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Sex differences in the effect of cannabinoid type 1 receptor deletion on locus coeruleus‐norepinephrine neurons and corticotropin releasing factor‐mediated responses
Author(s) -
Wyrofsky Ryan R.,
Reyes Beverly A. S.,
Yu Daohai,
Kirby Lynn G.,
Bockstaele Elisabeth J.
Publication year - 2018
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14103
Subject(s) - locus coeruleus , endocrinology , medicine , prefrontal cortex , cannabinoid , endocannabinoid system , norepinephrine , chemistry , tyrosine hydroxylase , receptor , electrophysiology , catecholamine , dopamine , biology , neuroscience , central nervous system , cognition
Cannabinoids are capable of modulating mood, arousal, cognition and behavior, in part via their effects on the noradrenergic nucleus locus coeruleus ( LC ). Dysregulation of LC signaling and norepinephrine ( NE ) efflux in the medial prefrontal cortex ( mPFC ) can lead to the development of psychiatric disorders, and CB 1r deletion results in alterations of α2‐ and β1‐adrenoceptors in the mPFC , suggestive of increased LC activity. To determine how CB 1r deletion alters LC signaling, whole‐cell patch‐clamp electrophysiology was conducted in LC ‐ NE neurons of male and female wild type ( WT ) and CB 1r‐knock out ( KO ) mice. CB 1r deletion caused a significant increase in LC ‐ NE excitability and input resistance in male but not female mice when compared to WT . CB 1r deletion also caused adaptations in several indices of noradrenergic function. CB 1r/ CB 2r‐ KO male mice had a significant increase in cortical NE levels and tyrosine hydroxylase and CRF levels in the LC compared to WT males. CB 1r/ CB 2r‐ KO female mice showed a significant increase in LC α2‐ AR levels compared to WT females. To further probe actions of the endocannabinoid system as an anti‐stress neuromediator, the effect of CB 1r deletion on CRF ‐induced responses in the LC was investigated. The increase in LC ‐ NE excitability observed in male and female WT mice following CRF (300 nM ) bath application was not observed in CB 1r‐ KO mice. These results indicate that cellular adaptations following CB 1r deletion cause a disruption in LC ‐ NE signaling in males but not females, suggesting underlying sex differences in compensatory mechanisms in KO mice as well as basal endocannabinoid regulation of LC ‐ NE activity.