Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

Farb, David H.; Ratner, Marcia H.

doi:10.1124/pr.114.009126

Cited by 48 publications

(36 citation statements)

References 324 publications

(351 reference statements)

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“…These circuits are modulated by dopamine, norepinephrine, serotonin and CRF. Currently, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors or benzodiazepines are usually the first prescribed anxiolytic medications to target these neural connections [62]. …”

Section: The Mhb-ipn Axis and The Classical Anxiety Circuitrymentioning

confidence: 99%

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

Molas

DeGroot

Zhao-Shea

et al. 2017

Trends in Pharmacological Sciences

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While innovative modern neuroscience approaches have aided in discerning brain circuitry underlying negative emotional behaviors including fear and anxiety responses, how these circuits are recruited in normal and pathological conditions remains poorly understood. Recently, genetic tools that selectively manipulate single neuronal populations have uncovered an understudied circuit, the medial habenula (mHb)-interpeduncular (IPN) axis, that modulates basal negative emotional responses. Interestingly, the mHb-IPN pathway also represents an essential circuit that signals heightened anxiety induced by nicotine withdrawal. Insights into how this circuit inter-connects with regions more classically associated with anxiety and how chronic nicotine exposure induces neuroadaptations resulting in an anxiogenic state, may thereby provide novel strategies and molecular targets for therapies that facilitate smoking cessation, as well as, anxiety relief.

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Section: The Mhb-ipn Axis and The Classical Anxiety Circuitrymentioning

confidence: 99%

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

Molas

DeGroot

Zhao-Shea

et al. 2017

Trends in Pharmacological Sciences

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“…Its anxiolytic effects and related agents are mediated by allosteric enhancement of the γ-aminobutyric acid, GABA A receptor complex thus potentiating inhibitory GABA-mediated neurotransmission (Farb and Ratner 2014, review). This mechanism of action of BZs has led to hypotheses on a pivotal role for GABA neurotransmission in the pathophysiology of anxiety (Nutt et al 1990; Tiihonen et al 1997; Malizia et al 1998).…”

Section: Introductionmentioning

confidence: 99%

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

et al. 2016

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RationaleSedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects.ObjectivesThe current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability.MethodTwo PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests.ResultsThe [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively.ConclusionHigh GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4506-4) contains supplementary material, which is available to authorized users.

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“…Anxiety disorders, commonly occurring with depression and drug abuse, can be triggered or promoted by stress [3,4] . The most widely used therapeutic agents for the treatment of anxiety disorders include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, benzodiazepine anxiolytic and NMDA receptor modulators [5] . However, currently available anxiety disorder modulators are inadequate for patients because of the existence of "nonresponders" or unwanted side effects, such as ataxia, drowsiness, and impairment of cognition [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

The role of the dynorphin/κ opioid receptor system in anxiety

Hang

Wang

et al. 2015

Acta Pharmacol Sin

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Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.

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Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

Cited by 48 publications

References 324 publications

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

The role of the dynorphin/κ opioid receptor system in anxiety

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