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

Christopher B Engborg; Manaswini Pujar; Rahul N Kanadia; Natale R Sciolino

doi:10.1016/j.neuroscience.2025.08.046

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

Neuroscience. 2025 Oct 15:585:14-27. doi: 10.1016/j.neuroscience.2025.08.046. Epub 2025 Aug 28.

Authors

Christopher B Engborg¹, Manaswini Pujar¹, Rahul N Kanadia², Natale R Sciolino³

Affiliations

¹ Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
² Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA; Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.
³ Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA; Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA; Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269, USA; Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: natale.sciolino@uconn.edu.

PMID: 40885375
PMCID: PMC12421906 (available on 2026-08-28)
DOI: 10.1016/j.neuroscience.2025.08.046

Abstract

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 (Cnr1^cKO-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 Cnr1^cKO-Dbh mice, confirming targeted deletion. Behaviorally, Cnr1^cKO-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. Cnr1^cKO-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.

Keywords: Anxiety; Cannabinoid; Catecholamine; Fear; Knockout mouse; Stress.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adrenergic Neurons* / metabolism
Animals
Anxiety / metabolism
Epinephrine* / metabolism
Locus Coeruleus / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons* / metabolism
Norepinephrine* / metabolism
Receptor, Cannabinoid, CB1* / genetics
Receptor, Cannabinoid, CB1* / metabolism
Restraint, Physical
Stress, Psychological* / metabolism
Stress, Psychological* / physiopathology

Substances

Receptor, Cannabinoid, CB1
Norepinephrine
Epinephrine
CNR1 protein, mouse

Grants and funding

R00 DK119586/DK/NIDDK NIH HHS/United States