Research reportRole of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses
Introduction
Corticotropin-releasing factor (CRF) plays a critical role in initiating the cascade of biological events during the stress response 24, 44. Although initially CRF was recognized for its role in regulating the hormonal response to stress, CRF has been found to have a part in mediating the behavioral aspect of stress as well. CRF administered into the central nervous system will induce anxiety-like behaviors in several animal models [11]. Transgenic mice which overproduce CRF show increased anxiety-like behaviors which are reversed by central administration of the CRF antagonist α-helical CRF 9-41 [29a]. Thus, there is strong evidence that CRF may act as a neurotransmitter/neuromodulator regulating stress and anxiety.
Currently, there have been at least two different CRF receptors identified 5, 6, 19, 21, 27, 28, 47. The anxiogenic behavior produced by CRF in rats appears to be mediated via the CRF-1 receptor [14]. Recently, a peptide which shares sequence identity with both urotensin I and CRF has been discovered and named urocortin (Ucn) [46]. In addition, it appears that Ucn is capable of eliciting anxiety-like behaviors after i.c.v. administration [23].
The amygdala has been implicated as a major anatomical site for regulation of the fight-or-flight response. In previous studies, we have shown that disruption of inhibitory neurotransmission within the BLA using the GABAA antagonist bicuculline methiodode (BMI) can lead to behavioral and physiological responses similar to that seen in anxiety disorders [37]. Further, daily injections of a subthreshold dose of BMI can alter the threshold for BMI effects within the BLA by day 5 [38]. Thus, a 6 pmol (subthreshold dose) injection of BMI on experimental day 5 can induce anxiety-like behaviors similar to a 20 pmol (threshold dose) in an untreated animal. These changes in synaptic activity were termed `priming' and were maintained for at least 6 weeks [38].
The development of anxiety-like behaviors in rats seen during `priming' was similar to panic disorder, a subtype of anxiety. Patients with this type of anxiety exhibit a unique sensitivity to sodium lactate 20, 29, 30, 31. Infusion of sodium lactate into primed rats can induce the development of both anxiety-like behavior and cardiovascular responses in these animals [32]. Thus, the long-term synaptic changes occurring during priming could be similar to subjects with panic disorder.
The first purpose of the study was to compare the effects of Ucn and CRF administered directly into the BLA on anxiety-like behaviors. Second was to characterize the effects of repeated microinjections of subthreshold doses of Ucn and CRF into the BLA on changes in anxiety threshold and lastly we tested the primed animals with lactate infusions to elicit panic responses.
Section snippets
Animals
All experiments were conducted on male Wistar rats (300–350 g) obtained from Harlan Laboratories (Indianapolis, IN). They were individually housed and given food and water ad libitum. The room temperature was controlled at 72°F (22°C) and maintained on a 12-h light, 12-h dark schedule.
Arterial/venous catheterization
Arterial and venous catheters were made up of 8 cm of 0.01 in Teflon tubing (Small Parts, Miami Lakes, FL). A 3-cm section of a 30-cm piece of 0.02 in Tygon tubing (Fisher Scientific, Pittsburgh, PA) was soaked in
Dose response of CRF and Ucn
In the initial experiments, animals received bilateral infusions of vehicle or various doses of CRF and Ucn. Both peptides produced dose-dependent reductions in SI time. Analysis of the resulting data with a one-way ANOVA revealed a significant difference among the doses for both CRF [Fig. 1A: F(3,24)=5.287; P=0.0061] and Ucn [Fig. 1B: F(3,24)=4.880; P=0.0087]. Post hoc analysis between the doses of CRF revealed a significant difference between the 200 fmol dose of CRF and vehicle [P=0.0074] as
Discussion
Central administration of CRF has been shown to have an important role in initiating the biological events known to occur during the stress response 24, 44. It has also been shown to produce anxiogenic-like behavior in several behavioral tests such as open field 17, 41, 43, elevated plus maze [1], conflict test [2], social interaction [12], acoustic startle 18, 42and conditioned fear paradigm [7]. The anxiogenic-like response to CRF in rats appears to be mediated via the CRF-1 receptor [14].
References (49)
Emotional memory systems in the brain
Behav Brain Res
(1993)- et al.
Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions
Pharm Biochem Behav
(1996) - Baldwin HA, Rassnick S, Rivier J, Koob GF, Britton KT. CRF antagonist reverses the `anxiogenic' response to ethanol...
- Britton KT, Morgan J, Rivier J, Vale W, Koob GF. Chlordiazepoxide attenuates response suppression induced by...
- Campeau S, Davis M. Involvement of the central nucleus and the basolateral complex of the amygdala in fear conditioning...
- Chalmers DT, Lovenberg TW, Souza EBD. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA...
- Chang CP, Pearse RV, O'Connell S, Rosenfeld MG. Identification of a seven transmembrane helix receptor for...
- Chen R, Lewis KA, Perrin MH, Vale WW. Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl...
- Cole BJ, Koob GF. Propanolol antagonizes the enhanced conditioned fear produced by corticotropin-releasing factor. J...
- Cratty M, Ward H, Johnson E, Azzaro A, Birkle D. Prenatal stress increases corticotropin-releasing factor (CRF) content...
Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats
J Neurosci
Corticotropin-releasing factor: Long-lasting facilitation of the acoustic startle reflex
J Neurosci
Possible mechanisms for lactate's induction of panic
Am J Psychiatry
Microinfusion of corticotropin-releasing factor (CRF) into the locus coeruleus (LC) increases ceco-colonic myoelectric activity and LC neuronal activity simultaneously in anaesthetized rats
Gastroenterology
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