Opposing effects of NMDA receptor antagonists on early life stress-induced aggression in mice.

Rates of childhood trauma are high amongst violent offenders who frequently recidivate. Few clinical options are available to treat excessive and recurring violent aggression associated with childhood trauma. Those that do exist are largely ineffective and often replete with side effects. One promising pharmacological target is the glutamate binding N-methyl- d-aspartate receptor (NMDAR). Clinically available NMDAR antagonists have proven successful in mitigating violent and aggressive behavior associated with a host of psychiatric diseases and have both immediate and long-term effects on nervous system function and behavior. This study examined the impact of three NMDAR antagonists on long-lasting aggression brought on by early-life stress: MK-801, memantine, and ketamine. We find that social isolation early in adolescence followed by acute traumatic stress in the form of noncontingent foot shock (FS) late in adolescence works in tandem to promote long-lasting excessive aggression in mice when measured 1 week later. Systemic injections of MK-801 and memantine 30 min before FS suppressed the long-lasting attack behavior induced by our early life stress induction protocol. Systemic injections of ketamine, on the other hand, significantly enhanced the long-lasting attack behavior when injected before FS. These findings indicate that MK-801, memantine, and ketamine have distinct and opposing effects on early life stress-induced aggression, suggesting these drugs may be mechanistically distinct. This study identifies memantine as a promising pharmacological treatment for aggressive behavior associated with early life stress and demonstrates the need for greater care when using glutamate receptor antagonists to treat aggression.

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.

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. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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

Traumatic stress has been shown to contribute to persistent behavioral changes, yet the underlying neural pathways are not fully explored. Structural plasticity, a form of long-lasting neural adaptability, offers a plausible mechanism. To scrutinize this, we used the mGRASP imaging technique to visualize synaptic modifications in a pathway formed between neurons of the posterior ventral segment of the medial amygdala and ventrolateral segment of the ventromedial hypothalamus (MeApv-VmHvl), areas we previously showed to be involved in stress-induced excessive aggression. We subjected mice (7-8 weeks of age) to acute stress through foot shocks, a reliable and reproducible form of traumatic stress, and compared synaptic changes to control animals. Our data revealed an increase in synapse formation within the MeApv-VmHvl pathway post-stress as evidenced by an increase in mGRASP puncta and area. Chemogenetic inhibition of CaMKIIα-expressing neurons in the MeApv during the stressor led to reduced synapse formation, suggesting that the structural changes were driven by excitatory activity. To elucidate the molecular mechanisms, we administered the NMDAR antagonist MK-801, which effectively blocked the stress-induced synaptic changes. These findings suggest a strong link between traumatic stress and enduring structural changes in an MeApv-VmHvl neural pathway. Furthermore, our data point to NMDAR-dependent mechanisms as key contributors to these synaptic changes. This structural plasticity could offer insights into persistent behavioral consequences of traumatic stress, such as symptoms of PTSD and social deficits.

Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression.

Treatment options for chronically aggressive individuals remain limited despite recent medical advances. Traditional pharmacological agents used to treat aggression, such as atypical antipsychotics, have limited efficacy and are often replete with dangerous side effects. The non-competitive NMDAR antagonists ketamine and memantine are promising alternatives, but their effects appear to be highly dependent on dosage, context, and personal experience. Importantly, these drugs can increase aggression when combined with substances of abuse or during periods of heightened stress. This is likely due to mechanistic differences operating at specific synapses under different contexts. Previous findings from our lab and others have shown that early life stress, substance abuse, and attack experience promote aggression through NMDAR-dependent synaptic plasticity within aggression-related brain circuits. Ketamine and memantine affect these types of aggression in opposite ways. This has led us to propose that ketamine and memantine oppositely affect aggression brought on by early life stress, substance abuse, or attack experience through opposite effects on NMDAR-dependent synaptic plasticity. This would account for the persistent effects of these drugs on aggression and suggest they could be leveraged as a more long-lasting treatment option. However, a more thorough examination of the effects of ketamine and memantine on cellular and synaptic function will be necessary for responsible administration. Additionally, because the effects of ketamine and memantine are highly dependent on prior drug use, traumatic stress, or a history of aggressive behavior, we propose a more thorough medical evaluation and psychiatric assessment will be necessary to avoid possible adverse interactions with these drugs.