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The role of GABA in anxiety disorders
Abstract
Anxiety stems from and perpetuates dysregulation of neurobiological systems, but the exact mechanisms of anxiety disorders are still only partially understood. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter known to counterbalance the action of the excitatory neurotransmitter glutamate. Several pharmacologic agents target the GABA system and modulate the overall effect of GABA. This article highlights multiple neurobiological interactions that play a role in anxiety and reviews selected studies of plasma neurosteroid levels, plasma GABA levels, and benzodiazepine binding site sensitivity and density in patients with anxiety disorders. The article concludes with further support for the role of the GABA system in anxiety by summarizing the current evidence supporting the use of novel GABAergic agents including tiagabine in the treatment of anxiety disorders.
... Six groups of six mice each were used in our experiment. The negative control group received distilled water (10 mL/kg; orally), the positive control group received diazepam (3 mg/kg; intraperitoneally), and the four test groups received four different doses of Crassocephalum bauchiense (25,50, 100 and 200 mg/kg; orally). One hour after treatment, the mice were individually placed on the elevated plus maze centre platform facing an open arm and observed for 5 minutes [13]. ...
... GABA is an important inhibitory neurotransmitter widely distributed in the brain. Its reduction is associated with anxiety [25]. GABAergic neurotransmission in the amygdala is a promising candidate for modulation of anxiety-related responses. ...
... GABAergic neurotransmission in the amygdala is a promising candidate for modulation of anxiety-related responses. A number of lines of research in experimental animals have provided evidence for an important role of GABAergic neurotransmission in the amygdala in modulating anxiety-related behaviours [25]. Administration of Crassocephalum bauchiense aqueous extract enhanced the brain GABA levels which suggested an anxiolytic activity of the extract [11,26,27]. ...
Background and Objective: Crassocephalum bauchiense Hutch is a species of flowering plant from the Asteraceae family. It’s used in traditional medicine for the treatment of brain disorders including epilepsy, depression and anxiety. This study evaluated the anxiolytic effects of Crassocephalum bauchiense aqueous extract and its possible mechanism of action. Materials and Methods: The aqueous extract of Crassocephalum bauchiense (25, 50, 100 and 200 mg/kg) were administered orally to mice one hour before the behavioural testing. Elevated plus maze and open field tests were used, respectively for detecting it anxiolytic properties. Immediately after the open field test, animals were sacrificed and the brain GABA content, and the activities of GAD and GABA-T were measured. Results: Crassocephalum bauchiense (100 and 200 mg/kg) significantly increased the number of entries into, percentage of entries into, and percentage of time in open arms, and reduced rearing, head dipping, and the percentage of time in closed arms, in the elevated plus maze. The plant extract significantly increased crossing and reduced rearing and defecation, in the open field test. In biochemical experiments, the concentration of GABA and the activity of GAD were increased; while the GABA-T activity was decreased, respectively, in the brain of Crassocephalum bauchiense treated-mice. Conclusion: These results suggest that Crassocephalum bauchiense aqueous extract possess anxiolytic properties in the models employed. The extract might potentially act by GABAergic activation in the central nervous system. These data justify and explain the use of Crassocephalum bauchiense to treat anxiety empirically in traditional medicine.
... CNS arousal and neuronal excitability is regulated by the mutual homeostasis between glutamate and GABA, and the excitatory action of glutamate is counterbalanced by GABA, which avoids unnecessary neuronal hyperexcitability that occurs in seizure disorders and pathologic anxiety (Lydiard, 2003). The interaction is central to the adaptation to stress and the avoidance of the development of anxiety disorders (Lydiard, 2003) inasmuch as it has been proposed that balancing the activities of the glutamatergic and GABAergic systems may be considered an approach for the management of anxiety disorders (Sajdyk and Shekhar, 1997). ...
... CNS arousal and neuronal excitability is regulated by the mutual homeostasis between glutamate and GABA, and the excitatory action of glutamate is counterbalanced by GABA, which avoids unnecessary neuronal hyperexcitability that occurs in seizure disorders and pathologic anxiety (Lydiard, 2003). The interaction is central to the adaptation to stress and the avoidance of the development of anxiety disorders (Lydiard, 2003) inasmuch as it has been proposed that balancing the activities of the glutamatergic and GABAergic systems may be considered an approach for the management of anxiety disorders (Sajdyk and Shekhar, 1997). To investigate this further, the present research aimed to study the interactions between the CA3 glutamatergic system and GABA A receptor on the anxiety level and emotional memory of rats performing in an EPM test. ...
