The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

Li, Xia; Kaczanowska, Katarzyna; Finn, M. G.; Markou, Athina; Risbrough, Victoria B.

doi:10.1016/j.neuropharm.2015.05.001

Cited by 21 publications

(9 citation statements)

References 49 publications

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“…Very similar results were obtained with other positive GABAB receptor modulators such as CGP7930 [20], ADX1441 [19] or BHF117 [24,27]. However, in some anxiety tests, the positive GABA B receptor modulators had no effects on anxiety-like behavior [18,20,[24][25][26][27].…”

Section: Discussionsupporting

confidence: 76%

“…Indeed, many studies showed anxiolytic-like properties of GS39783, one of the first positive GABA B receptor modulators, in a variety of anxiety tests in laboratory rodents, while some of the side-effects of benzodiazepines or the GABA B receptor agonist baclofen, such as sedation, hypothermia, interaction with ethanol, or development of tolerance, were not observed with GS39783 [17,18]. Very similar results were obtained with other positive GABAB receptor modulators such as CGP7930 [20], ADX1441 [19] or BHF117 [24,27]. However, in some anxiety tests, the positive GABA B receptor modulators had no effects on anxiety-like behavior [18,20,[24][25][26][27].…”

Section: Discussionsupporting

confidence: 57%

“…GABA B receptor-deficient mice exhibit an anxiogenic-like phenotype [6,16] while treatment with positive GABA B receptor modulators has shown anxiolytic-like effects in several animal paradigms of anxiety, including the light-dark box [17], the elevated plus maze [18,19], the elevated zero maze [17,18,20], stress-induced hyperthermia [18,[20][21][22], the staircase test [18,23], and light-enhanced startle [24]. However, positive GABA B receptor modulators did not show anxiolytic-like effects in some of these tests as well as in other tests for anxiety [18,20,[24][25][26][27] (see also Supplementary Material). There are several possible explanations for these variability in the efficacy of positive GABA B receptor modulators: (1) different positive GABA B receptor modulators might have different efficacy due to their binding profile to the receptor; (2) positive GABA B receptor modulators are only effective in particular behavioral paradigms of anxiety but not in others; and/or (3) the anxiety levels in the studies presented here were different and positive GABA B receptor modulators are only effective at particular anxiety levels.…”

Section: Introductionmentioning

confidence: 99%

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Anxiolytic-like Effects of the Positive GABAB Receptor Modulator GS39783 Correlate with Mice’s Individual Basal Anxiety and Stress Reactivity

et al. 2022

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Positive gamma-aminobutyric acid type B (GABAB) receptor modulators such as GS39783 have showed anxiolytic-like effects in several studies while such effects were absent in other studies. These conflicting findings led us hypothesize that the anxiolytic-like effects of such compounds depend on the individual basal anxiety and/or the anxiogenic properties of the used tests. The present study addresses this hypothesis by testing GS39783 effects on mice’s anxiety-like behavior in a light–dark box. We found that GS39783 had no effects on a whole-group level. However, after grouping the mice for their basal anxiety, GS39783 reduced anxiety-like behavior in the subgroup with highest basal anxiety. Moreover, GS39783 effects correlated with individual basal anxiety. Next, the anxiogenic properties of the light–dark box test were increased by prior stress exposure. Again, GS39783 was not effective on a whole-group level. However, GS39783 had an anxiolytic-like effect in the most stress-responsive subgroup. Moreover, GS39783 effects correlated with individual stress responsiveness. Finally, we show that GS39783 brain levels were within a behaviorally relevant range. Overall, our study demonstrates that GS39783 effects depend on individual basal anxiety and stress responsiveness. This suggests that anxiety tests should generally be designed to capture individual basal anxiety and/or stress responsiveness as well as individual compound effects.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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Anxiolytic-like Effects of the Positive GABAB Receptor Modulator GS39783 Correlate with Mice’s Individual Basal Anxiety and Stress Reactivity

et al. 2022

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“…This was consistent with data obtained in adult mice of this mouse line [ 34 ]. Other studies involving a wide range of alterations in the GABAergic system have also not shown changes in fear learning [ 34 , 35 , 81 ]. In particular, knockdown of GAD67 in amygdala did not cause changes in cued fear conditioning [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons

