Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P08908 (
5-HT1A
)
5,574
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 (
1AcKO
) were tested for response to SSRIs.
Tamoxifen
-induced recombination in adult
1AcKO
mice specifically reduced
5-HT1A
autoreceptor levels. The
1AcKO
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
1AcKO
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 (
WT
) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of
1AcKO
but not
WT
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
1AcKO
mice, suggesting increased raphe activation. In
WT
but not
1AcKO
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.
SIGNIFICANCE STATEMENT
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.
...
PMID:Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment. 3055 80
