CB1 Cannabinoid Receptor Agonists Induce Acute Respiratory Depression in Awake Mice

Recreational use of synthetic cannabinoid agonists (i.e., Spice compounds) that target the Cannabinoid Type 1 receptor (CB1) can cause acute respiratory failure in humans. However, Δ9-tetrahydrocannabinol (THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with the brain respiratory system, based largely upon sparse labeling of CB1 receptors in the medulla and widespread human use. The respiratory effects of CB1 agonists have rarely been studied in vivo, suggesting that additional inquiry is required to reconcile the conflict between conventional wisdom and human data. Here we used whole body plethysmography to examine the respiratory effects of the synthetic CB1 full agonist CP55,940, and the partial CB1 agonist Δ9-tetrahydrocannabinol in male and female mice. CP55,940 and THC, administered systemically, produced robust suppression of minute ventilation. Both cannabinoids also produced sizable reductions in tidal volume, decreasing both peak inspiratory and expiratory flow - measures of respiratory effort. Similarly, both drugs reduced respiratory frequency, decreasing both inspiratory and expiratory time while markedly increasing expiratory pause, and to a lesser extent, inspiratory pause. Respiratory suppressive effects occurred at lower doses in females than in males, and at many of the same doses shown to produce cardinal behavioral signs of CB1 activation. We also used RNAscope in situ hybridization to localize CB1 mRNA to the medullary pre-Botzinger Complex, a critical nucleus of respiratory control. Our results show that, contrary to previous conventional wisdom, CB1 mRNA is expressed in glutamatergic neurons in a brain region essential for breathing and may directly contribute to respiratory depression. ### Competing Interest Statement The authors have declared no competing interest.