et al. 2018

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GABAergic dysfunction has been implicated in a variety of neurological and psychiatric disorders, including anxiety disorders. Anxiety disorders are the most common type of psychiatric disorder during adolescence. There is a deficiency of GABAergic transmission in anxiety, and enhancement of GABA transmission through pharmacological means reduces anxiety behaviors. GAD67—the enzyme responsible for GABA production–has been linked to anxiety disorders. One class of GABAergic interneurons, Neuropeptide Y (NPY) expressing cells, is abundantly found in brain regions associated with anxiety and fear learning, including prefrontal cortex, hippocampus and amygdala. Additionally, NPY itself has been shown to have anxiolytic effects, and loss of NPY+ interneurons enhances anxiety behaviors. A previous study showed that knockdown of Gad1 from NPY+ cells led to reduced anxiety behaviors in adult mice. However, the role of GABA release from NPY+ interneurons in adolescent anxiety is unclear. Here we used a transgenic mouse that reduces GAD67 in NPY+ cells (NPYGAD1-TG) through Gad1 knockdown and tested for effects on behavior in adolescent mice. Adolescent NPYGAD1-TG mice showed enhanced anxiety-like behavior and sex-dependent changes in locomotor activity. We also found enhancement in two other innate behavioral tasks, nesting construction and social dominance. In contrast, fear learning was unchanged. Because we saw changes in behavioral tasks dependent upon prefrontal cortex and hippocampus, we investigated the extent of GAD67 knockdown in these regions. Immunohistochemistry revealed a 40% decrease in GAD67 in NPY+ cells in prefrontal cortex, indicating a significant but incomplete knockdown of GAD67. In contrast, there was no decrease in GAD67 in NPY+ cells in hippocampus. Consistent with this, there was no change in inhibitory synaptic transmission in hippocampus. Our results show the behavioral impact of cell-specific interneuron dysfunction and suggest that GABA release by NPY+ cells is important for regulating innate prefrontal cortex-dependent behavior in adolescents.

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“…GABA plays an important role in reducing blood pressure, improving memory, and alleviating anxiety, due to its CNS inhibitory effects. [ 8,9 ] In Europe and the United States, GABA is considered as a “food constituent” and a “dietary supplement,” [ 10,11 ] respectively. GABA health products are patronized by a number of people, especially, the white‐collar working‐class women.…”

Section: Introductionmentioning

confidence: 99%

GABA consumption during early pregnancy impairs endometrial receptivity and embryo development in mice

Tian

Liang

Luo

et al. 2020

J Biochem & Molecular Tox

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γ-Aminobutyrate (GABA) is commonly used as a food supplement and a health care product by young females, due to its positive roles in relieving stress, alleviating anxiety, and improving sleep. However, its recommended daily dose in different products varies widely. Besides, it is unknown whether, and how, GABA consumption during early pregnancy influences pregnancy establishment. In this study, we found that when pregnant mice were treated with a high (12.5 mg/g) dose of GABA (orally) during preimplantation, there was a reduction in the number of implantation sites on day 5 of pregnancy. Also, among these unimplanted embryos, most exhibited morphological degeneration and developmental retardation, and only a few of them developed into blastocysts but could not implant into the uterus. Moreover, the expression of uterine receptivity-related factors-LIF, E-cadherin, and HOXA10were all downregulated, while the number of uterine glands was reduced in the high GABA dose group. Finally, in vitro results demonstrated that GABA (ranging from 10 to 50 μg/μL) markedly inhibited preimplantation embryo development in a doseresponse manner. However, this inhibitory effect was not observed when the embryos were pretreated with 40 μΜ 2-hydroxysaclofen, a GABA B antagonist, indicating that GABA exerts its inhibitory effects via its B-type receptor. Our results suggest that exposure to certain GABA concentrations, during early pregnancy, can impair preimplantation embryo development via its B-type receptor, and endometrial receptivity, which greatly disturbs early embryo implantation in mice. These findings could raise concerns about GABA consumption during the early stages of pregnancy. K E Y W O R D S blastocyst formation, embryo implantation, embryonic development, endometrial receptivity, GABA

show abstract

The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

Cited by 21 publications

References 49 publications

Anxiolytic-like Effects of the Positive GABAB Receptor Modulator GS39783 Correlate with Mice’s Individual Basal Anxiety and Stress Reactivity

Anxiolytic-like Effects of the Positive GABAB Receptor Modulator GS39783 Correlate with Mice’s Individual Basal Anxiety and Stress Reactivity

Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons

GABA consumption during early pregnancy impairs endometrial receptivity and embryo development in mice

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