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Antidepressant effects on kinase gene expression patterns in rat brain
J L Rausch1, C F Gillespie, Y Fei
1Veterans Administration, Medical College of Georgia, Augusta, GA 30912, USA. jeffreyr@mail.mcg.edu
Abstract:
Multiple kinase pathways determine serotonin transporter (SERT) regulation. We hypothesized a decrease in kinase expression with chronic selective serotonin reuptake inhibitor (SSRI) administration necessary to regulate extracellular serotonin. We studied whole brain kinase mRNA expression on Affymetrix gene chips in rats treated with placebo 3 and 21 days, fluoxetine 3 and 21 days, and citalopram 21 days. Protein kinase C (PKC)-delta, PKC-gamma, stress-activated protein kinase, cAMP-dependent protein kinase beta isoform, Janus protein kinase, and phosphofructokinase M were all down regulated chronically with citalopram and fluoxetine, but not with acute fluoxetine. The results are consistent with homeostasis of SERT function through a decrease in PK expression.
Insights
Chronic SSRI treatment downregulates specific protein kinases (PKs) involved in serotonin transporter (SERT) regulation. This decrease in PK expression may represent a homeostatic mechanism to manage extracellular serotonin levels.
Area of Science:
- Neuropharmacology
- Molecular Biology
- Biochemistry
Background:
- Serotonin transporter (SERT) regulates extracellular serotonin levels.
- Multiple kinase pathways are implicated in SERT regulation.
- Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants.
Purpose of the Study:
- To investigate the hypothesis that chronic SSRI administration decreases kinase expression.
- To understand the role of kinase downregulation in SERT homeostasis.
Main Methods:
- Whole brain kinase mRNA expression was analyzed using Affymetrix gene chips in rats.
- Rats were treated with placebo, fluoxetine (acute and chronic), or citalopram (chronic).
Main Results:
- Chronic fluoxetine and citalopram treatment led to the downregulation of specific kinases, including Protein Kinase C (PKC)-delta and -gamma, stress-activated protein kinase, cAMP-dependent protein kinase beta isoform, Janus protein kinase, and phosphofructokinase M.
- Acute fluoxetine treatment did not result in significant kinase downregulation.
- These changes were observed after 21 days of chronic treatment.
Conclusions:
- The findings support the hypothesis that chronic SSRI administration downregulates key protein kinases.
- This downregulation of protein kinases is consistent with a homeostatic mechanism for regulating SERT function and extracellular serotonin.
