Priming of experimental anxiety by repeated subthreshold GABA blockade in the rat amygdala

doi:10.1016/0006-8993(95)00915-D

Brain Research

Volume 699, Issue 2, 20 November 1995, Pages 250-259

https://doi.org/10.1016/0006-8993(95)00915-D Get rights and content

Abstract

Blockade of GABA_A receptor function in the area of the anterior basolateral amygdala of rats elicits physiological (increases in heart rate and blood pressure) and behavioral changes similar to symptoms of human anxiety states. Repeated subthreshold blockade of GABA_A receptors in this region appears to result in a long-term ‘priming’ of these anxiety-like responses. The present study was conducted to characterize the ‘priming’ of the heart rate and blood pressure responses and to test if these ‘primed’ animals would show increases in anxiety responses. Male Wistar rats with arterial catheters placed for physiological measurements were implanted with chronic microinjection cannulae in the anterior basolateral amygdaloid nucleus (BLA) under pentobarbital anesthesia. Repeated daily injections of a subthreshold dose of bicuculline methiodide (GABA_A receptor antagonist; BMI) into the BLA elicited ‘priming’ of physiological responses after 3–5 injections and this response was maintained for at least 6 weeks. The primed animals also showed increased anxiogenic responses to GABA_A blockade in the BLA. The ‘priming’ of anxiety responses were clearly elicited before kindling of seizures as measured by EEG. These results suggest that this ‘priming’ phenomenon may be similar to kindling and long-term potentiation. This could be one potential mechanism for developing pathological emotional response, such as chronic, high levels of anxiety.

References (41)

FontaineR. et al.
Temporal lobe abnormalities in panic disorder: an MRI study
Biol. Psychiatry
(1990)
IwataJ. et al.
Cardiovascular responses elicited by stimulation of neurons in the central amygdaloid nucleus in awake but not anesthetized rats resemble conditioned emotional responses
Brain Res.
(1987)
KimM. et al.
Infusion of the non-NMDA receptor antagonist CNQX into the amygdala blocks the expression of fear-potentiated startle
Behav. Neural Biol.
(1993)
KnottV.J.
Neuroelectrical activity related to panic disorder
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(1990)
LepolaU. et al.
EEG and CT findings in patients with panic disorder
Biol. Psychiatry
(1990)
NagyJ. et al.
Anti-anxiety action of diazepam after intra-amygdaloid application in the rat
Neuropharmacology
(1979)
PetersenE.N. et al.
Evidence that the anticonflict effect of midazolam in amygdala is mediated by the specific benzodiazepine receptors
Neurosci. Lett.
(1985)
RacineR.J.
Modification of seizure activity by electrical stimulation: II. Motor seizure
Electroencephalogr. Clin. Neurophysiol.
(1972)
SandersS.K. et al.
Blockade of GABA_A receptors in the region of the anterior basolateral amygdala of rats elicits increases in heart rate and blood pressure
Brain Research
(1991)
SandersS.K. et al.
Anxiolytic effects of chlorodiazepoxide blocked by injection of GABA_A and benzodiazepine receptor antagonists in the region of the anterior basolateral amygdala of rats
Biol. Psychiatry
(1995)

Scheel-KrügerJ. et al.

Anticonflict effect of the benzodiazepines mediated by a gabaergic mechanism in the amygdala

Eur. J. Pharmac.

(1982)

WuJ.C.

PET in generalized anxiety disorder

Biol. Psychiatry

(1991)

BeckA.T. et al.

Ideational components of anxiety neurosis

Arch. Gen. Psych.

(1974)

BettsT.A.

Epilepsy and Psychiatry

(1981)

BingleyT.

Mental symptoms in temporal lobe epilepsy and temporal lobe gliomas

Acta Psychiatr. Neuro. Scand. (Suppl. 120)

(1958)

BrodskyL. et al.

Refractory anxiety: a masked epileptiform disorder?

Psychiatr. J. Univ. Ottawa

(1983)

CampeauS. et al.

