Angiotensin-II Is a Putative Neurotransmitter in Lactate-Induced Panic-Like Responses in Rats with Disruption of GABAergic Inhibition in the Dorsomedial Hypothalamus

Shekhar, Anantha; Johnson, Philip L.; Sajdyk, Tammy J.; Fitz, Stephanie D.; Keim, Stanley R.; Kelley, Pamela; Gehlert, Donald R.; DiMicco, Joseph A.

doi:10.1523/jneurosci.2491-06.2006

Cited by 74 publications

(62 citation statements)

References 90 publications

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“…For example, similar L-AG infusions into the DMH produces anxiety-like behaviors in SI, but also makes the animals susceptible to displaying panic-like characteristics (i.e., tachycardia, tachypnea and increases in blood pressure) in response to i.v. infusions of 0.5M sodium lactate Johnson and Shekhar, 2006;Shekhar et al, 2006). Overall, this data supports the hypothesis that BNST plays an important role in regulating general anxiety.…”

Section: Discussionsupporting

confidence: 81%

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Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior

et al. 2008

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The current study tested the hypotheses that chronic loss of inhibitory GABAergic tone in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety behavior, results in generalized anxiety disorder-like behaviors without panic-like responses (i.e., tachycardia, hypertension and tachypnea) following panicogenic stimuli (e.g., sodium lactate infusions). To test this hypothesis, the GABA synthesis inhibitor L-allylglycine (L-AG) or its inactive isomer D-AG was chronically infused into the BNST of male rats via osmotic minipumps. L-AG, but not D-AG, treated rats had increased anxiety-like behavior as measured by social interaction (SI) and elevated plus maze paradigms. Restoring GABAergic tone, with 100pmoles/100nl of muscimol (a GABAA receptor agonist), in the BNST of L-AG treated rats attenuated L-AG-induced anxiety-like behavior in the SI test. To assess panic-like states, L-AG treated rats were intravenously infused with 0.5M sodium lactate, a panicogenic agent, prior to assessing SI and cardiorespiratory responses. L-AG decreased SI duration again; however, sodium lactate did not induce panic-like cardiorespiratory responses. These findings demonstrate that GABA inhibition in the BNST elicits anxiety-like behavior without increasing sensitivity to lactate, thus suggesting a behavioral profile similar to that of generalized anxiety-like behavior rather than that of panic.

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Section: Discussionsupporting

confidence: 81%

“…infusions of 0.5M sodium lactate Johnson and Shekhar, 2006;Shekhar et al, 2006). In light of this, SI tests and peripheral physiological measures (i.e., heart rate, blood pressure and respiration rate) were recorded in a separate group of rats at baseline as well as after they had L-AG pumps following i.v.…”

Section: Sodium Lactate Infusionsmentioning

confidence: 99%

Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior

et al. 2008

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“…In the DMH/PeF anxiety model with vulnerability to panic, local chronic l-AG treatment produces increased anxiety at baseline and a vulnerability to paniclike cardiorespiratory responses to i.v. infusions of sodium lactate (Shekhar et al, 1996;Shekhar andKeim, 1997, 2000;Johnson and Shekhar, 2006;Shekhar et al, 2006). In contrast, repeated subthreshold BMI (Sajdyk and Shekhar, 2000) injections into the basolateral amygdaloid complex produces rats that exhibit no baseline increases in anxietybut panic-like responses (i.e., decreased SI duration and increased cardiovascular responses) after the i.v.…”

Section: Clinical Considerationsmentioning

confidence: 99%

“…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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“…infusions. Previous studies have determined that the dose of L-AG utilized here reduces local GABA concentrations by approximately 60% following unilateral infusions (based on microdialysis study (Abshire et al, 1988), and enzyme assays Shekhar et al, 1996;Shekhar and Keim, 1997;Shekhar et al, 2006), and supported by immunohistochemistry , and increases anxiety-like behavior (ie as measured by the social interaction (SI) test, and elevated plus-maze (EPM)) without increasing cardiorespiratory responses Shekhar et al, 1996;Shekhar and Keim, 1997;Shekhar et al, 2006).…”

Section: Surgical Proceduresmentioning

confidence: 99%

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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Angiotensin-II Is a Putative Neurotransmitter in Lactate-Induced Panic-Like Responses in Rats with Disruption of GABAergic Inhibition in the Dorsomedial Hypothalamus

Cited by 74 publications

References 90 publications

Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior

Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior

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

Neural Pathways Underlying Lactate-Induced Panic

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