Ketamine blocks the short-term anxiety and social withdrawal linked to adolescent social defeat

A recent study published in Physiology & Behavior suggests that administering ketamine during periods of social stress in adolescence can prevent the development of anxiety and social withdrawal. These findings provide evidence that targeted medical interventions might one day help build resilience against the negative mental health impacts of bullying.

Exposure to stressful life events during the sensitive developmental period of adolescence is closely linked to an increased risk of psychiatric illnesses and drug use disorders. In animal models, experiencing repeated social defeat, which mimics the human experience of bullying, tends to cause short-term anxiety and depressive symptoms. It also increases an animal’s sensitivity to the rewarding effects of drugs like cocaine later in adulthood.

Scientists wanted to explore ways to interrupt this pathway from early stress to later psychological and addiction issues. Previous research indicated that the brain’s glutamate system, a major network of chemical messengers, is heavily involved in how the brain processes social stress and drug reward.

Ketamine is a fast-acting antidepressant that works by blocking specific glutamate receptors in the brain. Because of its known ability to alter these chemical pathways and relieve depressive symptoms, the scientists designed this study to see if ketamine could act as a protective shield. They aimed to determine if giving ketamine before stressful encounters could prevent both immediate anxious behaviors and long-term vulnerability to cocaine addiction.

“Adolescence is a critical period of development, so exposure to stress during this stage, such as bullying, can have negative consequences for mental health, such as the onset of anxiety and/or depression and increased vulnerability to drug abuse,” explained corresponding author Maria A. Aguilar, a professor at the University of Valencia and member of the Neurobehavioral Mechanisms and Endophenotypes of Addictive Behavior research group.

“Using an animal model of social stress in adolescent mice (defeat in intermittent encounters with a more aggressive mouse), we have observed that the development of depression shortly after exposure to stress predicts greater sensitivity to cocaine in adulthood. Therefore, we hypothesize that the administration of ketamine, which has rapid antidepressant effects, could reduce the development of depression and subsequent vulnerability to cocaine.”

To test this, the researchers used a sample of 56 male mice. Forty of these mice were the experimental subjects, while 16 larger, more aggressive mice were used to create a stressful environment.

The experimental mice were divided into four groups, including a non-stressed control group of eight mice that received saltwater injections. A second group of eight mice received saltwater injections and underwent social stress. The remaining two groups, each consisting of 12 mice, received either a low or high dose of ketamine before facing stress.

The stress procedure involved placing an experimental mouse into the home cage of an aggressive mouse for brief encounters. This happened four times, with three days between each event. Before each encounter, the mice in the treatment groups received their assigned dose of ketamine.

Shortly after the final stressful event, the researchers ran a series of behavioral tests. They used an elevated maze shaped like a plus sign to measure anxiety. Mice naturally prefer dark, enclosed spaces, so spending less time in the open, wall-less arms of the maze indicates higher anxiety.

The scientists also used a social interaction test to see if the mice would approach or avoid a new, unfamiliar mouse. To measure symptoms resembling depression, the researchers used a splash test. This test involves spraying the mouse with a sticky sugar solution to see how quickly and often it cleans itself.

A lack of grooming suggests a loss of interest in normal activities, a concept known as anhedonia. They also used a tail suspension test, where mice are briefly held by their tails. This measures how long they try to escape versus how long they remain still, which models behavioral despair.

Three weeks later, the scientists tested the adult mice for cocaine vulnerability. In this procedure, mice receive a very small dose of cocaine in a specific, distinct compartment. Later, the mice are allowed to roam freely between that compartment and a neutral one to see if they associate the space with a drug reward.

The researchers found that the mice exposed to social stress without ketamine exhibited clear signs of anxiety. They spent significantly less time exploring the open arms of the elevated maze compared to the unstressed control group. These stressed mice also displayed social avoidance, choosing to stay away from an unfamiliar mouse during the social interaction test.

