Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Miles, Leigh; Davis, Michael; Walker, David

doi:10.1038/npp.2011.29

Cited by 44 publications

(41 citation statements)

References 70 publications

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“…Log transforms of ratio data have been recommended for a variety of reasons, including normalization of skewed distributions prior to parametric analyses (for a concise review, see Keene 1995). Although the results of the analyses included here were not appreciably different for raw ratio vs. log-transformed scores, we include the latter for consistency with prior analyses from our group (Miles et al 2011).…”

Section: Statistical Analysesmentioning

confidence: 94%

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CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

2013

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Calcitonin gene-related peptide (CGRP) infusions into the bed nucleus of the stria terminalis (BNST) evoke increases in startle amplitude and increases in anxiety-like behavior in the plus maze. Conversely, intra-BNST infusions of the CGRP antagonist CGRP 8 -37 block unconditioned startle increases produced by fox odor. Here we evaluate the contribution of CGRP signaling in the BNST to the development and expression of learned fear. Rats received five pairings of a 3.7-sec light and footshock and were tested for fear-potentiated startle one or more days later. Neither pre-training (Experiment 1) nor pre-test (Experiment 2) infusions of the CGRP antagonist CGRP 8 -37 (800 ng/BNST) disrupted fear-potentiated startle to the 3.7-sec visual cue. However, in both experiments, CGRP 8 -37 infusions disrupted baseline startle increases that occurred when rats were tested in the same context as that in which they previously received footshock (Experiment 3). Intra-BNST CGRP 8 -37 infusions did not disrupt shock-evoked corticosterone release (Experiment 4). These data confirm previous findings implicating BNST CGRP receptors in fear and anxiety. They extend those results by showing an important contribution to learned fear and, specifically, to fear evoked by a shock-associated context rather than a discrete cue. This pattern is consistent with previous models of BNST function that have posited a preferential role in sustained anxiety as opposed to phasic fear responses. More generally, the results add to a growing body of evidence indicating behaviorally, possibly clinically, relevant modulation of BNST function by neuroactive peptides.

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Section: Statistical Analysesmentioning

confidence: 94%

“…4A). Log scores are included as they are often recommended for these types of data (see Keene 1995) and have previously been reported by our laboratory (Miles et al 2011). As the session wore on, potentiation scores of the two groups converged such that the overall difference was not statistically significant.…”

Section: Cannula Tip Placementsmentioning

confidence: 99%

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

2013

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“…For example, Miles et al (2011) demonstrated that both benzodiazepine (chlordiazepoxide) and chronic administration of a serotonin selective reuptake inhibitor (SSRI; fluoxetine) significantly reduced sustained fear responses but had no effect on phasic fear responses. In contrast, the 5HT 1A agonist (buspirone) reduced phasic but not sustained responses, highlighting a pharmacological dissociation.…”

Section: Building Blocks For Human Studies: Current Evidence In Rodenmentioning

confidence: 99%

The Human BNST: Functional Role in Anxiety and Addiction

Avery

Clauss

Blackford

2015

Neuropsychopharmacol

284

206

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The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region-the bed nucleus of the stria terminalis (BNST)-in the body's stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stressrelated disorders and identify novel neural targets for treatment.

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“…Rats show an enhanced ASR when levels of anxiety are increased (8,30,31). Therefore, we defined molecules as positive (+) for anxiogenic activity when we observed a significant increase in the amplitude of the ASR following exposure.…”

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confidence: 99%

Identification of a pheromone that increases anxiety in rats

Inagaki

Kiyokawa

Tamogami³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Chemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called pheromones. Rats release a specific odor into the air when stressed. This stress-related odor increases the anxiety levels of other rats; therefore, it is possible that the anxiety-causing molecules are present in the stress-related odorants. Here, we have tried to identify the responsible molecules by using the acoustic startle reflex as a bioassay system to detect anxiogenic activity. After successive fractionation of the stress-related odor, we detected 4-methylpentanal and hexanal in the final fraction that still possessed anxiogenic properties. Using synthetic molecules, we found that minute amounts of the binary mixture, but not either molecule separately, increased anxiety in rats. Furthermore, we determined that the mixture increased a specific type of anxiety and evoked anxiety-related behavioral responses in an experimental model that was different from the acoustic startle reflex. Analyses of neural mechanisms proposed that the neural circuit related to anxiety was only activated when the two molecules were simultaneously perceived by two olfactory systems. We concluded that the mixture is a pheromone that increases anxiety in rats. To our knowledge, this is the first study identifying a rat pheromone. Our results could aid further research on rat pheromones, which would enhance our understanding of chemical communication in mammals.stress-related odor | alarm pheromone | acoustic startle reflex | anxiety | rat C hemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called "pheromones." Because the term pheromone was coined and defined based on findings in insects (1), there is still a debate as to whether the original definition can be applied to mammals (2). Researchers have proposed revised definitions by modifying the original definition and/or specifying additional requirements (3-6). On the basis of the original and revised definitions, we set a working definition of pheromone within this study as (i) substances that are secreted to the outside by an individual and received by a second individual of the same species, in which they cause a specific reaction; (ii) substances that are effective in minute amounts; (iii) substances that are released from living individuals; and (iv) substances that mediate communication for an evolutionarily adaptive function.Rats release a specific odor into the air when stressed (7). This stress-related odor increases anxiety levels (8, 9) and induces a variety of anxiety-related responses depending on their situation with other rats (9-18). Rats respond to their own stressrelated odor in a similar manner to odor released from the other rats, suggesting that the odor has general effects (10,19). In addition, the stress-related odor appears to be effective in minute amounts (20,21). Therefore, the molecules responsible for increasing anxiety levels should exist in the...

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Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Cited by 44 publications

References 70 publications

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

The Human BNST: Functional Role in Anxiety and Addiction

Identification of a pheromone that increases anxiety in rats

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