... As the CNS's fast inhibitory responses are mediated by GABA receptors, they are expressed on virtually every neuron (Lydiard, 2003). A high degree of diversity and specificity has been recognized among GABA-releasing cells (Freund and Buzsaki, 1996;Klausberger and Somogyi, 2008), which control the activity of local networks and constitute the output of some brain regions and nuclei (Mody and Pearce, 2004). ...
Cognitive functions are influenced by memory and anxiety states. However, a non-linear relation has been shown between these two domains. The important role of the hippocampus in memory and emotional responses may link the pathogenesis of anxiety to memory-related GABAergic and glutamatergic processes in the hippocampus. To investigate the role of GABAA receptors in relation to blocking N-methyl-D-aspartate (NMDA) receptors in the CA3 region, and balancing the glutamatergic and GABAergic system activities as an approach for the management of related disorders, the elevated plus-maze test-retest paradigm was used to investigate the anxiolytic-like state on the test day and avoidance memory state on the retest day. The data showed that injection of D-AP5, the NMDA receptor antagonist, induced anxiolytic-like behavior and impaired avoidance memory. Injection of GABAA agonist (muscimol), but not the antagonist (bicuculline), induced avoidance memory impairment. Neither muscimol nor bicuculline altered anxiety-like behaviors. Muscimol pretreatment did not change D-AP5-induced anxiolytic-like behaviors but potentiated avoidance memory impairment. Bicuculline pretreatment blocked D-AP5-induced anxiolytic-like behaviors and contradicted its effect on avoidance memory. Our findings indicate that alteration of the CA3 GABAA receptor activity can effectively affect the anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5.
... The first studies implicating the E/I molecular pathway in autism were based on the association between ASD and epilepsy, a condition that was already attributed to altered E/I signalling (42,260,261). Other conditions such as Obsessive Compulsive Disorder (OCD), Attention Deficit Hyperactivity Disorder (ADHD), anxiety and depression which are highly co-occurring in ASD have demonstrated disruption to E/I balance (262)(263)(264)(265). ...
... The E/I network is modulated by numerous families of genes encoding scaffolding, cell migration and synaptic functions (9,10,235,266). Post-mortem findings have demonstrated differences in E/I gene and protein expression in those with ASD (267)(268)(269)(270)(271). Exposure to prenatal environmental factors such as maternal immune activation and valproic acid directly alters GABA synthesis [263][264][265] indicating that the E/I pathway is susceptible to both genetic and external factors. There is now increasing evidence for the E/I imbalance theory in humans. ...
Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition typically
diagnosed at 2-4 years of age when deficits in social interaction and communication are noted
by carers. Our knowledge of ASD is advancing with greater awareness of the needs of autistic
children and adults and a move towards improving services for these patients. The underlying
neurobiology of ASD is a unifying aetiological agent, likely altered through both genetic and
environmental influences. There is compelling evidence to suggest that abnormalities in
Excitatory (E) glutamate and inhibitory (I) Gamma-Aminobutyric Acid (GABA) signalling in the brain may underpin ‘atypical’ development. Therefore I chose to examine relationships within the glutamatergic system in the striatum.
First I looked at metabotropic glutamate receptor 5 (mGluR5) in adults with and without ASD and found higher levels of mGluR5 among autistic participants. This is consistent with other recent studies. Despite the close functional ties between mGluR5 and E/I signalling, no-one had directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. I found a strong negative relationship between GABA+ and mGluR5. I then looked at mGluR5 in three animal models associated with ASD to see whether
any of these models might explain the greater availability of mGluR5 in autism. CNTNAP2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice. Given that CNTNAP2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, this finding suggests that an increase in mGluR5 in ASD may relate to developmental GABAergic interneuron abnormalities.
