Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
Project Number1I01BX003893-01A1
Contact PI/Project LeaderLIU, SIQIONG JUNE
Awardee OrganizationSOUTHEAST LOUISIANA VETERANS HEALTH CARE
Description
Abstract Text
One debilitating mental health problem among veterans is post-traumatic stress disorder
(PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life-
threatening psychological trauma. Individuals with PTSD have reduced circulating levels of
endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood
disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress-
induced change in 2-AG production/degradation holds great potential for the treatment of PTSD.
Given the importance of 2-AG signaling in the stress response and associative fear learning, an
understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge
the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG
content. Exposure of rodents to natural predator odors causes psychological stress, leading to
enhanced associative fear learning and thus has been used to model several aspects of PTSD.
We have previously shown that fox urine exposure produced a lasting increase in excitatory
synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This
brain region is required for the innate response to predator odor and for the consolidation of fear
memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the
cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore
our central hypothesis is that predator odor stress enhances excitability of GABAergic
interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that
inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced
decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2-
AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the
hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron
activity. We will test whether several FDA approved drugs that reduce neuronal activity can
reverse the stress-induced change. Because the proposed study investigates a new mechanism
underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel
treatment strategies for PTSD and new therapeutic targets.
Public Health Relevance Statement
Experience of a life-threatening psychological trauma significantly increases the likelihood of
developing post-traumatic stress disorder (PTSD), an anxiety disorder. Exposure of rodents to natural
predator odors causes emotional stress, alters endocannabinoid (2-AG) levels and leads to anxiety-
like behaviors. Our investigation of the cellular mechanisms underlying a psychological stress-induced
reduction in 2-AG tone and possible pharmacological interventions to reverse such a change may
suggest new therapeutic approaches by which an increase in 2-AG levels could be used to treat
PTSD.
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