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.

Keywords: CB1; CB2; HPA axis; endocannabinoid system; hippocampus; neuroplasticity; stress.

Figure 1

Classical representation of endocannabinoid modulation in the hippocampus. Anandamide (AEA) and 2-AG are produced “on demand” in a calcium (Ca²⁺)-dependent manner (via the previous activation of a metabotropic or ionotropic receptor in the post-synaptic terminal). After the synthesis of endocannabinoids (eCBs) by specialized enzymes, they can act as retrograde messengers by activating CB₁ receptors located at pre-synaptic terminals. In neurons, CB₁ is a Gi/o-coupled receptor, and its activation reduces Ca2+ currents and increases K+ currents, leading to the inhibition of neurotransmitter release. Fatty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes hydrolyze AEA (postsynaptically) and 2-AG (presynaptically), respectively, limiting eCB action. The CB₁ receptor is also expressed in astrocytes and microglia and the CB₂ receptor is expressed in activated microglia and putatively expressed in neurons (still under debate). *It has been speculated, that in the hippocampus, stress-induced activation of the HPA could lead, depending on genomic actions of glucocorticoids acting at glucocorticoid receptors, to an increase in 2-AG levels. 2-AG, 2-arachidonoylglycerol; AEA, anandamide; CB₁, type 1 cannabinoid receptor; CB₂, type 2 cannabinoid receptor; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; GR, glucocorticoid receptors; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D.

Figure 2

(A) Hippocampal endocannabinoid-mediated signaling participates in the negative feedback of the Hypothalamic-pituitary-adrenal (HPA) axis. During exposure to stressful events, neurons located in the paraventricular nuclei of hypothalamus (PVN) actively secrete corticotrophin-released-hormone (CHR) in the pituitary portal system. In the pituitary, the secretion of the adrenocorticotropic hormone (ACTH) is stimulated. Circulating ACTH reaches the cortex of the adrenal gland and stimulates the production and secretion of glucocorticoids. The PVN receives projections from limbic areas, including the hippocampus that participates in the glucocorticoid-mediated negative feedback inhibition of the HPA axis. It has been hypothesized that during stress response, activation of glucocorticoid receptors in the hippocampus could induce the production of 2-AG that would activate CB₁ receptors in GABAergic interneurons, leading to disinhibition of glutamatergic neurons. These latter neurons would send projections to GABAergic neurons in the PVN, inhibiting corticotrophin release hormone (CRH) release and stopping the stress response. (B) Stress responses have complex modulation on the genes related to the endocannabinoid system (eCBS) in the hippocampus, depending on individual factors (gender, age) and on the intensity, duration and nature of the stress.