“Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes. Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.” https://www.ncbi.nlm.nih.gov/pubmed/28249817]]>
Category Archives: Anxiety
Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents.
CONCLUSION:
We propose that the rapid anti-anxiety effects of FAAH inhibition are due to AEA activation of astroglial CB1R and subsequent basolateral amygdala LTD in vivo.” https://www.ncbi.nlm.nih.gov/pubmed/28234213Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation.
“Intermittent alcohol exposure is a common pattern of adolescent alcohol use that can lead to binge drinking episodes. Alcohol use is known to modulate the endocannabinoid system (ECS), which is involved in neuronal communication, neuroplasticity, neuroinflammation and behavior.
In conclusion, rats exposed to adolescent intermittent alcohol displayed anxiety-like behavior and cognitive deficits in adulthood and these alterations were accompanied by brain region-dependent changes in the gene expression of the ECS and other signals associated with neuroinflammation and behavior.
An intermittent adolescent alcohol exposure has behavioral and molecular consequences in the adult brain, which might be linked to higher vulnerability to addictive behaviors and psychopathologies.”
https://www.ncbi.nlm.nih.gov/pubmed/28223925
Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.
“The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.” https://www.ncbi.nlm.nih.gov/pubmed/28222356]]>
Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype.
“Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling. Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects.
Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype. Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses.” https://www.ncbi.nlm.nih.gov/pubmed/28209423]]>Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.
“Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.” https://www.ncbi.nlm.nih.gov/pubmed/28161196]]>
The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.
“Memory reconsolidation is the process in which reactivated long-term memory becomes transiently sensitive to amnesic agents. We evaluated the ability of post reactivation administration of the mTOR inhibitor rapamycin, separately and in combination with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN), given systemically or specifically into the hippocampal CA1 area, basolateral amygdala (BLA) or insular cortex (IC), to reduce inhibitory avoidance fear in rats. Taken together, the results suggest that rapamycin or a combined treatment that involves blocking mTOR and activating cannabinoids may be a promising pharmacological approach for the attenuation of reactivated emotional memories, and thus, it could represent a potential treatment strategy for disorders associated with traumatic memories.” https://www.ncbi.nlm.nih.gov/pubmed/28131675]]>
The Endocannabinoid System and Anxiety.
“The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed.” https://www.ncbi.nlm.nih.gov/pubmed/28061971]]>
Association of cannabis use with the development of elevated anxiety symptoms in the general population: a meta-analysis.
“The aim of this meta-analysis was to investigate the association of cannabis use with the development of elevated anxiety symptoms in the general population. The findings indicate that cannabis use is no more than a minor risk factor for the development of elevated anxiety symptoms in the general population.” https://www.ncbi.nlm.nih.gov/pubmed/28053188]]>
Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction
“Cannabidiol (CBD) is the major non-psychotropic constituent of the Cannabis plant and has anxiolytic therapeutic potential.
Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression.
We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test.
This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.
In summary, CBD had bidirectional effects on the extinction of contextual fear conditioning, depending on the nature of the initial fear conditioning. Nevertheless, in the more translationally-relevant stronger conditioning setting, CBD both acutely inhibited fear expression and enhanced extinction to produce longer lasting reductions in fear.
These observations provide further support for the potential translational use of CBD in conditions such as posttraumatic stress disorder and specific phobias.”