Intra-amygdala infusion of theN-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression o f fear-potentiated startle to an auditory conditioned stimulus

Behav. Neurosci.

(1992)

FallsW.A. et al.

Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala

J. Neurosci.

(1992)

FeindelW. et al.

Localization of discharge in temporal lobe automatism

Arch. Neurol. Psych.

(1954)

FinkM. et al.

Anxiety precipitated by lactate

N. Engl. J. Med.

(1969)

Cited by (63)

Neonatal inflammation via persistent TGF-β1 downregulation decreases GABA<inf>A</inf>R expression in basolateral amygdala leading to the imbalance of the local excitation-inhibition circuits and anxiety-like phenotype in adult mice
2022, Neurobiology of Disease
Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. Based on the reports that early-life inflammation had adverse effects on GABAergic system, the aim of this study was to investigate whether and how neonatal inflammation affects excitatory-inhibitory circuits in the BLA resulting in anxiety disorder. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3–5. LPS-treated mice developed anxiety behaviors accompanied by the hyperactivity of adrenal axis in adulthood. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-BLA excitatory synapses of LPS mice which could be recovered by bath-application of GABA_AR agonist suggesting the impairment of GABAergic system in LPS mice. Compared with controls, GABA_ARα2 subunit expression and density of GABA-evoked current in BLA principal neurons were reduced in LPS mice. Additionally, neonatal LPS treatment resulted in the down-regulation of transforming growth factor-beta 1 (TGF-β1) expression and PKC signaling pathway in the adult BLA. The local TGF-β1 overexpression in the BLA improved GABA_ARα2 expression via up-regulating the activity of PKC signaling, which corrected GABA_AR-mediated inhibition leading to the abolishment of anxiety-like change in adrenal axis regulation and behaviors in LPS mice. These data suggest the persistent TGF-β1deficit induces the down-regulation of GABA_ARα2 expression and subsequent disruption of the excitation-inhibition balance in the BLA circuits, which is the important mechanisms of neonatal inflammation-induced anxiety disorder.
Exposure of male mice to perfluorooctanoic acid induces anxiety-like behaviors by increasing corticotropin-releasing factor in the basolateral amygdala complex
2022, Chemosphere
Citation Excerpt :
The powerful GABAergic inhibitory circuit in the BLA is very important in controlling motion and attention behavior (Martijena et al., 2002). The removal of tonic inhibition in the BLA by local infusion of GABA antagonists in vivo results in anxiety-like behaviors (Sanders et al., 1995). An increase in the excitability of BLA neurons by acute CRF receptor activation has been proposed to be a critical molecular component of anxiety-like behavior (Walker and Davis, 2008).
Perfluorooctanoic acid (PFOA), a hazardous environmental pollutant, has been found to enhance hepatic synthesis of fibroblast growth factor 21 (FGF21). FGF21 can enter the brain and increase the expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN). In this study, adult male mice were orally administered PFOA to evaluate how it regulates emotion. Exposure of mice to PFOA (1 mg kg-1 bw) for 10 consecutive days (PFOA-mice) caused anxiety-like behaviors and a peroxisome proliferator-activated receptor α (PPARα)-dependent increase in hepatic FGF21 synthesis. The levels of CRF expression in not only PVN but also basolateral amygdala complex (BLA) neurons of PFOA-mice were increased via FGF receptor 1 (FGF-R1) activation. However, the microinjection of FGF-R1 or CRF 1 receptor (CRF-R1) antagonist in the BLA rather than the PVN of PFOA-mice could relieve their anxiety-like behaviors. In addition, external capsule-BLA synaptic transmission in PFOA-mice was enhanced by increasing CRF-R1-mediated presynaptic glutamate release, which was corrected by the blockade of PPARα, FGF-R1 and CRF-R1 or the inhibition of PKA. Furthermore, the threshold of frequency-dependent long-term potentiation (LTP) induction was decreased in the BLA of PFOA-mice, which depended on the activation of PPARα, FGF-R1, CRF-R1, PKA and NMDA receptor (NMDAR), whereas long-term depression (LTD) induction was unchanged. Thus, the results indicate that the exposure of male mice to PFOA (1 mg kg-1 bw) enhances CRF expression in BLA neurons by increasing hepatic FGF21 synthesis, which then enhances CRF-R1-mediated presynaptic glutamate release to facilitate NMDAR-dependent BLA-LTP induction, leading to the production of anxiety-like behaviors.
