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Updated: May 6, 2026
The Forced Swim Test as a Model of Depressive-like Behavior
Published on: March 2, 2015
Depressive behavior in the forced swim test can be induced by TRPV1 receptor activity and is dependent on NMDA
Ramy E Abdelhamid1, Katalin J Kovács1, Myra G Nunez1
1Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA.
Abstract:
Blocking, desensitizing, or knocking out transient receptor potential vanilloid type 1 (TRPV1) receptors decreases immobility in the forced swim test, a measure of depressive behavior. We questioned whether enhancing TRPV1 activity promotes immobility in a fashion that is prevented by antidepressants. To test this we activated heat-sensitive TRPV1 receptors in mice by water that is warmer than body temperature (41 °C) or a low dose of resiniferatoxin (RTX). Water at 41 °C elicited less immobility than cooler water (26 °C), indicating that thermoregulatory sites do not contribute to immobility. Although a desensitizing regimen of RTX (3-5 injections of 0.1 mg/kg s.c.) decreased immobility during swims at 26 °C, it did not during swims at 41 °C. In contrast, low dose of RTX (0.02 mg/kg s.c.) enhanced immobility, but only during swims at 41 °C. Thus, activation of TRPV1 receptors, endogenously or exogenously, enhances immobility and these sites are activated by cold rather than warmth. Two distinct types of antidepressants, amitriptyline (10mg/kg i.p.) and ketamine (50 mg/kg i.p.), each inhibited the increase in immobility induced by the low dose of RTX, verifying its mediation by TRPV1 sites. When desensitization was limited to central populations using intrathecal injections of RTX (0.25 μg/kg i.t.), immobility was attenuated at both temperatures and the increase in immobility produced by the low dose of RTX was inhibited. This demonstrates a role for central TRPV1 receptors in depressive behavior, activated by conditions (cold stress) distinct from those that activate TRPV1 receptors along thermosensory afferents (heat).
Insights
Activating transient receptor potential vanilloid type 1 (TRPV1) receptors enhances immobility, a sign of depression. Antidepressants block this effect, suggesting TRPV1 plays a role in depressive behavior, particularly in the central nervous system.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Transient receptor potential vanilloid type 1 (TRPV1) receptors are implicated in pain and temperature sensation.
- TRPV1 receptor activity is inversely correlated with immobility in the forced swim test, a common measure of depressive behavior.
Purpose of the Study:
- To investigate whether enhancing TRPV1 receptor activity promotes depressive-like behavior (immobility).
- To determine if antidepressants can prevent TRPV1-mediated increases in immobility.
Main Methods:
- Mice were exposed to warm water (41 °C) or treated with resiniferatoxin (RTX) to activate TRPV1 receptors.
- Immobility was measured in the forced swim test.
- The effects of antidepressants (amitriptyline, ketamine) and central TRPV1 desensitization (intrathecal RTX) on immobility were assessed.
Main Results:
- Activating TRPV1 receptors, particularly with low-dose RTX, enhanced immobility, but only at 41 °C.
- Warm water (41 °C) alone did not increase immobility, ruling out thermoregulation as a factor.
- Antidepressants and central TRPV1 desensitization significantly inhibited RTX-induced immobility.
Conclusions:
- TRPV1 receptor activation, especially under conditions mimicking cold stress, contributes to depressive-like behavior.
- Central TRPV1 receptors play a significant role in depression.
- Targeting central TRPV1 receptors may offer a novel therapeutic strategy for depression.
