The results of a preclinical study led by researchers at Northwestern Medicine have added support to the hypothesis that endogenous cannabinoid molecules released by the brain act as the body’s natural coping response to stress.

The team reported the study in mice found that endogenous cannabinoid molecules released under stress by the brain’s amygdala—a key emotional brain center—dampen the incoming stress alarm from the brain’s memory and emotion center, the hippocampus.

The study could indicate that impairments in this endocannabinoid (eCB) signaling system in the brain might lead to a greater susceptibility to developing stress-related psychiatric disorders including depression and post-traumatic stress disorder (PTSD), although this remains to be determined in humans, suggested research lead Sachi Patel, MD, PhD, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and a Northwestern Medicine psychiatrist. The findings could also point to new therapeutic targets for stress-related disorders.

“Understanding how the brain adapts to stress at the molecular, cellular, and circuit level could provide critical insight into how stress is translated into mood disorders and may reveal novel therapeutic targets for the treatment of stress-related disorders,” said Patel, who is corresponding author of the researchers’ published paper in Cell Reports, titled “Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation.”

Stress exposure heightens the risk for the development or worsening of psychiatric disorders from generalized anxiety and major depression to PTSD, the authors noted.  “Understanding stress-induced molecular-, cellular-, and circuit-level adaptations may provide critical insight into how stress is translated into affective pathology and may reveal novel therapeutic targets for the treatment of stress-related disorders.”

“Human and rodent studies have implicated activity of the amygdala and its functionally connected region, the hippocampus, in fear learning and stress-related pathological states, such as PTSD,” the investigators commented.. It’s thought that in response to stress, the brain may release its own cannabinoid molecules that activate the same brain receptors as THC derived from cannabis plants, so having a calming influence. The team further explained, “The ventral portion of the hippocampus (vHPC) provides strong input to the basolateral amygdala (BLA) that undergoes robust activity-dependent eCB mobilization.” The eCB signaling system comprises the CB receptor type 1 (CB1R) and its endogenous endocannabinoid ligand, which is called 2-arachidonoylglycerol (2-AG). This system, they noted, has been “heavily implicated in the modulation of the physiological stress response, of stress adaptability and susceptibility, and of fear responding,” and has been identified as “a prominent drug-development candidate for stress-related psychiatric disorders.” To date, however, the brain activity patterns and neural circuits that are regulated by brain-derived endocannabinoid molecules haven’t been well understood.

For their reported study, the Northwestern scientists and colleagues used a new protein sensor to detect the presence of these cannabinoid molecules at specific brain synapses in real time. “Here, we utilized in vivo optogenetic- and biosensor-based approaches to determine the temporal dynamics of activity-dependent and stress-induced eCB release at vHPC-BLA synapses.” Their study showed that specific high-frequency patterns of amygdala activity can generate these eCB molecules, and that they were released as a result of several different types of stress in mice.

Interestingly, selectively deleting the endocannabinoid receptor CB1R at the hippocampal-amygdala synapses resulted in poorer ability to cope with stress and motivational deficits in the mice. These animals adopted more passive and immobile responses to stress and had a lower preference to drink a sweetened sucrose water after stress exposure. The latter finding may relate to anhedonia, or the decrease in pleasure, which is often experienced by patients with stress-related disorders such as depression and PTSD. “… genetic deletion of CB type-1 receptors selectively at vHPC-BLA synapses decreases active stress coping and exacerbates stress-induced avoidance and anhedonia phenotypes,” the team stated.

Activity within the amygdala and the vHPC (the anterior hippocampus in humans) has been implicated in the pathogenesis of stress-related neuropsychiatric disorders, and preclinical studies have confirmed that vHPC-amygdala circuits are critical for driving affective behavioral responses to stress, the team commented. Noting limitations of their study, the team nevertheless concluded that their findings “suggest that 2-AG released within the synapse during stress exposure plays an important role in buffering against subsequent adverse behavioral consequences of stress …”

The collective data, they noted, “indicate that 2-AG-CB signaling at vHPC-BLA synapses plays an important role in regulating behavioral responses during and after stress exposure and provides further support for the contention that 2-AG signaling within defined limbic circuits is a critical mechanism buffering against the adverse effects of stress exposure.” And the newly reported study results, combined with those from prior research, “… provide accumulating support for the notion that impairments in 2-AG-CB1R signaling could contribute to the pathogenesis of stress-related neuropsychiatric disorders.” The data also provide support for the continued investigation of “pharmacological 2-AG augmentation strategies” in the potential treatment of stress-related neuropsychiatric disorders.”

“Determining whether increasing levels of endogenous cannabinoids can be used as potential therapeutics for stress-related disorders is a next logical step from this study and our previous work,” said Patel, who is the Lizzie Gilman Professor of Psychiatry and Behavioral Sciences. “There are ongoing clinical trials in this area that may be able to answer this question in the near future.”

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