Stress reactivity is modulated by cannabinoid type-1 receptors in norepinephrine and epinephrine neurons in a context-dependent manner.

Disruptions in the endocannabinoid system (ECS) and norepinephrine/epinephrine (NE/E) system are individually linked to stress-related neuropsychiatric disorders, but their interaction in shaping stress responses remains unclear. We investigated the role of the ECS's primary receptor, cannabinoid type-1 receptor (CB1R), in NE/E-producing neurons using anatomical, behavioral, and physiological analyses in a conditional knockout mouse model (Cnr1cKO-Dbh), in which the Cnr1 gene-encoding CB1R-was selectively deleted in dopamine beta-hydroxylase-expressing cells. In situ hybridization in control mice revealed Cnr1 is broadly expressed in medullary C1/A1 and C2/A2 and sparsely in the locus coeruleus, marking the first cell-type-specific characterization of Cnr1 in brainstem catecholaminergic populations. Cnr1 was reduced across all nuclei in Cnr1cKO-Dbh mice, confirming targeted deletion. Behaviorally, Cnr1cKO-Dbh mice showed normal baseline anxiety-like behavior, but reduced avoidance in the open field after acute restraint stress. However, no genotype differences were found after foot shock in the elevated plus maze and light-dark box, suggesting context-dependent CB1R effects. Cnr1cKO-Dbh mice also exhibited reduced immobility in the forced swim test, but not the tail suspension test. In response to looming visual threats, they showed increased escape behavior across trials, reduced rearing and exploration during the first disc presentation, and no changes in freezing. Heart rate responses following foot shock stress were unchanged. These findings suggest that CB1R in NE/E neurons selectively modulate components of the acute stress response in a manner dependent on behavioral context. This work underscores the need for further investigation into the circuit- and state-specific roles of CB1R signaling in stress regulation.