A CRH₁ Antagonist into the Amygdala of Mice Prevents Defeat‐Induced Defensive Behavior

Abstract

Corticotropin-releasing hormone (CRH) is believed to play an important role in the regulation of behavioral responses to stress. CRH(1) receptor antagonists may reduce stress responsivity. Stress increases CRH in the amygdala, important in memory consolidation. We hypothesized that infusion of a CRH(1) antagonist into the amygdala following social defeat would prevent the development of generalized fear responses. Acute social defeat in mice increases defense towards intruders, even nonaggressive intruders, placed within their home cage. We infused the CRH(1) antagonist antalarmin (0.25 microg/125 nl) bilaterally into the amygdala of mice immediately after defeat and measured their response to a nonaggressive intruder stimulus mouse placed within their home cage 24 h after defeat. Defeated mice that received vehicle displayed high levels of crouch defensive posture and numerous flights from intruders, relative to nondefeated mice that received vehicle. Defeated mice that received antalarmin into the amygdala exhibited significantly less defensive posture than did vehicle-treated defeated mice. Display of defensive posture in antalarmin-treated mice approached that of vehicle-treated nondefeated mice. These findings support a role for CRH in the amygdala to promote consolidation of emotional memory and indicate that antagonism of CRH(1) receptors in the amygdala may prevent the development of exaggerated fear responses in stressed mice.

Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear

“…Furthermore, BLA CRF 1 receptor antagonism was not occurring during the acquisition of fear conditioning, which rules out potential confounding fear conditioning factors such as motivational, performance, or footshock pain sensitivity processes (Cahill et al, 1999). We are aware of only one other report suggesting a role of BLA CRF 1 receptors in the consolidation of emotional memory (Robison et al, 2004). In that study, mice injected with 250 μg antalarmin into the BLA immediately after exposure to social defeat subsequently exhibited lower levels of defensive posturing to a nonaggressive opponent than vehicle-injected controls.…”

“…This putative BLA CRF 1 fear consolidation effect was further examined in mice using the CRF 1 antagonist antalarmin. When microinjected into the BLA immediately after social defeat, antalarmin-treated mice exhibited a reduction in defensive behavior to a nonaggressive intruder when tested the next day (Robison et al, 2004). Whether BLA CRF 1 receptors play a role in contextual fear conditioning and the CRF 1 receptor consolidation effects are specific to the BLA and not the CeA remains to be determined.…”

Subtype-Selective Corticotropin-Releasing Factor Receptor Agonists Exert Contrasting, but Not Opposite, Effects on Anxiety-Related Behavior in Rats

“…Infusion of D-Phe-CRF 12-41 into the lateral ventricle or extended amygdala (Jasnow et al, 2004) reduced "submissive/defensive behavior" in previously defeated Syrian hamsters encountering an unfamiliar male. Intra-amygdala antalarmin similarly reduced "defensive posturing" in defeated mice exposed to an unfamiliar male (Robison et al, 2004). CRF receptor agonists (i.c.v.)…”

Hormonal Responses to Psychological Stress and Family History of Alcoholism

“…Although the processes underlying this relationship remain inconclusive, there is evidence in preclinical models that glucocorticoids influence alcohol consumption by enhancing mesolimbic dopamine accumulation (Marinelli and Piazza, 2002). In addition, glucocorticoids increase the expression of CRH in the amygdala (Cook, 2002;Robison et al, 2004), which plays a crucial role in anxiety behaviors and in promoting alcohol intake (McBride, 2002;Koob, 2003;Pandey, 2003).…”