A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats

Rodrigo Moraga-Amaro, Cyprien G. J. Guerrin, Luiza Reali Nazario, Bruno Lima Giacobbo, Rudi A. J. O. Dierckx, Jimmy Stehberg, Erik F. J. de Vries, Janine Doorduin
Stress. 2022-01-02; 25(1): 145-155
DOI: 10.1080/10253890.2022.2045269

1. Stress. 2022 Jan;25(1):145-155. doi: 10.1080/10253890.2022.2045269.

A single dose of ketamine cannot prevent protracted stress-induced anhedonia and
neuroinflammation in rats.

Moraga-Amaro R(1), Guerrin CGJ(1), Reali Nazario L(1), Lima Giacobbo B(1), J O
Dierckx RA(1), Stehberg J(2), de Vries EFJ(1), Doorduin J(1).

Author information:
(1)Department of Nuclear Medicine and Medical Imaging, University Medical Center
Groningen, University of Groningen, Groningen, GZ, The Netherlands.
(2)Laboratorio de Neurobiología, Instituto de Ciencias Biomédicas, Facultad de
Medicina y Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago,
Chile.

Worldwide, millions of people suffer from treatment-resistant depression.
Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant
effect even in treatment-resistant patients. A proposed mechanism for the
antidepressant effect of ketamine is the reduction of neuroinflammation. To
further explore this hypothesis, we investigated whether a single dose of
ketamine can modulate protracted neuroinflammation in a repeated social defeat
(RSD) stress rat model, which resembles features of depression. To this end,
male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A
combination of behavioral analyses and PET scans of the inflammatory marker TSPO
in the brain were performed. Rats submitted to RSD showed anhedonia-like
behavior in the sucrose preference test, decreased weight gain, and increased
TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195
PET. Whole brain TSPO levels correlated with corticosterone levels in several
brain regions of RSD exposed animals, but not in controls. Ketamine injection
1 day after RSD disrupted the correlation between TSPO levels and serum
corticosterone levels, but had no effect on depressive-like symptoms, weight
gain or the protracted RSD-induced increase in TSPO expression in male rats.
These results suggest that ketamine does not exert its effect on the
hypothalamic-pituitary-adrenal axis by modulation of neuroinflammation.