S-ketamine Administration in Pregnant Mice Induces ADHD- and Depression-like behaviors in Offspring Mice.

Pregnant mice given high-dose S-ketamine (60 mg/kg) all miscarried after the first injection. Low- and medium-dose S-ketamine (15 and 30 mg/kg) administered from gestational day 14 to 18 led to ADHD-like behaviors (increased open-arm time, reduced freezing in fear conditioning) and, at the medium dose, depression-like behaviors (reduced locomotion, increased immobility) in offspring. Changes in astrocytic activation, synaptic dysfunction, and decreased inhibitory presynaptic proteins were observed in the hippocampus, amygdala, and habenula nucleus. The authors conclude that S-ketamine may cause detrimental effects on developing brains and call for further study.

Study at a glance

Abstract

BACKGROUND Anesthesia and psychotropic drugs in pregnant women may cause long-term effects on the brain development of unborn babies. The authors set out to investigate the neurotoxicity of S-ketamine, which possesses anesthetic and antidepressant effects and may cause attention deficit hyperactivity disorder (ADHD)- and depression-like behaviors in offspring mice. METHODS Pregnant mice were administered with low-, medium-, and high-dose S-ketamine (15, 30, and 60mg/kg) by intraperitoneal injection for 5 days from gestational day 14 to 18. At 21 days after birth, an elevated plus-maze test, fear conditioning, open field test, and forced swimming test were used to assess ADHD- and depression-like behaviors. Neuronal amount, glial activation, synaptic function indicated by ki67, and inhibitory presynaptic proteins revealed by GAD2 in the hippocampus, amygdala, habenula nucleus, and lateral hypothalamus (LHA) were determined by immunofluorescence assay. RESULTS All the pregnant mice exposed to high-dose S-ketamine administration had miscarriage after the first injection. Both low-dose and medium-dose S-ketamine administration significantly increased the open-arm time and attenuated frozen time in the fear conditioning, which indicates impulsivity and memory dysfunction-like behaviors. Medium-dose S-ketamine administration reduced locomotor activity in the open field and increased immobility time in the forced swimming test, indicating depression-like behaviors. Changes in astrocytic activation, synaptic dysfunction, and decreased inhibitory presynaptic proteins were found in the hippocampus, amygdala, and habenula nucleus. CONCLUSIONS These results demonstrate that S-ketamine may lead to detrimental effects, including ADHD-and depression-like behaviors in offspring mice. More studies should be promoted to determine the neurotoxicity of S-ketamine in the developing brain.