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MacGillivray, 2011 Inhibition of the serotonin transporter induces microglial activation and downregulation of dopaminergic neurons in the substantia nigra.


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Synapse. 2011 Nov;65(11):1166-72. doi: 10.1002/syn.20954. Epub 2011 Jun 10.

Inhibition of the serotonin transporter induces microglial activation and downregulation of dopaminergic neurons in the substantia nigra.

MacGillivray L1, Reynolds KB, Sickand M, Rosebush PI, Mazurek MF.


Abstract at http://www.ncbi.nlm.nih.gov/pubmed/21584867#


Drugs that selectively inhibit the serotonin transporter (SERT) are widely used in the treatment of depression and anxiety disorders. These agents are associated with a range of extrapyramidal syndromes such as akathisia, dystonia, dyskinesia and parkinsonism, suggesting an effect on dopaminergic transmission. We studied the time course of changes in dopaminergic neurons in the substantia nigra (SN) after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (N = 9) or mixed with citalopram 5 mg/kg/day (N = 27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of SN were processed for tyrosine hydroxylase (TH) immunohistochemistry. Citalopram induced a significant decrease in TH-positive cell counts at 24 h (44%), 7 days (38%) and 28 days (33%). No significant differences among the citalopram treatment groups were observed in the SN. To determine whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28 day course of fluoxetine. As was observed with citalopram, fluoxetine induced a significant 21% reduction of TH cell counts in the SN. Immunoblot analysis showed that fluoxetine also induced a 45% reduction of striatal TH. To investigate a possible role for the innate immune system in mediating these changes, we also studied the microglial marker OX42 after administration of fluoxetine and noted a significant 63% increase in the SN of fluoxtine-treated animals. These results indicate that SERT inhibition can activate microglia and alter the regulation of TH, the rate limiting enzyme for dopamine biosynthesis. These changes may play a role in mediating the extrapyramidal side effects associated with SERT inhibitors.

Copyright © 2011 Wiley-Liss, Inc.


PMID: 21584867 [PubMed - indexed for MEDLINE]





The authors have presented a possible mechanism for EPS during (and, I will personally add, potentially after?) SSRI use.


Anyhow, authors of this study noted (as many others have), that SSRI use (yes, in rats) reduces tyrosine hydroxylase and therefore dopamine, in the substantia nigra. They examined acute as well as, importantly, chronic use, to come to this conclusion.


What makes this study different, in my opinion, is the emphasis of the immune system in inducing those changes. Previous studies I have read indicated that SSRI use decreased microglial activation. I would like to get my hands on the full text.


Also, I wonder what is in "rice pudding", Lol.

Edited by Altostrata
added lead author to title, link to Pubmed

April / 2016: Cipralex 10 mg, Mirtazapine 30 mg, Lyrica 600 mg, Diazepam 20 mg, Bystolic 5 mg

2018: Lots of polypharmacy which is undocumented here. Started and stopped several drugs and changed doses of existing ones

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September 2018: Cipralex 15 mg -> 12.5 mg

October 2018: Cipralex 12.5 mg -> 10 mg, Mirtazapine 7.5 mg -> 3.75 mg -> Stopped, Diazepam 15 mg

November 2019: Cipralex 5 mg, Diazepam 10 mg

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