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

The cannabinoid receptor 1 (CB₁) is famous as the target of Δ⁹-tetrahydrocannabinol (THC), which is the active ingredient of marijuana. Suppression of CB₁ is frequently suggested as a drug target or gene therapy for many conditions (e.g., obesity, Parkinson's disease). However, brain networks affected by CB₁ remain elusive, and unanticipated psychological effects in a clinical trial had dire consequences. To better understand the whole brain effects of CB₁ suppression we performed in vivo imaging on mice under complete knockout of the gene for CB₁ (cnr1^-/-) and also under the CB₁ 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 CB₁ (e.g., chronic pain) do not always provide insight into the side effects of CB₁ suppression (e.g., clinical depression), and thus urge more preclinical studies for any drugs that suppress CB₁.