Stress, Panic, and Central Serotonergic Inhibition
2017, Stress: Neuroendocrinology and Neurobiology
Panic disorder (PD) is an anxiety disorder associated with the occurrence of panic attacks, which arise suddenly without warning. Panic disorder represents a serious psychiatric condition and it can induce complications related to the fear of having subsequent panic attacks and avoidance behaviors. Given its importance, many studies have been conducted to elucidate the circuitry involved in this disorder. Clinical and preclinical studies suggest that PD can be modulated by a specific network of brain structures controlling emotional behaviors and autonomic responses. Using animal models that allow measurement of responses related to behavioral and autonomic symptoms of panic attacks in humans, it has been shown that the neuromodulator serotonin plays an inhibitory role in control of panic attacks associated with PD. Understanding the pathways through which serotonergic systems modulate panic-like responses is key to understanding the biological basis of panic attacks and PD, and, consequently, to establishing novel therapeutic strategies for treatment of PD.
The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: Relation to anxiety-like behavior
2014, Neuropharmacology
Citation Excerpt :
Some of the victims of the Tokyo sarin attacks, for example, presented posttraumatic stress disorder, five or seven years after the events (Hoffman et al., 2007). Hyperexcitability of the amygdala, and the BLA in particular, is a characteristic feature of anxiety-like behavior in animals (Bueno et al., 2005; Davis et al., 1994; Sanders et al., 1995) and anxiety disorders in humans (Koenigs and Grafman, 2009; Rauch et al., 2000; Villarreal and King, 2001). Therefore, the increased anxiety in animals and humans after nerve agent exposure is likely to be due to neuropathological and pathophysiological alterations that have increased the excitability of the BLA network.
Organophosphorus nerve agents are powerful neurotoxins that irreversibly inhibit acetylcholinesterase (AChE) activity. One of the consequences of AChE inhibition is the generation of seizures and status epilepticus (SE), which cause brain damage, resulting in long-term neurological and behavioral deficits. Increased anxiety is the most common behavioral abnormality after nerve agent exposure. This is not surprising considering that the amygdala, and the basolateral nucleus of the amygdala (BLA) in particular, plays a central role in anxiety, and this structure suffers severe damage by nerve agent-induced seizures. In the present study, we exposed male rats to the nerve agent soman, at a dose that induce SE, and determined the time course of recovery of AChE activity, along with the progression of neuropathological and pathophysiological alterations in the BLA, during a 30-day period after exposure. Measurements were taken at 24 h, 7 days, 14 days, and 30 days after exposure, and at 14 and 30 days, anxiety-like behavior was also evaluated. We found that more than 90% of AChE is inhibited at the onset of SE, and AChE inhibition remains at this level 24 h later, in the BLA, as well as in the hippocampus, piriform cortex, and prelimbic cortex, which we analyzed for comparison. AChE activity recovered by day 7 in the BLA and day 14 in the other three regions. Significant neuronal loss and neurodegeneration were present in the BLA at 24 h and throughout the 30-day period. There was no significant loss of GABAergic interneurons in the BLA at 24 h post-exposure. However, by day 7, the number of GABAergic interneurons in the BLA was reduced, and at 14 and 30 days after soman, the ratio of GABAergic interneurons to the total number of neurons was lower compared to controls. Anxiety-like behavior in the open-field and the acoustic startle response tests was increased at 14 and 30 days post-exposure. Accompanying pathophysiological alterations in the BLA – studied in in vitro brain slices – included a reduction in the amplitude of field potentials evoked by stimulation of the external capsule, along with prolongation of their time course and an increase in the paired-pulse ratio. Long-term potentiation was impaired at 24 h, 7 days, and 14 days post-exposure. The loss of GABAergic interneurons in the BLA and the decreased interneuron to total number of neurons ratio may be the primary cause of the development of anxiety after nerve agent exposure.