Neurodevelopment requires careful coordination of neuronal and glial processes spanning proliferation, differentiation, myelination and pruning. Disruption to this process can result in neurodevelopmental difficulties and disorders such as ASD. Therefore I conducted early life studies examining the relationship between subcortical Glx (Glutamate and Glutamine), N-acetylaspartate (a marker of neuronal health) and myo-Inositol (a marker of glial activity) at three early life time points: in utero, within 4 weeks of birth (neonatal time point) and at 4-6-months of age (‘infant’ time point). I compared these to later neurodevelopmental outcomes
finding that higher neonatal NAA concentrations corresponded to better general
neurodevelopmental scores and lower ADOS-2 scores. As NAA is a marker of neuronal health this implies that we can mark neuronal health at birth and demonstrate that this correlates with neurodevelopmental outcomes. I then went on to examine these same relationships at the 4-6-month timepoint. Higher levels of myo-Inositol (and therefore greater glial activity) corresponded to poorer general and social developmental outcomes. Higher levels of Glx and therefore excess excitation predicted greater social deficits. This is in keeping with the theory of
E/I imbalance.
... Further, vagus nerve stimulation by the gut microbiota can alter concentration of serotonin, GABA and glutamate within the brain in animals and humans 42,74 and germ-free male mice exhibit anxiety-like behaviors and altered serotonin abundance in the brain 14 . GABA is the main inhibitory neurotransmitter of the central nervous system that counterbalances the action of glutamate 75 . Low levels of GABA are linked to depression and mood disorders 75 . ...
... GABA is the main inhibitory neurotransmitter of the central nervous system that counterbalances the action of glutamate 75 . Low levels of GABA are linked to depression and mood disorders 75 . Animal studies show that gut microbiota can alter GABA activity in the brain through the vagus nerve 76 . ...
Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup , and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.
... It has been found that mood disorders such as depression and anxiety are linked with an imbalance of dopamine, serotonin, and norepinephrine (Moret and Briley 2011;Blier and El Mansari 2013;El Mansari et al. 2010). Reduced levels of GABA were found to increase depression (Anisman et al. 2012) and anxiety (Nuss 2015;Lydiard 2003), whereas GABA, when secreted normally, is found to increase the experience of relaxation and lowers anxiety and mood disorders (Liu et al. 2020;Wierońska et al. 2011). Studies have shown that interruption in the secretions of various neurotransmitters leads to mental disorders (Mittal et al. 2017). ...
Health has always been a matter of concern for all. Changes in behaviours related to health and climate variability have been evident in the past few years. Alterations in ambient air, water, food, and shelter due to changing climate are weakening health infrastructure. Though people in all age groups are more focussed on dietary patterns and lifestyle in general and with the increasing attention towards health-related aspects, preservation of health has become the most important concern globally. Various dimensions of health such as physical, social, psychological, and spiritual are now separately considered contributing factors to the overall maintenance of well-being. Personal, social, and environmental factors significantly impact the state of health and wellness in individuals. Additionally, biological factors such as genetics, gut microbiota, and neurotransmitters affect mental health. Dietary patterns, nutrition, physical exercises, emotional factors, personality traits, socio-environmental, and demographic conditions also play a significant role in promoting health-related behaviours and building the immune system. Creating awareness and spreading knowledge regarding the need and importance of various aspects of health and opting for sustainable developmental strategies specifically in the industrial and agricultural sectors are the need of the hour. An overall assessment and analysis of factors contributing to a healthy state can be influential in developing a multidimensional approach which can, in turn, be beneficial to the society at large to overcome challenging situations such as a pandemic and the stressors generated due to changing climate.KeywordsBehaviourClimate changeHealthImmunityWell-being
... Specifically, while the hippocampus regulates this axis through the transmission of inhibitory signals, the amygdala excites it by transmitting disinhibitory signals [3,4]. GABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter in the brain and a major player in anxiety and mood disorders [5]. GABA is converted from glutamate by the enzyme glutamic acid decarboxylase (GAD). ...
Epigenetics is a gene-environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (GAD65, GAD67). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of GAD65 in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend was captured, and higher GAD65 methylation was found in JS. In addition, RNA levels were found to be decreased in JS compared to JSe and JS + AS. These findings can point to a possible mechanism: while juvenile stress may enhance a better coping strategy with life challenges, additional stress in adulthood may trigger a contradictory response, either beneficial or harmful.
... GABA is the main inhibitory neurotransmitter in the brain, counterbalancing the action of the excitatory neurotransmitter glutamate. Intracortical GABAergic inhibition induces the dystonic movement, while alterations in the GABA system have been linked to the pathophysiology of anxiety disorders where patients with anxiety showed lover GABA levels in comparison to healthy control group [21][22][23][24]. Women under the age of 40 have been shown to have higher levels of GABA than men but a greater age-related decline in GABA levels. ...
