The NLRP3 Inflammasome in Stress Response: Another Target for the Promiscuous Cannabidiol.

Many psychiatric patients do not respond to conventional therapy. There is a vast effort to investigate possible mechanisms involved in treatment resistance, trying to provide better treatment options, and several data points toward a possible involvement of inflammatory mechanisms. Microglia, glial, and resident immune cells are involved in complex responses in the brain, orchestrating homeostatic functions, such as synaptic pruning and maintaining neuronal activity. In contrast, microglia play a major role in neuroinflammation, neurodegeneration, and cell death. Increasing evidence implicate microglia dysfunction in neuropsychiatric disorders. The mechanisms are still unclear, but one pathway in microglia has received increased attention in the last 8 years, i.e., the NLRP3 inflammasome pathway. Stress response and inflammation, including microglia activation, can be attenuated by Cannabidiol (CBD). CBD has antidepressant, anti-stress, antipsychotic, anti-inflammatory, and other properties. CBD effects are mediated by direct or indirect modulation of many receptors, enzymes, and other targets. This review will highlight some findings for neuroinflammation and microglia involvement in stress-related psychiatric disorders, particularly addressing the NLRP3 inflammasome pathway. Moreover, we will discuss evidence and mechanisms for CBD effects in psychiatric disorders and animal models and address its potential effects on stress response via neuroinflammation and NLRP3 inflammasome modulation.

Inducible Nitric Oxide Synthase Inhibition in the Medial Prefrontal Cortex Attenuates the Anxiogenic-Like Effect of Acute Restraint Stress via CB1 Receptors.

Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB1 cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB1 antagonist; 100 pmol), and/or 1400W (iNOS selective inhibitor; 10-4, 10-3, or 10-2 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400W prevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects.

Differential modulation of the contextual conditioned emotional response by CB1 and TRPV1 receptors in the ventromedial prefrontal cortex: Possible involvement of NMDA/nitric oxide-related mechanisms.

BACKGROUND: Blockade of cannabinoid CB1 or vanilloid TRPV1 receptors in the ventromedial prefrontal cortex of rats respectively increases or decreases the conditioned emotional response during re-exposure to a context previously paired with footshocks. Although these mechanisms are unknown, they may involve local modulation of glutamatergic and nitrergic signaling. AIM: We investigated whether these mechanisms are involved in the reported effects of CB1 and TRPV1 modulation in the ventromedial prefrontal cortex. METHODS: Freezing behavior and autonomic parameters were recorded during the conditioned response expression. RESULTS: The CB1 receptors antagonist NIDA, or the TRPV1 agonist capsaicin (CPS) in the ventromedial prefrontal cortex increased the conditioned emotional response expression, and these effects were prevented by TRPV1 and CB1 antagonism, respectively. The increased conditioned emotional response evoked by NIDA and CPS were prevented by an NMDA antagonist or a neuronal nitric oxide synthase inhibitor. A nitric oxide scavenger or a soluble guanylate cyclase inhibitor prevented only the NIDA effects and the CPS effect was prevented by a non-selective antioxidant drug, as nitric oxide can also induce reactive oxygen species production. CONCLUSION: Our results suggest that CB1 and TRPV1 receptors in the ventromedial prefrontal cortex differently modulate the expression of conditioned emotional response through glutamatergic and nitrergic mechanisms, although different pathways may be involved.

Cannabinoid Modulation of the Stressed Hippocampus.

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.