Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2

Abstract

The differential modulation of learning and anxiety by corticotropin-releasing factor (CRF) through CRF receptor subtypes 1 (CRFR1) and 2 (CRFR2) is demonstrated. As learning paradigm, context- and tone-dependent fear conditioning of the mouse was used. Injection of CRF into the dorsal hippocampus before training enhanced learning through CRFR1 as demonstrated by the finding that this effect was prevented by the local injection of the unselective CRFR antagonist astressin, but not by the CRFR2-specific antagonist antisauvagine-30 (anti-Svg-30). In contrast, injection of CRF into the lateral intermediate septum impaired learning through CRFR2, as demonstrated by the ability of antisauvagine-30 to block this effect. When antisauvagine-30 was injected alone into the lateral intermediate septum, learning was enhanced. Such tonic control of learning was not observed when astressin or antisauvagine-30 was injected into the dorsal hippocampus. Injection of CRF after the training into the dorsal hippocampus and the lateral intermediate septum also enhanced and impaired learning, respectively. Thus, it was indicated that CRF acted on memory consolidation. It was concluded that the observed effects reflected changes of associative learning and not arousal, attention, or motivation. Although a dose of 20 pmol human/rat CRF was sufficient to affect learning significantly, a fivefold higher dose was required to induce anxiety by injection into the septum. Immobilization for 1 hr generated a stress response that included the induction of anxiety through septal CRFR2 and the subsequent enhancement of learning through hippocampal CRFR1. The involvement of either receptor subtype was demonstrated by region-specific injections of astressin and antisauvagine-30.

Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors

“…Thus, CRA1000 and CP-154,526 counteracted the adaptive changes in some system impacted by CRF during the repeated withdrawals from ethanol. A number of earlier reports implicated CRF 1 receptors in the anxiogenic effects of CRF or stress (e.g., Heinrichs et al, 1997;Landgraf, 2001) and in the anxiolytic effects of CRF receptor antagonists (Brauns et al, 2001;Radulovic et al, 1999;Seymour et al, 2003). The present results are consistent with these reports but add a new dimension.…”

“…Rats received intraventricular injections of antisauvagine-30 (20 μg) or artificial cerebrospinal fluid (5 μl) 4 h into the first and second withdrawals. The dose of antisauvagine-30 was selected on the basis of published reports (Brauns et al, 2001;Radulovic et al, 1999). The rat pairs were placed in the social interaction arena 5 h after the removal of ethanol.…”

Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors

“…In support of this hypothesis, Radulovic et al reported in fact that the modulation of learning and anxiety in the mouse are regulated di erentially by CRH-R1 and 2 (Radulovic et al, 1999).…”

“…CRH-R1 and CRH-R2 have been shown to produce di erent e ects in the same murine behavioural model (Radulovic et al, 1999).…”

Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

“…In a previous study, a modest nonsignificant reduction of CRH-LI was seen in the hippocampus of FSL rats (Owens et al, 1991). Intrahippocampal injections of CRH have been shown to enhance learning in mice (Radulovic et al, 1999) and, conversely, injections of antisense CRH gene oligonucleotides impaired memory retention in rats (Wu et al, 1997). The observed decrease of CRH-LI in the hippocampus may possibly reflect aspects of the impaired learning performance and cognitive deficits, which are previously described features of the FSL rat (Yadid et al, 2000;Overstreet, 1993).…”