Cannabinoid Modulation of the Stressed Hippocampus

Abstract

Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia. The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function. Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus. Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes. Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels. Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.

Genetic, epigenetic and pharmacological influences modulating tissue specific regulation of the cannabinoid receptor-1 gene (CB1); implications for cannabinoid pharmacogenetics

“…As we have shown that the C-allele of ECR1 is more active in hippocampal cells, these observations suggest that the human specific C-allele of ECR1 may drive higher expression of CNR1 in hippocampus consistent with previous observations (Zhang et al, 2004). Considering the known neuroprotective role of CB1 activation against the effects of stress in the hippocampus (Scarante et al, 2017) it has not escaped our attention that the C-allele may play a role in protecting the hippocampus against the depressive and anxiety inducing effects of stress. In this context, and from the perspective of adaptive evolution, it is interesting that the C-allele has undergone positive selection in European and Asian populations where its frequency exceeds 80% compared to the ancestral T-allele.…”

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review

“…They serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids also participate in the modulation of the hypothalamic–pituitary–adrenal (HPA) axis and regulation of stress [ 30 , 75 ]. Preclinical and clinical data support the involvement of the eCB in the etiopathogenesis of mental disorders [ 24 , 35 , 44 , 73 ].…”

Long-Term Stress and Concomitant Marijuana Smoke Exposure Affect Physiology, Behavior and Adult Hippocampal Neurogenesis

“…Cannabinoid receptors are highly expressed in the hippocampus, and recent studies suggest that facilitation of the cannabinoid signaling in the hippocampus may prevent stress-induced behavioral changes ( Campos et al, 2013 ; Scarante et al, 2017 ; Fogaça et al, 2018 ). Numerous studies investigated the effect of various cannabinoids on adult hippocampal neurogenesis ( Prenderville et al, 2015 ), but these studies used either plant-derived extracts or synthetic cannabinoids.…”