Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD.
Clinical studies suggest that administration of ketamine hydrochloride-an antagonist at the N-methyl-d-aspartate ionophore-provides short-term amelioration for depressive symptoms. The effects of a brief course of ketamine given immediately following exposure to psychogenic stress on the behavioral stress responses were assessed in an animal model of posttraumatic stress disorder. Animals exposed to stress were treated 1h later with ketamine (0.5, 5, and 15 mg/kg) or vehicle for three days (N = 107). Outcome measures included behavior in the elevated plus maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into "extreme," "minimal," or "partial" behavioral response for analysis of prevalence rates of "PTSD-like behavior." Circulating corticosterone levels were assessed 20 min after injection of ketamine in exposed and unexposed animals (N = 62). The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Prevalence rates of extremely-, partially-, or minimally-disrupted behavior demonstrated that ketamine administered immediately following stress exposure was ineffective in alleviating "PTSD-like behavior" at day 30 after exposure. Administration of ketamine was associated with increase in freezing behavior after exposure to a trauma-cue on day 31. Corticosterone levels were significantly suppressed by ketamine only in the exposed animals. Administration of ketamine immediately following trauma-exposure may not only be ineffective but actually detrimental in the long term. A disruption of the post-stress HPA-response has been raised as a contributing factor.
The Chaim Sheba Medical Center, Division of Psychiatry, Sackler Medical School, Tel Aviv University, Tel Hashomer, Israel.
Alzbeta
A
Juven-Wetzler
Ministry of Health, Anxiety and Stress Research Unit, Ben-Gurion University of the Negev Faculty of Health Sciences, Beer Sheva, Israel.
Hagit
H
Cohen
Ministry of Health, Anxiety and Stress Research Unit, Ben-Gurion University of the Negev Faculty of Health Sciences, Beer Sheva, Israel.
Zeev
Z
Kaplan
The Chaim Sheba Medical Center, Division of Psychiatry, Sackler Medical School, Tel Aviv University, Tel Hashomer, Israel.
Avi
A
Kohen
The Chaim Sheba Medical Center, Division of Psychiatry, Sackler Medical School, Tel Aviv University, Tel Hashomer, Israel.
Oren
O
Porat
The Chaim Sheba Medical Center, Division of Psychiatry, Sackler Medical School, Tel Aviv University, Tel Hashomer, Israel; Sackler Medical School, Tel Aviv University, Israel. Electronic address: joseph.zohar@sheba.health.gov.il.
Joseph
J
Zohar
D000161:Acoustic Stimulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D015995:Prevalence; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D013997:Time Factors
D014151:Anti-Anxiety Agents; D005938:Glucocorticoids; D007649:Ketamine; D003907:Dexamethasone; D003345:Corticosterone
Animal model; Early drug intervention; Extreme/minimal behavioral response; Ketamine; Post-traumatic stress disorder; Secondary prevention