Open Access Dissertation
Date of Award
Antidepressant drugs are widely used but their mechanism of action remains only partially understood. One leading hypothesis holds that a key effect of chronic treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) is loss of somatodendritic 5-HT1A receptor-mediated autoinhibition in serotonergic neurons of the dorsal raphe nucleus (DRN). However, technical limitations have prevented direct testing of this hypothesis. In the current study we took advantage of optogenetic strategies to assess the effects of the classic SSRI fluoxetine on 5-HT1A receptor-mediated autoinhibition. We conducted these experiments in mice expressing the light-sensitive ion channel Channelrhodopsin (ChR) in 5-HT neurons to facilitate their unambiguous identification and achieve precise temporal control over endogenous 5-HT release and 5-HT1A autoreceptor activation. Whole-cell intracellular recordings of DRN 5-HT neurons in in vitro brainstem slices revealed that light-induced 5-HT1A autoreceptor-mediated currents in chronically treated mice (14 days) were smaller in amplitude but longer in duration, thereby resulting in an overall greater charge transfer compared to controls. Consistent with this, 5-HT dose response curves constructed in the presence of bath fluoxetine also provided no evidence for a reduction in autoreceptor sensitivity. To test whether an attenuation of 5-HT clearance could potentially account for the alterations observed from chronic treatment, responses were compared to those obtained following acute or subchronic fluoxetine treatment (bath application or 3 days). In both conditions the 5-HT1AR Ilight responses resembled those of chronic treatment and differed substantially from controls, suggesting that reduced 5-HT reuptake was likely to be a contributing factor. Collectively, instead of autoreceptor desensitization, our results suggest that the 5-HT1A autoreceptor-mediated signal is actually preserved after chronic SSRI treatment.
Mcgregor, Kelly Marie, "Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment" (2015). Wayne State University Dissertations. 1316.