Psychedelic compound shows promise in stress relief for socially aggressive mice

By Dr. Sanchari Sinha Dutta, Ph.D.Apr 30 2024Reviewed by Benedette Cuffari, M.Sc.

A recent study published in the journal Neuropharmacology reports the effectiveness of a psychedelic compound in improving stress-related behaviors of mice exposed to repeated social aggression.

Study: Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress. Image Credit: G-Stock studio / Shutterstock.com

Depression and stress

Depressive mood disorders are highly prevalent mental health conditions, as they affect about 322 million individuals worldwide. These conditions are typically associated with anxiety and post-traumatic stress disorder (PTSD).

Serotonin or norepinephrine reuptake inhibitors, tricyclic antidepressants, and benzodiazepines are considered first-line therapeutic interventions for depressive mood disorders and anxiety. However, these treatments often produce inadequate results, induce dependency, and cause serious side effects.   

Chronic exposure to socially stressful conditions is a leading contributor to the development of depression and anxiety. Stress-mediated induction in signaling within stress neural networks, sustained elevation in stress hormone levels, and chronic inflammation are some of the mechanisms that have been implicated in these mental health conditions.

In the current study, scientists investigate whether a single dose of a psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] can improve stress-coping strategies in mice exposed to escapable and repeated social aggression. 

Psychedelic compounds are serotonergic hallucinogens that can exert active and strong stress-coping behaviors in humans and rodents. The psychedelic compound used in the current study is a selective partial agonist of the serotonin receptor.

Study design

Male mice between six and eight weeks of age were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which experimental animals develop either dynamic or reactive coping strategies. A group of older male mice about six months of age were used to provide social aggression to the experimental mice.   

In the dynamic coping strategy, mice can escape the stress through holes, whereas mice that utilize the reactive coping strategy remain in the SAM area. These mice were otherwise referred to as the ‘Escape’ and ‘Stay’ mice, respectively.

Experimental mice were initially exposed to social aggression for two days to separate them into the stress-vulnerable and stress-resilient groups, which were determined based on whether the mice chose the dynamic or reactive coping strategies, respectively. Subsequently, a single high, middle, or low dose of (R)-DOI was administered to the mice, followed by monitoring any changes in their stress-coping behaviors in response to social aggression.  

Important observations

Following a low-dose treatment with (R)-DOI, a significantly higher proportion of Stay mice escaped in response to social aggression compared to placebo-treated Stay animals. Phenotypic behaviors remained stable throughout the experiment in placebo-treated Escape mice.

Regarding the time spent with aggressive mice, both middle—and low-dose treatments significantly reduced escape latency in Stay mice compared to placebo-treated mice.

Existing evidence indicates that Escape mice exhibit faster escape latency from the SAM over time, thus reflecting a successful learning process. In the current study, Escape mice from all treatment groups showed a similar spatial learning response.

Regarding the time spent freezing in the SAM in response to social aggression, middle-dose treatment of (R)-DOI significantly reduced the freezing duration in Stay animals compared to placebo-treated mice. The low-dose treatment also reduced the freezing duration, although this effect was insignificant.

In Escape mice, both high- and low-dose treatments significantly reduced freezing duration compared to placebo-treated Escape mice.

Regarding attention to the escape route, low-dose treatment of (R)-DOI significantly increased the time spent attentive to the escape routes in Stay mice as compared to placebo-treated mice. However, no significant impact of (R)-DOI treatments on time spent attentive to the escape routes was observed in Escape mice.  

Effect of psychedelic compound on plasma proinflammatory cytokine levels

Significantly increased plasma levels of tumor necrosis factor-α (TNF-α) were observed in Stay mice in response to social aggression. A moderate increase in TNF-α levels was also observed in stress-exposed Escape mice.

Among different treatment groups, the low dose of (R)-DOI in Stay mice and high—or low-dose treated Escape mice showed significant reductions in plasma TNF-α levels in response to social stress. This finding highlights the anti-inflammatory effects of (R)-DOI.

The transcriptomic analysis of the anterior basolateral amygdala, a critical brain region for stress-related signaling, exhibited increased expression of genes associated with aggression-induced stress responsivity in stress-exposed mice. Stay mice also exhibited more potent effects than Escape mice.

The analysis of TNF-α expression in different brain regions revealed that the low-dose treatment led to a reduction in stress-induced TNF-α expression in the basolateral amygdala and prefrontal cortex in both Stay and Escape mice.

Study significance

The psychedelic compound (R)-DOI was found to improve stress-coping behaviors in stress-vulnerable mice. Moreover, (R)-DOI effectively reduced plasma and brain levels of the proinflammatory cytokine TNF-α.