Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autorecept...
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Published in | The Journal of neuroscience Vol. 39; no. 8; pp. 1334 - 1346 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
20.02.2019
|
Subjects | |
Online Access | Get full text |
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Summary: | Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (
) were tested for response to SSRIs. Tamoxifen-induced recombination in adult
mice specifically reduced 5-HT1A autoreceptor levels. The
mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in
mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type (
) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of
but not
mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB
cells were quantified. FosB
cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of
mice, suggesting increased raphe activation. In
but not
mice, FLX reduced FosB
cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment.
Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: V.T.-C., F.V.-A., and P.R.A. wrote the first draft of the paper; V.T.-C., F.V.-A., C.L., M.D., S.D.G., K.F.T., R.H., J.J., Z.M., J.-C.B., and P.R.A. edited the paper; V.T.-C., F.V.-A., C.L., S.D.G., and P.R.A. designed research; V.T.-C., F.V.-A., C.L., M.D., S.D.G., and J.J. performed research; K.F.T. and R.H. contributed unpublished reagents/analytic tools; V.T.-C., F.V.-A., C.L., M.D., S.D.G., J.J., Z.M., J.-C.B., and P.R.A. analyzed data; P.R.A. wrote the paper. |
ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/jneurosci.0352-18.2018 |