Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

Abstract

Rationale-Corticotropin releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established.Objectives-We used selective CRF receptor antagonists to determine the receptor subtypes involved in the anxiogenic-like and aversive effects CRF in the BNST. Methods-MaleLong-Evans rats were bilaterally infused with CRF (0.2 or 1.0 nmol) either alone or in combination with the CRF 1 receptor antagonist CP154,526 or the CRF 2 receptor antagonist anti-sauvagine 30 (AS30) prior to behavioral testing in the elevated plus maze or place conditioning paradigms.Results-Intra-BNST administration of CRF produced a dose-dependent reduction in open arm entries and open arm time in the elevated plus maze, indicating an anxiogenic-like effect. These effects were inhibited by co-infusion of CP154,526 but not AS30, indicating that the anxiogeniclike effects of CRF in the BNST are mediated by CRF 1 receptors. Place conditioning with intra-BNST administration of CRF produced a dose-dependent aversion to the CRF-paired environment that was prevented by co-infusion of either CP154,526 or AS30, indicating that both CRF receptor subtypes mediate the aversive effects of this peptide. Intra-BNST infusions of the CRF receptor antagonists alone produced no effects in either behavioral paradigm.Conclusions-CRF 1 receptors in the BNST mediate the anxiogenic-like effects CRF in this region, whereas both CRF 1 and CRF 2 receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST.

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…Using specific CRF 1 and CRF 2 receptor antagonists, we found circumstantial evidence for both converging and opposing receptor functions, dependent on the behavior under investigation. Although our results support previous reports of CRF receptor function on the anxiety-like behavior in the EPM (Sahuque et al, 2006;Sink et al, 2013) and modulation of somatic pain processing (Ji and Neugebauer, 2008), the observed changes in visceral sensitivity contradicted previous studies using peripherally restricted CRF 1 and CRF 2 receptor antagonists (Greenwood- Nijsen et al, 2005). This suggested that the effects of CRF 1 and CRF 2 receptor activation, at least on visceral sensitivity, may differ depending on the localization of the receptors.…”

Repeated Stimulation of CRF Receptors in the BNST of Rats Selectively Induces Social but not Panic-Like Anxiety

“…For instance, priming of the BNSTinduced anxiety-like behavior in SI test without affecting performance in EPM. Considering that the intra-BNST CRF system has been implicated in anxiety responses measured in EPM (Sahuque et al, 2006), the lack of changes in EPM measure in the current study is intriguing. One possible explanation is that CRF injections into the BNST were given bilaterally in the study by Sahuque et al, where as in the present study, priming was done with unilateral injections.…”

“…results of Sahuque et al, 2006, demonstrating that the anxiogenic effects of CRF in the BNST was mediated by CRF1 receptors, where as the stress-induced reinstatement of drug-seeking behavior was mediated by both CRF1 and CRF2 receptors.…”

Corticotropin-releasing hormone receptors in the medial prefrontal cortex regulate hypothalamic–pituitary–adrenal activity and anxiety-related behavior regardless of prior stress experience

“…It was surprising that a higher dose of CRH had no substantial effect on EPM behavior, but the lower dose did. CRH generally produces dose-dependent increases in anxietyrelated behaviors when microinjected into limbic regions such as the BNST (Sahuque et al, 2006) or periaqueductal grey (Martins et al, 1997). However, very little is known about CRH receptor activation specifically in cortical regions and its effects on behavior.…”