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.

Keywords: Behavioral arrest; N-acyl-phosphatidylethanolamines-specific phospholipase D; Negative BOLD; Olfaction; PTSD; Reticular activating system; Tonic immobility.

Fig. 1

Polarized Positive and Negative BOLD. The color-coded 3D reconstructions for positive and negative BOLD denote the location of the brain areas comprising the hindbrain, midbrain, and forebrain, respectively. The bar graphs below show the average median number of voxels from each of these brain regions for vehicle, 3, 10, and 30 mg/kg I.P. doses of CBD. For forebrain positive BOLD: (****p < 0.0001, 10 mg > Veh); (*p = 0.0133, 10 mg > 3 mg). For hindbrain positive BOLD: (**p = 0.0012, 10 mg < Veh); (****p < 0.00001, 10 mg < 3 mg); (**p = 0.0019, 10 mg < 3 mg). For forebrain negative BOLD: (*p = 0.0197, 10 mg < Veh); (**p = 0.0043 10 < 3 mg). For midbrain negative BOLD: (*p = 0.0389; 3 mg > Veh); (***p = 0.0006, 3 mg > 30 mg). For hindbrain negative BOLD:D voxels (median ca 16) that is significantly increased with the 10 mg dose of CBD over vehicle and 3 mg (****p ≤ 0.0001, 10 mg > Veh, 10 mg > 3 mg)

Fig. 2

Acute Effects of 10 mg Dose of CBD. The tables show a truncated list of 31 and 13 out of 138 brain areas ranked in order of their significance for changes in negative and positive BOLD volume of activation, respectively in response to the 10 mg/kg I.P. dose of CBD. The 3D image (a) summarizes the location of these brain areas presenting with positive (red) and negative (blue) BOLD volume of activation. Below are graphs of BOLD signal change over the 15 min imaging session for the ascending reticular activating system (ARAS) (b) and forebrain (c). Comparisons are made between vehicle and the 10 mg dose of CBD. Shades of red denote positive changes and shades of blue negative changes. For ARAS positive BOLD: (p = 0.0045; CBD < Veh). For ARAS negative BOLD: (p < 0.0001; CBD > Veh). For forebrain positive BOLD (p = 0.0199; CBD > Veh). For forebrain negative BOLD: (p = 0.026 CBD > Veh)

Fig. 3

Regional Changes in Connectivity. Shown are 3D color coded images summarizing CBD-induced changes in connectivity (a) and box and whiskers plots (b) depicting differences in degree centrality in various subregions between vehicle and rats treated with 10 mg/kg CBD 60 min prior to imaging. The CBD group had significantly lower degree centrality of nodes within the hippocampus, hypothalamus, cortex, cerebellum, brainstem, basal ganglia, midbrain, and pons (**p < 0.05, not significant = ns). There were no significant differences in degree within nodes of the amygdala, olfactory system, prefrontal cortex, or thalamus

Fig. 4

Hyperconnectivity to the ARAS with CBD Treatment. Shown to the left (a) are 2D axial maps showing the location of brain areas (red) with enhanced coupling to the ARAS following CBD treatment. Areas in gray denote the location of brain areas comprising the ARAS. The 2D images are summarized in the 3D reconstruction of the red and gray brain areas (b). The circle of connections beneath (c), display the neighboring nodes of the ARAS in the CBD treated group within the olfactory system. Nodes that have a greater degree centrality in the CBD group have been colored red, while nodes that have a greater degree centrality in the vehicle group have been colored blue. Node size has been scaled to reflect the relative difference in degree centrality between the vehicle and CBD group, with the larger nodes reflecting a larger difference in degree centrality

Fig. 5

N-acyl-phosphatidylethanolamines -specific phospholipase D mRNA. Shown are autoradiograms of in situ hybridization of NAPD-PLD messenger RNA in mouse brain. The sagittal section A and B extend medial to lateral. Abbreviations PAG—periaqueductal gray. Image credit: Allen Institute