Sex-related differences in intravenous ketamine effects on dissociative stereotypy and antinociception in male and female rats

Ketamine, a multimodal dissociative anesthetic drug, is widely used to treat various conditions including acute pain and treatment-resistant depression. We previously reported that subanesthetic doses of intravenous (i.v.) ketamine produced transient dissociative stereotypy and antinociception in male rats. However, sex-related differences in the effects of i.v. ketamine on these measures are not well characterized. Adult male and female Sprague-Dawley rats (10 weeks old) received an i.v. bolus saline or ketamine (2 and 5 mg/kg), and dissociative stereotypy (head weaving, ataxia, and circling) and natural behaviors (horizontal activity, rearing, and grooming) were quantified over a 10-min period. Ten minutes after the behavioral observation, antinociception was measured using a tail flick test. The i.v. ketamine administration increased head weaving, ataxia, circling, and horizontal activity while decreasing rearing and grooming behaviors in male and female rats. Following 5 mg/kg ketamine administration, ataxia was greater in female rats, while head weaving was greater in male rats. Among the female rats, head weaving was greater in the low estrogen group (diestrus phase) as compared to the high estrogen group (proestrus/estrus phase). Ketamine doses (2 and 5 mg/kg) produced antinociception in male and female rats, and female rats were more sensitive to the antinociceptive effects of 2 mg/kg ketamine. The current findings suggest that i.v. ketamine administration, a clinically relevant route of administration, may produce sex-related differences in dissociative behaviors and analgesia between males and females.