Panic-Prone State Induced in Rats with GABA Dysfunction in the Dorsomedial Hypothalamus Is Mediated by NMDA Receptors

Johnson, Philip L.; Shekhar, Anantha

doi:10.1523/jneurosci.0408-06.2006

Cited by 84 publications

(79 citation statements)

References 81 publications

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“…Consequently, the SI test may be a sensitive measure of an increase in anxiety-like state following intra-DMH infusions of L-AG. The SI test procedure as used in our laboratory has been described previously (Shekhar and Katner, 1995;Johnson and Shekhar, 2006). See also Supplementary methods for detailed description.…”

Section: Social Interaction Testmentioning

confidence: 99%

“…In light of this, Shekhar and colleagues developed an animal model of panic disorder where chronically inhibiting GABA synthesis in the DMH/PeF of rats leads to heightened anxiety and panic-like responses following exposure to i.v. infusions of 0.5 M sodium lactate (Shekhar et al, 1996;Shekhar and Keim, 1997;Johnson and Shekhar, 2006) or 7.5% CO 2 inhalation (Fitz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Neural Pathways Underlying Lactate-Induced Panic

Johnson

Truitt

Fitz

et al. 2007

Neuropsychopharmacol

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Panic disorder is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as 0.5 M sodium lactate infusions. Although studied for four decades, the mechanism of lactate sensitivity in panic disorder has not been understood. The dorsomedial hypothalamus/perifornical region (DMH/PeF) coordinates rapid mobilization of behavioral, autonomic, respiratory and endocrine responses to stress, and rats with disrupted GABA inhibition in the DMH/PeF exhibit panic-like responses to lactate, similar to panic disorder patients. Utilizing a variety of anatomical and pharmacological methods, we provide evidence that lactate, via osmosensitive periventricular pathways, activates neurons in the compromised DMH/PeF, which relays this signal to forebrain limbic structures such as the bed nucleus of the stria terminalis to mediate anxiety responses, and specific brainstem sympathetic and parasympathetic pathways to mediate the respiratory and cardiovascular components of the panic-like response. Acutely restoring local GABAergic tone in the DMH/PeF blocked lactate-induced panic-like responses. Autonomic panic-like responses appear to be a result of DMH/PeF-mediated mobilization of sympathetic responses (verified with atenolol) and resetting of the parasympathetically mediated baroreflex. Based on our findings, DMH/PeF efferent targets such as the C1 adrenergic neurons, paraventricular hypothalamus, and the central amygdala are implicated in sympathetic mobilization; the nucleus of the solitary tract is implicated in baroreflex resetting; and the parabrachial nucleus is implicated in respiratory responses. These results elucidate neural circuits underlying lactate-induced panic-like responses and the involvement of both sympathetic and parasympathetic systems.

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Section: Social Interaction Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neural Pathways Underlying Lactate-Induced Panic

Johnson

Truitt

Fitz

et al. 2007

Neuropsychopharmacol

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“…In the anxiety model with increased vulnerability to panic developed by Shekhar and colleagues, chronically inhibiting GABA synthesis in the DMH/PeF of rats leads to heightened baseline anxiety-like responses and facilitation of anxiety-and panic-like responses following exposure to mild interoceptive stressors [i.e., i.v. infusions of 0.5 M sodium lactate (Shekhar et al, 1996;Shekhar andKeim, 1997, 2000;Johnson and Shekhar, 2006;Shekhar et al, 2006) or 7.5% CO 2 inhalation (Fitz et al, 2003)]. …”

Section: Introductionmentioning

confidence: 99%

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

et al. 2008

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Panic patients are vulnerable to induction of panic attacks by subthreshold interoceptive stimuli such as intravenous (i.v.) sodium lactate infusions. Facilitation of serotonergic signaling with selective serotonin re-uptake inhibitors (SSRIs) can suppress anxiety and panic-like responses, but the mechanisms involved are not clearly defined. We investigated the effects of i.v. 0.5M sodium lactate or saline, in control and panic-prone rats on c-Fos expression in serotonergic neurons within subdivisions of the midbrain/pontine raphe nuclei. Rats were chronically infused with either the GABA synthesis inhibitor l-allylglycine (l-AG) into the dorsomedial hypothalamus (DMH) to make them panic-prone, or the enantiomer d-allylglycine (d-AG) in controls. Lactate increased c-Fos expression in serotonergic neurons located in the ventrolateral part of the dorsal raphe nucleus (DRVL) and ventrolateral periaqueductal gray (VLPAG) of control, but not panicprone, rats. The distribution of lactate-sensitive serotonergic neurons in d-AG-treated rats is virtually identical to previously defined pre-sympathomotor serotonergic neurons with multisynaptic projections to peripheral organs mediating "fight-or-flight"-related autonomic and motor responses. We hypothesize that serotonergic neurons within the DRVL/VLPAG region represent a "sympathomotor control system" that normally limits autonomic/behavioral responses to innocuous interoceptive and exteroceptive stimuli, and that dysfunction of this serotonergic system contributes to an anxiety-like state and increases vulnerability to panic in animals and humans.

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“…Glutamate is the major excitatory synaptic neurotransmitter in the brain and is found in 80% of neurons, and there is increasing evidence that antagonists of glutamate action at NMDA receptors have antidepressant-like action and anxiolytic action [56][57][58][59]. Glutamate is reported to be largely responsible for the ability of the nervous system to rapidly transmit information from one part of the body to another, and to be important in thought formation and memories [60].…”

Section: Hypothesis-driven Research Using Enantiomers In Homeopathmentioning

confidence: 99%

“…The term excitotoxicity refers to the excessive exposure to the neurotransmitter glutamate or to stimulation of its membrane receptors and is considered a main contributor to neuronal injury and death in numerous conditions [60]. In the case of the NMDA receptors these include Alzheimer's disease, Parkinson's disease, Huntington's disease, HIVassociated dementia, multiple sclerosis, amyotrophic lateral sclerosis, and glaucoma, obsessive-compulsive disorder, stroke, dementia and neuropathic pain [60], and also anxiety and depression [57,59,62,63].…”

Section: Hypothesis-driven Research Using Enantiomers In Homeopathmentioning

confidence: 99%

A review of use of enantiomers in homeopathy

Kuzeff

2014

Homeopathy

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This paper reviews publications of laboratory experiments using pairs of enantiomers in homeopathy. Many molecules in nature have geometry which enables them to exist as nonsuperimposable mirror images or enantiomers. Modulation of toxicity of such molecules provides possibility for therapeutics, since they target multiple points in biochemical pathways. It was hypothesized that toxicity of a chemical agent could be counteracted by a homeopathic preparation of the enantiomer of the chemical agent (patents applied for: PCT/AU2003/000219-PCT/AU2008/001611). A diverse body of data, including controlled laboratory studies, supports the conclusion that toxicity of optical isomers may be inhibited by homeopathic enantiomer preparations. These data were obtained with minimal or no pretesting to determine optimal test solutions. Inhibition of the excitotoxic neurotransmitter Lglutamic acid with homeopathic preparations of D-glutamic acid indicates the latter may be of use for amelioration of symptoms of disturbances of mood. Similarly, homeopathic preparation of (+)-nicotine may be of use for inhibition of effects of nicotine in tobacco.

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Panic-Prone State Induced in Rats with GABA Dysfunction in the Dorsomedial Hypothalamus Is Mediated by NMDA Receptors

Cited by 84 publications

References 81 publications

Neural Pathways Underlying Lactate-Induced Panic

Neural Pathways Underlying Lactate-Induced Panic

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

A review of use of enantiomers in homeopathy

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