Sex differences in the effect of cannabinoid type 1 receptor deletion on locus coeruleus‐norepinephrine neurons and corticotropin releasing factor‐mediated responses

Abstract

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 CB1r deletion results in alterations of α2- and β1-adrenoceptors in the mPFC, suggestive of increased LC activity. To determine how CB1r deletion alters LC signaling, whole-cell patch-clamp electrophysiology was conducted in LC-NE neurons of male and female wild type (WT) and CB1r-knock out (KO) mice. CB1r deletion caused a significant increase in LC-NE excitability and input resistance in male but not female mice when compared to WT. CB1r deletion also caused adaptations in several indices of noradrenergic function. CB1r/CB2r-KO male mice had a significant increase in cortical NE levels and tyrosine hydroxylase and CRF levels in the LC compared to WT males. CB1r/CB2r-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 CB1r 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 CB1r-KO mice. These results indicate that cellular adaptations following CB1r 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.

Noradrenergic depletion causes sex specific alterations in the endocannabinoid system in the Murine prefrontal cortex

“…In a recent whole-cell patch-clamp electrophysiology study conducted on LC brain sections taken from mice lacking the CB1r (CB1r-KO), it was demonstrated that male CB1r-KO mice had heightened LC-NE activity compared to female CB1r-KO mice and to WT mice. This was evident as increased NE cell excitability in male CB1r KOs, whereas there were no significant changes in CB1r-KO females (Wyrofsky et al, 2018). Further support for the sex differences observed in this study were corroborated by NE ELISA, in which there was increased NE in CB1r-KO males compared to CB1r-KO females and WT controls (Wyrofsky et al, 2018).…”

Commentary on “Sex differences in the effect of cannabinoid type 1 receptor deletion on locus coeruleus‐norepinephrine neurons and corticotropin releasing factor‐mediated responses”

“…It was reported in this study that cannabinoid receptor type 1 (Cnr1) deletion resulted in increased locus‐coeruleus norepinephrine excitability in male but not female mice. The study also reported increased norepinephrine, tyrosine hydroxylase and corticotrophin hormone levels in male but not female Cnr1 knockout mice (Wyrofsky et al., ). Both of these findings support the hypothesis that the endocannabinoid system is recruited to a greater extent in males than females during acutely stressful experiences, and may therefore provide buffering against short and long‐term negative health effects of traumatic or severe stress for males more so than females (Ney, Matthews, Bruno, & Felmingham, ).…”

“…The study by Wyrofsky et al. () further suggests that phasic regulation of stress hormones is more strongly influenced by endocannabinoid signalling in males compared to females, and also further suggests that the endocannabinoid “buffer” towards stress may be reduced in females compared to males. This study therefore adds further evidence that differences in endocannabinoid signalling between the sexes may explain the discrepancy observed in clinical prevalence of stress and anxiety disorders following severe stress or trauma.…”

“…We therefore hypothesized as part of this review that a potential mechanism for sex differences in the prevalence of stress and anxiety disorders may be differential recruitment of endocannabinoid signalling as part of the stress response (Ney et al, 2018). The study by Wyrofsky et al (2018) further suggests that phasic regulation of stress hormones is | 1211 FEATURED PAPER COMMENTARY more strongly influenced by endocannabinoid signalling in males compared to females, and also further suggests that the endocannabinoid "buffer" towards stress may be reduced in females compared to males. This study therefore adds further evidence that differences in endocannabinoid signalling between the sexes may explain the discrepancy observed in clinical prevalence of stress and anxiety disorders following severe stress or trauma.…”

“…The recent study by Wyrofsky, Reyes, Yu, Kirby, and Van Bockstaele () has provided important new evidence for sex‐driven modulation of endogenous cannabinoid (endocannabinoid) signalling during the stress response. It was reported in this study that cannabinoid receptor type 1 (Cnr1) deletion resulted in increased locus‐coeruleus norepinephrine excitability in male but not female mice.…”