Administering ketamine before the stressful encounters provided a protective effect against these behavioral changes. The mice that received the higher dose of ketamine behaved similarly to the unstressed control group in the maze, showing that the drug prevented the stress-induced anxiety. Similarly, the higher dose of ketamine completely prevented the social avoidance behavior, prompting the stressed mice to interact normally with new peers.

The results from the tests measuring depressive symptoms were less definitive. In the tail suspension test, all mice exposed to stress spent less time immobile than the control mice, and ketamine did not change this outcome. In the splash test, the scientists did not observe any significant differences in grooming behavior between any of the groups.

In the final test evaluating long-term vulnerability to cocaine, the researchers encountered an unexpected outcome. The small dose of cocaine failed to produce a rewarding effect in any of the groups, including the stressed mice that did not receive ketamine. Because the stress itself did not induce the expected preference for the drug, the scientists could not draw conclusions about ketamine’s ability to prevent this specific long-term consequence.

“It is possible to increase resilience to the negative effects of exposure to social stress during adolescence on mental health,” Aguilar told PsyPost. “For example, administering ketamine to mice during episodes of stress prevents the development of symptoms of anxiety, depression (such as social avoidance) and increased vulnerability to cocaine. These results support the conduct of clinical studies to assess the potential usefulness of ketamine in preventing the negative consequences of bullying on mental health.”

When reading about animal studies, it is easy to misinterpret the findings. Some might assume these results are completely irrelevant to humans, while others might think ketamine is a ready-to-use treatment for bullied teenagers. The scientists note that this basic research is just a preliminary step to understand the fundamental biological mechanisms of stress and resilience.

“Although the results obtained indicate the usefulness of ketamine in preventing the effects of stress, it is important to bear in mind that this is basic research in mice,” Aguilar noted. “However, validated animal models have been used both to induce stress and to study its consequences.”

“Using these models, in our laboratory we have repeatedly observed that mice exposed to social defeat exhibit symptoms similar to anxiety and depression, as well as an increase in the rewarding effects of low doses of cocaine. In this study, we demonstrate that ketamine is effective in reversing most of these effects, so we believe it could also be useful in humans.”

“Research with animal models allows us to study the pathophysiology and neurobiological mechanisms of diseases, in this case stress-related mental disorders, and to test the efficacy of different treatments as a preliminary step to conducting clinical trials in humans. The high genetic, anatomical and behavioural homology between rodents and humans facilitates the extrapolation of results, but this requires caution and further validation in humans.”

The study also has specific limitations, such as the lack of a group of unstressed mice that received ketamine. Ketamine can have its own complex effects on the brain, making it difficult to fully separate the drug’s general effects from its stress-blocking effects without this control group.

Additionally, the scientists only used male mice in this experiment. Future research will aim to address these gaps by conducting similar studies using female mice, as women tend to be more vulnerable to depression and the rewarding effects of cocaine.

“Our long-term goal is to determine the endophenotypes of resilience to social stress in mice of both sexes, study their neurobiological basis, and identify treatments and environmental interventions that increase it,” Aguilar explained.

“In agreement with the results of the present study, we have previously observed an increase in stress resilience with other pharmacological treatments (for example, memantine) and environmental interventions such as physical activity. This type of study also allows us to expand our knowledge of the neurobiological basis of vulnerability and resilience to stress.”

“Ketamine and memantine (used in a previous study) are antagonists of the neurotransmitter glutamate. Therefore, the effectiveness of these drugs in reversing the effects of stress and increasing resilience suggests the involvement of this neurotransmission system in the consequences of stress on mental health.”

The study, “Ketamine attenuates the effects of intermittent social defeat on anxiety, social interaction and cocaine-induced conditioned place preference in male mice,” was authored by M.A. Martínez-Caballero, M.P. García-Pardo, C. Calpe-López, M.C. Arenas, C. Manzanedo, and M.A. Aguilar.