Anaesthesia with ketamine or propofol on the antidepressant-like efficacy and cognitive outcome induced by electroconvulsive stimulation in adolescent rats

Electroconvulsive stimulation (ECS) represents a safe and effective intervention for treatment-resistant depression during adolescence. Nevertheless, additional studies are required to further elucidate the observed sex-dependent differences in therapeutic outcomes, as well as the potential influence of commonly used anesthetic agents on treatment response. It remains unclear whether anesthesia could modulate the efficacy of ECS, contribute to the observed variability in efficacy between male and female rats during adolescence, and/or participate in the induction of cognitive changes. Against this background, in the present experiment we utilized adolescent Sprague-Dawley rats (between 6 and 9 animals per group and sex) that were pre-treated with vehicle or one of the anesthetic agents frequently employed in pediatric clinical practice, namely propofol or ketamine (50 mg/kg, i.p.) daily right before ECS treatment. Adolescent rats were treated with ECS 5 min after pre-treatment at specific dose-intensities that were previously characterized to be effective for each sex (males: 95 mA; females: 35 mA; 0.6 s, 100 Hz; one session per day for 5 consecutive days). The control group was exposed to a SHAM procedure. The main results proved that, as expected, propofol and ketamine produced sex-related differences in anesthetic response, with females exhibiting a more rapid onset and a prolonged duration of loss of righting reflex (LORR) compared with males. Moreover, both anesthetics reduced the duration of ECS-induced tonic and clonic phases in males, whereas no significant changes were detected in females, since 35 mA rarely induced measurable seizures. Antidepressant-like effects were assessed 1-day post-treatment using the forced swim test (FST) and analyzed via two-way ANOVAs for each sex separately. Short-term cognitive function was evaluated 5-days post-treatment during adolescence using the 8-arm radial maze. Additionally, rats were housed until adulthood with no other experimental procedures until long-term cognitive performance was assessed using the Barnes maze test. As expected, the antidepressant-like efficacy of ECS was confirmed in both male (95 mA) and female (35 mA) adolescent rats. Importantly, prior administration of propofol or ketamine did not significantly modify the behavioral efficacy observed for either sex. Furthermore, performance in the radial maze task indicated no detectable impairments in working memory as measured during adolescence following the course of treatment, regardless of the anesthetic condition used. Similarly, no significant differences were observed in spatial memory in the Barnes maze when rats were tested in adulthood. These results indicate that both propofol and ketamine are great anesthetic options for their use in combination with ECS during adolescence. Neither agent diminished the antidepressant-like efficacy expected for ECS, and both demonstrated a favorable safety profile with respect to short-term and long-term cognitive performance. Collectively, this study supports their continued use in preclinical and potentially clinical settings involving adolescent populations. Current studies are evaluating the molecular correlates participating in the observed behavioral responses.

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