Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABAA transmission: comparison with NMDA transmission

Auger, Meagan L.; Meccia, Juliet; Floresco, Stan

doi:10.1007/s00213-017-4670-1

Cited by 14 publications

(11 citation statements)

References 69 publications

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“…Rodent models support the hypothesis that GABA dysfunction contributes to cognitive and social deficits observed in psychiatric conditions such as schizophrenia, autism and depression. Indeed, inhibition of cortical GABA A receptors causes impairments in attention [12,13,14,15], social behavior [16], set-shifting [17], working memory [18] and rewardrelated decision making [19]. These findings support a role for cortical GABA A receptors contributing to the cognitive deficits observed in psychiatric illness.…”

Section: Introductionmentioning

confidence: 80%

Contribution of GABAA receptor subunits to attention and social behavior

Paine

Chang

Poyle

2020

Behavioural Brain Research

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Introduction: GABA dysfunction is associated with a number of psychiatric conditions including schizophrenia, autism and depression. Blocking cortical GABA A receptors in rodents causes behavioral deficits, including impaired attention and sociability, that are consistent with the symptoms of these conditions. The subunit composition of GABA A receptors is diverse and can affect receptor function. The current experiment examined the role of GABA A receptors containing different α-subunits in social behavior and attention.Methods: Male Sprague-Dawley rats were administered FG7142 (0.0-5.0 mg/kg; a non-selective GABA A receptor inverse agonist), L-655,708 (0-1.0 mg/kg; a low efficacy inverse agonist at α 5containing GABA A receptors), MRK-016 (0.0-2.0 mg/kg; a high efficacy inverse agonist at α 5containing GABA A receptors), or L-838,417 (0.0-3.0 mg/kg; an antagonist at α 1 -containing receptors and a partial agonist at α 2 , α 3 , α 5 -containing GABA A receptors) and either tested on the social interaction and social preference tests or the 5-choice serial reaction time task.Results: FG7142 decreased social interactions and impaired attention. MRK-016 impaired attention but did not affect social behavior. Neither L-655,708 nor L-838,417 significantly affected either social behavior or attention.Discussion: Systemic reduction in GABA A receptor signaling decreased sociability and attention, a result consistent with past research demonstrating cortical GABA A receptor blockade impairs social behavior and attention. Overall, the effects of the receptor subtype selective ligands were minimal; α 5 -containing GABA A receptors may contribute to the attentional deficit but do not contribute to the decrease in sociability. Further research is needed to determine the GABA A receptor subunits that contribute to social behavior and attention.

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Section: Introductionmentioning

confidence: 80%

Contribution of GABAA receptor subunits to attention and social behavior

Paine

Chang

Poyle

2020

Behavioural Brain Research

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“…Other labs have demonstrated that acute MK-801 ( Howe and Burk, 2007 ; Rezvani et al, 2009 ; Levin et al, 2014 ) or ketamine treatment ( Hillhouse et al, 2015 ) induces similar VSDT impairments. Furthermore, several labs have demonstrated similar MK-801-induced impairments in alternate behavioral attention models after either systemic ( Auger et al, 2017 ) or intra-cerebral microinjection into the mPFC ( Auger et al, 2017 ), or the anterior cingulate cortex ( Pehrson et al, 2013a ).…”

Section: Discussionmentioning

confidence: 99%

“…In behavioral attention measures such as the 3 choice serial reaction time (3CSRT) task, electrophysiological data demonstrates that the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) play a role in representing attention-relevant information in rats ( Totah et al, 2009 ), and intra-ACC MK-801 injections selectively increased omissions in the 3CSRT task without altering the accuracy ( Pehrson et al, 2013a ). In the sustained attention task, intra-mPFC MK-801 injections impaired vigilance during high-difficulty conditions ( Auger et al, 2017 ). We could not find any study that evaluated non-competitive NMDA receptor antagonists in the VSDT using region-specific microinjections; thus, it is unknown whether these effects translate to this attention model.…”

Section: Discussionmentioning

confidence: 99%

“…Given that MK-801 has activity-dependent pharmacological effects at the NMDA receptor, and that vortioxetine indirectly increases mPFC glutamate neurotransmission, vortioxetine may potentiate MK-801 induced attention impairments by increasing depolarization of NMDA receptor-expressing cells, increasing access to the MK-801 binding site. This mechanism would likely be active in the mPFC ( Riga et al, 2016 , 2017 ), a brain region that mediates at least some MK-801 effects on attention performance ( Totah et al, 2009 ; Pehrson et al, 2013a ; Auger et al, 2017 ) but is irrelevant for MK-801’s locomotor effects. Furthermore, vortioxetine’s 5-HT 3 receptor-dependent disinhibitory effects would be inactive in the NAc, which may mediate a portion of MK-801-induced hyperlocomotion ( Raffa et al, 1989 ; Hatip-Al-khatib et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

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Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity

et al. 2018

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Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous non-clinical research suggests that vortioxetine has limited effects on attention. This laboratory previously found that vortioxetine did not improve attention function in animals impaired by acute scopolamine administration, using the visual signal detection task (VSDT). However, vortioxetine has limited effects on acetylcholinergic neurotransmission, and thus it is possible that attention impaired by other mechanisms would be attenuated by vortioxetine. This study sought to investigate whether acute vortioxetine administration can attenuate VSDT impairments and hyperlocomotion induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. We found that acute vortioxetine administration had no effect on VSDT performance on its own, but potentiated MK-801-induced VSDT impairments. Furthermore, vortioxetine had no effect on locomotor activity on its own, and did not alter MK-801-induced hyperlocomotion. We further investigated whether vortioxetine’s effect on MK-801 could be driven by a kinetic interaction, but found that plasma and brain exposure for vortioxetine and MK-801 were similar whether administered alone or in combination. Thus, it appears that vortioxetine selectively potentiates MK-801-induced impairments in attention without altering its effects on locomotion, and further that this interaction must be pharmacodynamic in nature. A theoretical mechanism for this interaction is discussed.

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“…Several studies have shown that inhibiting cortical GABA A receptors causes impaired attention [ 16 , 193 – 197 ], social behavior [ 198 ], and decision-making [ 199 ]. Recently, it has been demonstrated that mice models having impaired 5-alpha GABA A receptors were presented with behavioral deficits like symptoms associated with attention and social disorders [ 194 ].…”

Section: Gaba a Receptor Dysfunction And Neuro-psychiatric Disordersmentioning

confidence: 99%

GABAA receptors: structure, function, pharmacology, and related disorders

Ghit

Assal

Al‐Shami

et al. 2021

Journal of Genetic Engineering and Biotechnology

181

115

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Background γ-Aminobutyric acid sub-type A receptors (GABAARs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications. Main body GABAARs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABAARs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABAA receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development. Conclusion To date, few reviews have discussed GABAA receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABAARs, as well as shedding light on the most common associated disorders.

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Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABAA transmission: comparison with NMDA transmission

Abstract: These findings highlight a key role for PFC GABA transmission in reducing sensitivity to distractors during attentional performance. Furthermore, they reveal that disruption of GABA signaling can interfere with the ability to implement conditional rules.

Cited by 14 publications

References 69 publications

Contribution of GABAA receptor subunits to attention and social behavior

Contribution of GABAA receptor subunits to attention and social behavior

Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity

GABAA receptors: structure, function, pharmacology, and related disorders

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