receptor variability, as impacted by either genetic or epigenetic factors, may have dissociable effects on psychiatric disease risk at different points of the life course, adding a layer of complexity to our understanding of psychiatric risk alleles.…”

Section: -Ht1a-mediated Anxiety Phenotypes Are Developmental In Originmentioning

confidence: 99%

“…Manipulation of 5-HT1A receptors at different time points has revealed a dissociable role for autoreceptor versus heteroreceptor populations during development and adulthood Richardson-Jones et al, 2011). In particular, whole life, but not adult-specific, suppression of autoreceptors leads to increased anxiety, a finding recently confirmed via RNAi knockdown of autoreceptors in adulthood (Bortolozzi et al, 2012;Richardson-Jones et al, 2010). In contrast, developmental suppression of forebrain heteroreceptors does not affect anxiety levels but appears to be important for modulating stress reactivity and depression-related behaviors (Richardson-Jones et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Donaldson

Piel

Santos

et al. 2013

Neuropsychopharmacol

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The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.

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“…One of the widely discussed causes is a polymorphism of 5-HT1A receptor-encoding gene, Htr1a [32,33]. A mechanism by which SSRI exert their antidepressant effects involves the desensitization of presynaptic 5-HT1A receptors due to the rise of the extracellular 5-HT [34][35][36][37].…”

Section: Fluoxetine Monotherapymentioning

confidence: 99%

“…A mechanism by which SSRI exert their antidepressant effects involves the desensitization of presynaptic 5-HT1A receptors due to the rise of the extracellular 5-HT [34][35][36][37]. It has been suggested that the ability of SSRI to desensitize presynaptic 5-HT1A receptors requires certain maximal level of their expression, and that individuals with the Htr1a C(-1019)G polymorphism (referred to as G/G allele carriers), are resistant to SSRI due to the previously described normal levels of these receptors [32,38]. At the same time, several studies failed to prove the association between this genetic trait and failure of SSRI to improve depression [39].…”

Section: Fluoxetine Monotherapymentioning

confidence: 99%

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

et al. 2012

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Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitaryadrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamopituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

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5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants

Cited by 395 publications

References 63 publications

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

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