CB ₁ 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 (CB ₁ ) can cause respiratory depression in humans. However, Δ ⁹ -tetrahydrocannabinol (THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with CNS control of respiration, based largely upon sparse labeling of CB1 receptors in the medulla and few reports of clinically significant respiratory depression following cannabis overdose. The respiratory effects of CB ₁ 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 high efficacy CB ₁ agonist CP55,940, and the low efficacy CB ₁ agonist Δ ⁹ -tetrahydrocannabinol in male and female mice. CP55,940 and THC, administered systemically, both robustly suppressed 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 CB ₁ activation. We next used RNAscope in situ hybridization to localize CB ₁ mRNA to glutamatergic neurons in the medullary pre-Bötzinger Complex, a critical nucleus in controlling respiration. Our results show that, contrary to previous conventional wisdom, CB ₁ mRNA is expressed in glutamatergic neurons in a brain region essential for breathing and CB ₁ agonists can cause significant respiratory depression.