Transcriptional Regulation, Signaling Pathways, and Subcellular Localization of Corticotropin-Releasing Factor Receptors in the Central Nervous System.

Corticotropin-releasing factor (CRF) receptors CRF-R1 and CRF-R2 are differentially distributed in body tissues, and although they respond differentially to stimuli due to their association with different signaling pathways, both receptors have a fundamental role in the response and adaptation to stressful stimuli. Here, we summarize the reported data on different forms of CRF-R1 and CRF-R2 regulation as well as on their subcellular localization. Although the presence of R1 has been described at pre- and postsynaptic sites, R2 is mainly associated with postsynaptic densities. Different studies have provided valuable information on how these receptors regulate responses at a central level, elucidating different and sometimes synergistic roles in response to stress, but despite their high sequence identity, both receptors have been described to be differentially regulated both by their ligands and by transcriptional factors. To date, and from the point of view of their promoter sequences, it has not yet been reported how the different consensus sites identified in silico could be modulating the transcriptional regulation and expression of the receptors under different conditions, which strongly limits the full understanding of their differential functions, providing a wide field to increase and expand the study of the regulation and role of CRF receptors in the CRF system. SIGNIFICANCE STATEMENT: A large number of physiological functions related to the organization of the stress response in different body tissues are associated with the corticotropin-releasing factor system. This system also plays a relevant role in depression and anxiety disorders, as well as being a direct connection between stress and addiction. A better understanding of how the receptors of this system are regulated would help to expand the understanding of how these receptors respond differently to both drugs and stressful stimuli.

Social isolation of adolescent male rats increases anxiety and K+ -induced dopamine release in the nucleus accumbens: Role of CRF-R1.

Early life adversity can disrupt development leading to emotional and cognitive disorders. This study investigated the effects of social isolation after weaning on anxiety, body weight and locomotion, and on extracellular dopamine (DA) and glutamate (GLU) in the nucleus accumbens (NAc) and their modulation by corticotropin releasing factor receptor 1. On the day of weaning, male rats were housed singly or in groups for 10 consecutive days. Anxiety-like behaviors were assessed by an elevated plus maze (EPM) and an open field test (OF). Neurotransmitter levels were measured by in vivo microdialysis. Single-housed rats spent less time, and entered more, into the closed arms of an EPM than group-housed rats. They also spent less time in the center of an OF, weighed more and showed greater locomotion. In the NAc, no differences in CRF, or in basal extracellular DA or GLU between groups, were observed. A depolarizing stimulus increased DA release in both groups but to higher levels in isolated rats, whereas GLU increased only in single-housed rats. Blocking CRF-R1 receptors with CP-154,526 decreased DA release in single-housed but not in group-housed rats. The corticotropin releasing factor receptor type 1 receptor antagonist also decreased GLU in group-housed animals. These results show that isolating adolescent rats increases anxiety, body weight and ambulation, as well as the sensitivity of dopaminergic neurons to a depolarizing stimulus. This study provides further evidence of the detrimental effects of social isolation during early development and indicates that dysregulation of the CRF system in the NAc may contribute to the pathologies observed.