Ketamine Improves Anhedonic Phenotypes Across Species: Translational Evidence From the Probabilistic Reward Task

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• Ketamine shows promise for treatment-resistant depression (TRD) due to rapid antidepressant effects.
• The precise mechanisms of ketamine's action, particularly on reward pathways, remain unclear.
• Translational research is hindered by a lack of cross-species assessment paradigms for depressive phenotypes.

Purpose of the Study:

• To investigate ketamine's effects on reward responsiveness in TRD patients and chronically stressed rats.
• To utilize functionally identical tasks to enable cross-species comparison of ketamine's impact on reward processing.
• To explore the specific behavioral mechanisms underlying ketamine's antidepressant properties.

Main Methods:

• A subanesthetic dose of ketamine (0.5 mg/kg in humans, 10 mg/kg in rats) was administered.
• Humans with TRD and healthy controls (HCs) completed the Probabilistic Reward Task (PRT).
• Rats underwent a reverse-translated PRT before and after chronic stress and ketamine administration.

Main Results:

• Ketamine significantly increased reward bias in both humans with TRD and rats, normalizing to HC levels 24 hours post-administration.
• The effect of ketamine was most pronounced in humans with higher baseline anhedonia.
• Ketamine selectively enhanced reward learning, with no impact on stimulus discriminability in either species.

Conclusions:

• Ketamine administration normalizes reward responsiveness in TRD and stress models, indicating a shared behavioral mechanism.
• These findings suggest ketamine may alleviate anhedonic behaviors by improving reward learning.
• The study provides crucial insights for developing novel treatments for anhedonia in TRD and related disorders.