Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice

Abstract

Background The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense. Methods During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements. Results CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex. Conclusion The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study

“…The unique patter of anisotropy between forebrain and hindbrain could reflect a reorganisation and resetting in the balance of the endocannabinoid signalling system 46,52 . In a recent study, we found a pattern of bipolar activation emphasising the hindbrain and forebrain in mice exposed to CDB 53 . The brain areas involved matched much of the distribution of NAPE‐PLD messenger RNA, an enzyme that increases anandamide levels when activated by CBD.…”

“…46,52 In a recent study, we found a pattern of bipolar activation emphasising the hindbrain and forebrain in mice exposed to CDB. 53 The brain areas involved matched much of the distribution of NAPE-PLD messenger RNA, an enzyme that increases anandamide levels when activated by CBD. Thus, THC in inhaled cannabis vapour and injection of CBD could both be impacting endocannabinoid signalling producing this unique brain pattern.…”

Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study

“…An unexpected result was the hypometabolism in the region of the third ventricle and cerebellum in the group treated with the cannabidiol compared to baseline. This finding may be related to the migration of STZ injection and/or some action of CBD, for example, cerebellar deactivation [17].…”

Applications in Awake Animal Magnetic Resonance Imaging

“…In a just published study in mice treated with the phytocannabinoid cannabidiol (CBD) we reported a dose-dependent polarization of BOLD signal change along the rostral-caudal axis of the brain with the forebrain showing positive signal while the brainstem and cerebellum presented with negative signal ( Sadaka et al, 2021 ). The brainstem ascending reticular activating system (ARAS) was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex.…”

“…Essentially baseline CBF is stable in awake rats regardless of stress, a critical point when measuring changes in functional signal dependent upon blood flow. In our more recent studies, we acclimate for five consecutive days, increasing the duration of acclimation with each subsequent day ( Sadaka et al, 2021 ).…”