DEVELOPMENT OF AN EXPRESSION WHICH RELATES THE EXCITABLE STATE OF THE BRAIN TO THE LEVEL OF GAD ACTIVITY AND GABA CONTENT, WITH PARTICULAR REFERENCE TO THE ACTION OF HYDRAZINE AND ITS DERIVATIVES

Abstract Reduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1 tTA/STOP-tetO biallelic knock-in mice using Gad1 STOP-tetO and Gad1 tTA knock-in mice, and compared them with Gad1 +/+ mice. The expression level of GAD67 protein in brains of Gad1 tTA/STOP-tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1 tTA/STOP-tetO mice. In the open-field test, Dox-treated Gad1 tTA/STOP-tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1 tTA/STOP-tetO mice. These results suggest that global reduction in GAD67 elicits emotional and auditory abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.

Download Full-text

Neuromediator systems in some brain regions of rats subjected to morphine intoxication

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20105605562 ◽

2010 ◽

Vol 56 (5) ◽

pp. 562-569

Author(s):

S.V. Lelevich ◽

A.A. Novokshonov

Keyword(s):

Brain Stem ◽

Brain Tissue ◽

Brain Regions ◽

Cerebral Hemispheres ◽

Serotonin Level ◽

Chronic Morphine ◽

Chronic Morphine Intoxication ◽

System Functioning ◽

Gaba Content ◽

The Brain

The content of neuromediators and its metabolites in the cortex of cerebral hemispheres, in thalamus and brain stem was studied under chronic morphine intoxication (7-21 days). The morphine intake during 7-14 days was accompanied by changes of catecholamine system functioning, which was the most pronounced in the thalamus and the brain stem. These changes included increased secretion of dophamine and noradrenaline, their decrease in the brain tissue, and the increased content of their metabolites. The changes of serotonin and GABA content were less pronounced and included a decrease of serotonin level and the increase of the GABA content in different periods of narcotization.

Download Full-text

Putative Activation of the CB1 Cannabinoid Receptors Prevents Anxiety-Like Behavior, Oxidative Stress, and GABA Decrease in the Brain of Zebrafish Submitted to Acute Restraint Stress

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2020.598812 ◽

2021 ◽

Vol 14 ◽

Author(s):

Waldo Lucas Luz ◽

Mateus Santos-Silva ◽

Patrick Bruno Cardoso ◽

Nadyme Assad ◽

Edinaldo Rogério da Silva Moraes ◽

...

Keyword(s):

Oxidative Stress ◽

Restraint Stress ◽

Cannabinoid Receptors ◽

Acute Stress ◽

Control Treatment ◽

Cb1 Receptors ◽

Acute Restraint Stress ◽

Gaba Content ◽

The Brain

Anxiety disorder is a well-recognized condition observed in subjects submitted to acute stress. Although the brain mechanisms underlying this disorder remain unclear, the available evidence indicates that oxidative stress and GABAergic dysfunction mediate the generation of stress-induced anxiety. Cannabinoids are known to be efficient modulators of behavior, given that the activation of the cannabinoid receptors type-1 (CB1 receptors) induces anxiolytic-like effects in animal models. In the present study, we aimed to describe the effects of the stimulation of the CB1 receptors on anxiety-like behavior, oxidative stress, and the GABA content of the brains of zebrafish submitted to acute restraint stress (ARS). The animals submitted to the ARS protocol presented evident anxiety-like behavior with increased lipid peroxidation in the brain tissue. The evaluation of the levels of GABA in the zebrafish telencephalon presented decreased levels of GABA in the ARS group in comparison with the control. Treatment with ACEA, a specific CB1 receptor agonist, prevented ARS-induced anxiety-like behavior and oxidative stress in the zebrafish brain. ACEA treatment also prevented a decrease in GABA in the telencephalon of the animals submitted to the ARS protocol. Overall, these preclinical data strongly suggest that the CB1 receptors represent a potential target for the development of the treatment of anxiety disorders elicited by acute stress.

Download Full-text

Effect of centrally administered gamma-aminobutyric acid on metabolic function

Journal of Applied Physiology ◽

10.1152/jappl.1986.61.2.472 ◽

1986 ◽

Vol 61 (2) ◽

pp. 472-476 ◽

Cited By ~ 12

Author(s):

M. P. Kneussl ◽

P. Pappagianopoulos ◽

B. Hoop ◽

H. Kazemi

Keyword(s):

Minute Ventilation ◽

Aminobutyric Acid ◽

Co2 Production ◽

Metabolic Function ◽

Gamma Aminobutyric Acid ◽

Dead Space Volume ◽

Anesthetized Dogs ◽

Gaba Content ◽

The Brain ◽

Space Volume

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.

