title: Co-localization of the cannabinoid type 1 receptor with corticotropin-releasing factor-containing afferents in the noradrenergic nucleus locus coeruleus: implications for the cognitive limb of the stress response.
abstract: The noradrenergic system has been shown to play a key role in the regulation of stress responses, arousal, mood, and emotional states. Corticotropin-releasing factor (CRF) is a primary mediator of stress-induced activation of noradrenergic neurons in the nucleus locus coeruleus (LC). The endocannabinoid (eCB) system also plays a key role in modulating stress responses, acting as an "anti-stress" neuro-mediator. In the present study, we investigated the cellular sites for interactions between the cannabinoid receptor type 1 (CB1r) and CRF in the LC. Immunofluorescence and high-resolution immunoelectron microscopy showed co-localization of CB1r and CRF in both the core and peri-LC areas. Semi-quantitative analysis revealed that 44% (208/468) of CRF-containing axon terminals in the core and 35% (104/294) in the peri-LC expressed CB1r, while 18% (85/468) of CRF-containing axon terminals in the core and 6.5% (19/294) in the peri-LC were presynaptic to CB1r-containing dendrites. In the LC core, CB1r + CRF axon terminals were more frequently of the symmetric (inhibitory) type; while in the peri-LC, a majority were of the asymmetric (excitatory) type. Triple label immunofluorescence results supported the ultrastructural analysis indicating that CB1r + CRF axon terminals contained either gamma amino butyric acid or glutamate. Finally, anterograde transport from the central nucleus of the amygdala revealed that CRF-amygdalar afferents projecting to the LC contain CB1r. Taken together, these results indicate that the eCB system is poised to directly modulate stress-integrative heterogeneous CRF afferents in the LC, some of which arise from limbic sources.
authors.affiliation: Department of Pharmacology and Physiology, College of Medicine, Drexel University, 245 S. 15th Street, Philadelphia, PA, 19102, USA. rrw47@drexel.edu.
authors.forename: Ryan
authors.initials: R
authors.lastname: R Wyrofsky
authors.affiliation: Department of Pharmacology and Physiology, College of Medicine, Drexel University, 245 S. 15th Street, Philadelphia, PA, 19102, USA.
authors.forename: Beverly A S
authors.initials: BAS
authors.lastname: Reyes
authors.affiliation: Department of Pharmacology and Physiology, College of Medicine, Drexel University, 245 S. 15th Street, Philadelphia, PA, 19102, USA.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Van Bockstaele
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism* / Q000648:ultrastructure; D016622:Silver Staining; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C543264:Cnr1 protein, rat; D043884:Receptor, Cannabinoid, CB1; D016708:Synaptophysin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003346:Corticotropin-Releasing Hormone
keywords: Addiction; Arousal; Norepinephrine; Psychiatric disorders