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September 14, 2026StressOpen Access

Chronic stress persistently upregulates hippocampal histamine H1 and H2 receptors: dissociation from behavioral recovery with fluoxetine and exercise

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Why the study?

Does fluoxetine and/or exercise improve behavioral dysfunction and normalize hippocampal histamine receptor expression in a rat model of chronic stress?

Population

Male Wistar rats exposed to four weeks of chronic unpredictable mild stress (CUMS)

Comparison

Fluoxetine, treadmill exercise, or combined… vs Control (no CUMS) and CUMS without treatment

Design

Preclinical

Follow-up

4 weeks

Key result

Fluoxetine and exercise improved anxiety- and depression-like behaviors in a chronic stress rat model, but failed to fully reverse stress-induced elevations in hippocampal H1 and H2 receptors.

Authors

MYMahdi YousefiSMSahel MotaghiMAMehdi Abbasnejad

Discussion

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Overview

Rat model findings require human confirmation before any clinical consideration; leaves open necessity of reversing hippocampal H1/H2 elevations for behavioral recovery.

Key Points

  • Investigate the individual and combined effects of fluoxetine and treadmill exercise on depressive- and anxiety-like behaviors alongside hippocampal histamine H1 and H2 receptor expression in chronically stressed rats.
  • Assigned male Wistar rats exposed to 4 weeks of chronic unpredictable mild stress (CUMS) to seven groups: Control, CUMS, Exercise (EXC), Fluoxetine (FLX), CUMS+EXC, CUMS+FLX, and CUMS+FLX+EXC.
  • Evaluated anxiety-like and depressive-like behaviors using the open field test (OFT), elevated plus maze (EPM), and forced swim test (FST).
  • Quantified ventral hippocampal histamine H1 and H2 receptor mRNA expression levels using real-time PCR.
  • CUMS significantly increased depressive- and anxiety-like behaviors; fluoxetine significantly reduced immobility in the FST, and combined fluoxetine with exercise increased open-arm exploration in the EPM.
  • CUMS significantly upregulated ventral hippocampal H1 and H2 receptor mRNA expression compared with non-stressed controls.
  • Neither fluoxetine nor exercise monotherapy reversed stress-induced receptor elevations; combined treatment partially attenuated H1 receptor upregulation, while H2 receptor levels remained elevated across all groups.

Structured PICO

Does fluoxetine and/or exercise improve behavioral dysfunction and normalize hippocampal histamine receptor expression in a rat model of chronic stress?

P
Population
Male Wistar rats exposed to four weeks of chronic unpredictable mild stress to evaluate the effects of fluoxetine and exercise.
I
Intervention
Fluoxetine, treadmill exercise, or combined fluoxetine and exercise
C
Comparator
Control (no CUMS) and CUMS without treatment
O
Outcome
Anxiety-like behavior (EPM, OFT), depressive-like behavior (FST), and hippocampal H1 and H2 receptor mRNA levelssurrogate

Chronic stress induces persistent hippocampal histaminergic remodeling in rats that is not fully reversed by fluoxetine or exercise despite behavioral improvements.

Cite This Study

Yousefi et al. (2026) studied Chronic unpredictable mild stress (CUMS). Fluoxetine and treadmill exercise vs. Control and CUMS alone was evaluated on Anxiety-like behavior, depressive-like behavior, and hippocampal H1 and H2 receptor mRNA levels. Fluoxetine and exercise improved anxiety- and depression-like behaviors in a chronic stress rat model, but failed to fully reverse stress-induced elevations in hippocampal H1 and H2 receptors.

synapsesocial.com/papers/6aa7afef79e9260bc85aac76https://doi.org/10.1080/10253890.2026.2731037
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