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Chronic fluoxetine or desmethylimipramine treatment alters 5-HT2 receptor mediated c-fos gene expression
N Tilakaratne1, Z Yang, E Friedman
1Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Abstract:
These studies examined the effects of a 21-day treatment regime with either the tricyclic antidepressant, desmethylimipramine (DMI), or the selective 5-HT uptake inhibitor, fluoxetine, on 5-HT2 receptors in rat brain, as assessed by selective agonist-mediated c-fos gene expression. Chronic, but not acute, treatment with fluoxetine (10 mg/kg, i.p. for 21 days) resulted in supersensitization of the response to an acute challenge (4 mg/kg, i.p.) with the selective 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), both in frontal cortex and in hippocampus. Chronic treatment with DMI (10 mg/kg, i.p. for 21 days) resulted in a significant desensitization of the response to DOI. These findings are discussed in relation to the possible modes of action of these two clinically useful agents.
Insights
Chronic fluoxetine treatment supersensitized rat brain 5-HT2 receptors, while desmethylimipramine desensitized them. These findings offer insights into antidepressant mechanisms of action.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and tricyclic antidepressants (TCAs) like desmethylimipramine (DMI) are widely used for depression.
- The precise mechanisms underlying their therapeutic effects, particularly concerning serotonin (5-HT) receptor regulation, are still under investigation.
Purpose of the Study:
- To investigate the chronic and acute effects of fluoxetine and DMI on 5-HT2 receptor function in rat brain.
- To assess the impact of these antidepressants on c-fos gene expression mediated by 5-HT2 receptor agonists.
Main Methods:
- Rats received daily intraperitoneal injections of fluoxetine (10 mg/kg) or DMI (10 mg/kg) for 21 days.
- Receptor sensitivity was assessed by measuring c-fos gene expression in response to an acute challenge with the 5-HT2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI).
- Experiments were conducted on frontal cortex and hippocampus tissues.
Main Results:
- Chronic fluoxetine treatment led to a significant supersensitization of 5-HT2 receptor-mediated responses to DOI in both frontal cortex and hippocampus.
- Acute fluoxetine treatment did not alter the response to DOI.
- Chronic DMI treatment resulted in a significant desensitization of 5-HT2 receptor-mediated responses to DOI.
Conclusions:
- Chronic administration of fluoxetine induces 5-HT2 receptor supersensitivity, suggesting a potential mechanism for its antidepressant effects.
- Chronic DMI administration leads to 5-HT2 receptor desensitization, indicating a different neuroadaptive response compared to fluoxetine.
- These differential effects on 5-HT2 receptors highlight distinct pharmacological profiles of SSRIs and TCAs.
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