Oxytocin prevents ketamine-induced executive control deficits in macaque monkeys.

Background: Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has gained attention for its rapid antidepressant effects at subanesthetic doses. However, its potential for overdose and cognitive side effects, especially after misuse, remains a concern. The impact of ketamine on inhibitory control, a critical component of executive function, is not well understood. Oxytocin, a neuropeptide involved in emotional regulation and social cognition, may modulate cognitive functions, but its interaction with ketamine, particularly in relation to inhibitory control, remains unclear.

Aims: This study aimed to investigate the effects of ketamine on inhibitory control and explore whether oxytocin could mitigate these effects in a macaque monkey model.

Methods: In experiment 1, macaque monkeys (N = 4) received intramuscular ketamine (0.25, 0.5, or 1.0 mg/kg) or saline before performing the stop-signal task. In experiment 2, the 1.0 mg/kg ketamine dose was selected to assess whether intranasal oxytocin (50 IU) pretreatment could attenuate ketamine-induced cognitive impairments.

Results: Ketamine significantly impaired response inhibition and execution in a dose-dependent manner, with the greatest deficits at 1.0 mg/kg. Oxytocin pretreatment significantly restored inhibitory control, normalizing stop-signal reaction time to levels comparable to the saline control condition.

Conclusions: These findings suggest that low-dose ketamine disrupts executive control in non-human primates, and that oxytocin may counteract these effects, particularly in inhibitory control. This interaction highlights a promising therapeutic pathway for executive dysfunction in neuropsychiatric disorders.