A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice.

Abstract

Ketamine is a dissociative anesthetic that has been shown to have antidepressant effects in humans and has been proposed as a potential treatment for mood disorders such as posttraumatic stress disorder and aggression. However, previous studies from our lab and others have demonstrated that ketamine’s effects are highly context- and dose-dependent. In a recent study, we found that 10 mg/kg ketamine could exacerbate the effects of early life stress on excessive aggression in mice. To further investigate, the effect of ketamine on moods, such as fear, anxiety, depression, and aggression, we used a mouse model of early life stress, involving chronic social isolation followed by acute traumatic stress in the form of noncontingent, unpredictable foot shock during adolescence. We find this is necessary to induce long-lasting excessive aggression in a novel environment. Seven- to eight-week-old socially isolated mice were given IP injections of 10 mg/kg ketamine 30 min before being subjected to foot shock and then assessed 7 days later for changes in sociability, aggression, mobility, anxiety-like behavior, and depression-like behavior. The results show that ketamine selectively increases long-lasting aggression in mice exposed to foot shock, but does not affect mood-related behaviors or locomotion. These findings suggest that during early life stress, ketamine may exert its effects by specifically targeting aggression brain circuitry that is distinct from brain circuits responsible for nonaggressive social or emotional behaviors. Therefore, while ketamine may be a promising treatment for various mood disorders, caution should be exercised when using ketamine to treat disorders associated with early life stress.

Visualizing traumatic stress-induced structural plasticity in a medial amygdala pathway using mGRASP

“…After 2 weeks of social isolation, mice received IP injections of 3.75 μg/ml MK-801 ( n = 4 mice) diluted in 0.9% saline or 0.9% saline alone (Veh, n = 4 mice) 30 min before foot shock ( Figure 3A ) ( Petralia et al, 2007 ; Zhang et al, 2017 ; Nordman et al, 2020a , 2022 ). This concentration does not affect mobility nor act as an antidepressant ( Nordman et al, 2020a ; Bartsch et al, 2023 ). As before, IP injections of MK-801 were used because cannulae and direct infusion could damage the VmHvl, making it difficult to properly detect the mGRASP signal.…”

“…For traumatic stress induction, separate groups of 5–6-week-old mice were delivered injections of the mGRASP fragments and then socially isolated for 2 weeks. Mice were then placed into a fear conditioning chamber where they received 15 non-contingent foot shocks over 90 min (FS, 4 mice, Figure 1B ), a protocol we have developed and used extensively ( Nordman et al, 2020a , b , 2022 ; Bartsch et al, 2023 ). Control mice (Con, 3 mice) were left in the shock box for the same period of time but received no foot shocks.…”

“…All C57BL/6 mice used in this study were purchased from Charles River Laboratories and housed under a reverse 12-h light (8 pm–8 am)/dark (8 am–8 pm) cycle with ad libitum access to water and food. Starting at 3–4 weeks of age, mice were socially isolated for 4 weeks before testing ( Nordman et al, 2020a , b , 2022 ; Bartsch et al, 2023 ). Surgical procedures, outlined below, were performed at 5–6 weeks of age.…”

“…They were then placed into a fear conditioning chamber within a sound-attenuating cubicle (Med Associates). After a 3 min exploration period, 15 non-contingent electric foot shocks (0.4 mA, 1 s in duration) were administered through an electrified grate at random intervals (240–480 s) over 90 min ( Nordman et al, 2020a , b , 2022 ; Bartsch et al, 2023 ). For chemogenetic and pharmacology experiments, mice were injected with saline (vehicle), clozapine N-oxide (CNO), or MK-801 30 min before foot shock.…”

“…To further explore the neural mechanisms underlying maladaptive responses to traumatic stress, we employed a PTSD stress model devised for this purpose ( Nordman et al, 2020a , b , 2022 ; Bartsch et al, 2023 ). This model integrates chronic social isolation during early adolescence with acute traumatic stress in late adolescence, offering a multidimensional perspective that more closely resembles complex real-world trauma scenarios ( Vlachos et al, 2020 ).…”