Resting State Brain Networks under Inverse Agonist versus Complete Knockout of the Cannabinoid Receptor 1.

The cannabinoid receptor 1 (CB(1)) is famous as the target of Δ(9)-tetrahydrocannabinol (THC), which is the active ingredient of marijuana. Suppression of CB(1) is frequently suggested as a drug target or gene therapy for many conditions (e.g., obesity, Parkinson's disease). However, brain networks affected by CB(1) remain elusive, and unanticipated psychological effects in a clinical trial had dire consequences. To better understand the whole brain effects of CB(1) suppression we performed in vivo imaging on mice under complete knockout of the gene for CB(1) (cnr1(-/-)) and also under the CB(1) inverse agonist rimonabant. We examined white matter structural changes and brain function (network activity and directional uniformity) in cnr1(-/-) mice. In cnr1(-/-) mice, white matter (in both sexes) and functional directional uniformity (in male mice) were altered across the brain but network activity was largely unaltered. Conversely, under rimonabant, functional directional uniformity was not altered but network activity was altered in cortical regions, primarily in networks known to be altered by THC (e.g., neocortex, hippocampal formation). However, rimonabant did not alter many brain regions found in both our cnr1(-/-) results and previous behavioral studies of cnr1(-/-) mice (e.g., thalamus, infralimbic area). This suggests that chronic loss of cnr1 is substantially different from short-term suppression, subtly rewiring the brain but largely maintaining the network activity. Our results help explain why pathological mutations in CB(1) (e.g., chronic pain) do not always provide insight into the side effects of CB(1) suppression (e.g., clinical depression), and thus urge more preclinical studies for any drugs that suppress CB(1).