The most common native medicinal plants used for psychiatric and neurological disorders in Urmia city, northwest of Iran
2014, Asian Pacific Journal of Tropical Disease
To determine and introduce medicinal plants used in the treatment of psychological disorders in Urmia city of Iran.
Direct observation, interviews and collection of herbarium native medicinal herbs were used in this study. Questionnaires included herbalists' personal information, native herbs list to include local name of plant, used organ, application methods and therapeutic effect of the plant. Samples that listed in the questionnaires were collected to determine the genus and species.
By interviews, 22 medicinal plants of 10 families were determined in Urmia city. Asteraceae family had the most therapeutic effects (32%). Seeds of plants were the most used organs and common application method of plants was decoction (80%).
Indigenous knowledge of medicinal plants offers new ideas for modern pharmaceutical science. These study results might be tested experimentally in order to produce new herbal remedies for management of neurological and psychiatric disorders.
Chronic mild stress-induced changes of risk assessment behaviors in mice are prevented by chronic treatment with fluoxetine but not diazepam
2014, Pharmacology Biochemistry and Behavior
As an important part of risk-related defensive behavior and central element of anxiety, risk assessment in rodents is particularly sensitive to psychosocial stress and may consequently influence the following decision-making and behavioral output. In this study, using a mouse-test battery, we evaluated the possible impacts of chronic mild stress (CMS) on risk assessment behaviors and action selections. For non-stressed control animals, a close relationship between risk assessment and choice behavior was observed in EPM and LDT. For stressed animals, however, 5 weeks of CMS exposure not only increased risk assessment behaviors, but also abolished the correlations between risk assessment and action selection. Pharmacological intervention with GABA-A receptor modulator diazepam (0.25–4 mg/kg) blocked the alterations of conventional spatiotemporal behaviors in response to CMS, but had no effect on the CMS-induced risk assessment behavioral changes. In contrast, 4-weeks of chronic treatment with fluoxetine (4–20 mg/kg), a selective serotonin reuptake inhibitor, not only ameliorated the CMS-affected risk-assessment behaviors, but also restored the CMS-impaired correlations between risk assessment and decision making-related action selection. The present findings may shed new light on the better understanding of emotional reactivity and decision making under stressful situations. These results also indicate a differential pharmacological sensitivity in CMS-affected emotional response and risk-assessment behaviors.

View all citing articles on Scopus

: Preliminary results of this study were presented at the 1992 annual meeting of the Society for Neuroscience at New Orleans, LA.

View full text

Priming of experimental anxiety by repeated subthreshold GABA blockade in the rat amygdala

Abstract

Biol. Psychiatry

Brain Res.

Behav. Neural Biol.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Biol. Psychiatry

Neuropharmacology

Neurosci. Lett.

Electroencephalogr. Clin. Neurophysiol.

Brain Research

Biol. Psychiatry

Eur. J. Pharmac.

Biol. Psychiatry

Ideational components of anxiety neurosis

Arch. Gen. Psych.

Epilepsy and Psychiatry

Mental symptoms in temporal lobe epilepsy and temporal lobe gliomas

Acta Psychiatr. Neuro. Scand. (Suppl. 120)

Refractory anxiety: a masked epileptiform disorder?

Psychiatr. J. Univ. Ottawa

Intra-amygdala infusion of theN-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression o f fear-potentiated startle to an auditory conditioned stimulus

Behav. Neurosci.

Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala

J. Neurosci.

Localization of discharge in temporal lobe automatism

Arch. Neurol. Psych.

Anxiety precipitated by lactate

N. Engl. J. Med.