Download Full-text

Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice

Molecular Brain ◽

10.1186/s13041-020-00713-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Shigeo Miyata ◽

Toshikazu Kakizaki ◽

Kazuyuki Fujihara ◽

Hideru Obinata ◽

Touko Hirano ◽

...

Keyword(s):

Psychiatric Disorders ◽

Glutamate Decarboxylase ◽

Acoustic Startle ◽

Newborn Mice ◽

Consistent Finding ◽

Postmortem Brains ◽

Gaba Content ◽

The Brain ◽

Suppression System ◽

Global Reduction

AbstractReduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1tTA/STOP−tetO biallelic knock-in mice using Gad1STOP−tetO and Gad1tTA knock-in mice, and compared them with Gad1+/+ mice. The expression level of GAD67 protein in brains of Gad1tTA/STOP−tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1tTA/STOP−tetO mice. In the open-field test, Dox-treated Gad1tTA/STOP−tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1tTA/STOP−tetO mice. These results suggest that global reduction in GAD67 elicits emotional abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.

Download Full-text

Gamma-Aminobutyric Acid (GABA) and Sepsis-Related Encephalopathy

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100027128 ◽

1988 ◽

Vol 15 (1) ◽

pp. 23-25 ◽

Cited By ~ 15

Author(s):

T.R. Winder ◽

G.Y. Minuk ◽

E.J. Sargeant ◽

T.P. Seland

Keyword(s):

Rat Model ◽

Brain Cortex ◽

Cecal Ligation ◽

Elevated Serum ◽

Clinical Signs ◽

Aminobutyric Acid ◽

Gamma Aminobutyric Acid ◽

Bacterial Sepsis ◽

Gaba Content ◽

The Brain

ABSTRACT:In order to determine whether disturbances in GABA homeostasis might play a role in the pathogenesis of sepsis-related encephalopathy, serum and brain tissue GABA concentrations from six areas of the brain (cortex, diencephalon, striatum, hippocampus, midbrain, and pons-medulla) were determined in a rat model of bacterial sepsis (cecal ligation and perforation). The results were compared to those obtained from sham operated control animals. All septic animals demonstrated clinical signs of encephalopathy and had elevated serum GABA levels (0.92 ± 0.3 uM versus 0.48 ± 0.15 in controls, p < 0.01). GABA content in the specific subcompartments of the brain, however, were similar in the two groups. These results indicate that although serum GABA levels are elevated during sepsis, GABA is unlikely to play an important role in the pathogenesis of sepsis-related encephalopathy.

Download Full-text

GABAA Receptor-Mediated Sleep-Promoting Effect of Saaz–Saphir Hops Mixture Containing Xanthohumol and Humulone

Molecules ◽

10.3390/molecules26237108 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7108

Author(s):

Byungjick Min ◽

Yejin Ahn ◽

Hyeok-Jun Cho ◽

Woong-Kwon Kwak ◽

Hyung Joo Suh ◽

...

Keyword(s):

Gabaa Receptor ◽

Gabaa Receptors ◽

Sleep Disturbances ◽

Nrem Sleep ◽

Sleep Time ◽

Promoting Effect ◽

Amino Butyric Acid ◽

Gabaa Receptor Antagonist ◽

Gaba Content ◽

The Brain

Hops contain flavonoids that have sedative and sleep-promoting activities such as α-acid, β-acid, and xanthohumol. In this study, the sleep-enhancing activity of a Saaz–Saphir hops mixture was measured. In the caffeine-induced insomnia model, the administration of a Saaz–Saphir mixture increased the sleep time compared to Saaz or Saphir administration alone, which was attributed to the increase in NREM sleep time by the δ-wave increase. Oral administration of the Saaz–Saphir mixture for 3 weeks increased the γ-amino butyric acid (GABA) content in the brain and increased the expression of the GABAA receptor. As the GABA antagonists picrotoxin and bicuculline showed a decrease in sleep activity, it was confirmed that the GABAA receptor was involved in the Saaz–Saphir mixture activity. In addition, the GABAA receptor antagonist also reduced the sleep activity induced by xanthohumol and humulone contained in the Saaz–Saphir mixture. Therefore, xanthohumol and humulone contained in the Saaz–Saphir mixture showed sleep-promoting activity mediated by the GABAA receptors. The mixture of the Saaz and Saphir hop varieties may thus help mitigate sleep disturbances compared to other hop varieties.

Download Full-text