Browsing by Subject "Serotonin transporter"

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    Crh receptor priming in the bed nucleus of the stria terminalis induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety
    (Elsevier, 2020-01-10) Donner, Nina C.; Mani, Sofia; Fitz, Stephanie D.; Kienzle, Drake M.; Shekhar, Anantha; Lowry, Christopher A.; Psychiatry, School of Medicine
    The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1% bovine serum albumin in 0.9% saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior.
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    Serotonin Transporter Regulation by Cholesterol-Independent Lipid Signaling
    (Elsevier, 2021) Deveau, Carmen M.; Rodriguez, Eric; Schroering, Allen; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    Serotonin neurotransmission is largely governed by the regulation of the serotonin transporter (SERT). SERT is modulated in part by cholesterol, but the role of cholesterol and lipid signaling intermediates in regulating SERT are unknown. Serotonergic neurons were treated with statins to decrease cholesterol and lipid signaling intermediates. Contrary to reported decreases in 5-HT uptake after cholesterol depletion, biochemical and imaging methods both showed that statins increased 5-HT uptake in a fluoxetine-dependent manner. Simvastatin lowered the Km without changing Vmax for 5-HT or SERT distribution to the plasma membrane. Cholesterol repletion did not block enhanced 5-HT uptake by simvastatin but the enhanced uptake was blocked by lipid isoprenylation intermediates farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Blockade of geranylgeranylation alone without statins also enhanced 5-HT uptake. Overall, this study revealed a specific neuronal effect of statin drugs and identified lipid signaling through geranylgeranylation within the isoprenylation pathway regulates SERT in a cholesterol-independent manner.