So far there is not much research considering female sex as a risk factor for developing focal cervical dystonia and concomitant psychiatric symptoms such as anxiety. New research proposes ideas of CD baseline pathophysiology targeting neurobiological mechanisms of gamma aminobutyric acid GABAergic function underlying sexual dimorphism and psychiatric symptoms as an intrinsic factor of the disease itself. Our research examines the connection between motor and non-motor symptoms in female patients suffering from focal cervical dystonia and their response to treatment, cit- ing the available literature and hypothesising whether it can be linked to previously described alterations in GABA levels.
... Так, відомо, що тривога виникає внаслідок дисрегуляції нейробіологічних систем, але точні молекулярні механізми тривожних розладів досі вивчені лише частково. Було показано, що ГАМК-залежна система відіграє визначну роль у розвитку тривожності, тому використання ГАМК та ГАМКергічних агентів є ефективним у лікуванні тривожних розладів[10,11].Крім того, у складі ГАММАВІТАЛУ ГАМК має синергічну дію з магнію дигліцинатом, як було зазначено раніше.Шафран-рослинний антидепресант, основні активні компоненти -кроцин та сафранал, які інгібують зворотне синаптичне захоплення (реаптейк) серотоніну, допаміну та норадреналіну; це проявляється у гармонізації психоемоційного стану, зниженні тривожності та стабілізації настрою. Сафранал також діє як агоніст рецепторів ГАМК (синергічно з гамма-аміномасляною кислотою), що призводить до седації, нормалізації глибини та якості сну. ...
The article is devoted to the issues of effective pharmacotherapy in anxiety and non-psychoticdepressive disorders. Chronic stress and emotional overload, CoVID-19 disease lead to the appearance of neurogenic and psychosomatic diseasessymptoms. Recent events in the world and Ukraine have significant influenceonnervous systemgeneral state, so the nervous system needs support and help. The article provides an analysis of the scientific research resultsof effects on the nervous system for such active pharmaceutical ingredients as magnesium diglycinate, vitamin B 6 (pyridoxine), gamma-aminobutyric acid (GABA), saffron extracts and the amino acid 5-hydroxytryptophan. A rational combination of all these components is the domestic medicine «GAMMAVITAL», which has no analogues on the pharmaceutical market. The use of combined medicines, in particular Gammavital, the composition of which ensures the synergism of its components and potentiates their combined effect, opens up new perspectives in the prevention and treatment of anxiety and mild depressive states, sleep disorders, neurotic and vegetative disorders.
... Accumulating evidence links generalized anxiety in humans and animals to decreased function of GABAergic inhibition (Crestani et al., 1999;Lydiard, 2002;Cryan and Kaupmann, 2005). Further, neuronal activity and synaptic plasticity in the BLA is tightly controlled by GABAergic inhibition. ...
Survival requires appropriate fear learning while abnormally high fear and anxiety or generalized fear are detrimental. The amygdala plays a role in both cue-specific fear learning and anxiety-like behavior. Moreover, stress induced changes in amygdalar structure and function correlates with stress mediated enhanced cue-specific and generalized fear. Thus, the neural basis of normal to generalized fear transition is important to understand stress disorders characterized by high anxiety and generalized fear.
This thesis addresses the question of how neuronal activity within interconnected structures, lateral amygdala (LA), auditory cortex (ACx) and the hippocampus, relates to the cue-specific fear learning and it’s transition to generalized fear using a combination of in vivo electrophysiology, pharmacology and optogenetics in rodent models of auditory discriminative fear conditioning. Neural activity in the LA is necessary for fear generalization. A more aversive unconditioned stimulus (US, foot-shock) led to greater behavioral generalization accompanied by an increased proportion of LA neurons that failed to discriminate between conditioned (CS+, tone 1) and neutral stimuli (CS-, tone 2). The same neurons that responded preferentially to CS+ over CS- before the behavioral switch to generalized fear, failed to do so afterwards. Optogenetic activation of basal forebrain cholinergic cells during conditioning, enhanced fear generalization. Simultaneous measurements of neuronal spiking in the LA revealed a transition from cue-specific to generalized responses. In contrast, ACx neurons exhibited enhanced associative responses after cholinergic activation despite enhanced behavioral generalization. Thus, LA neuronal activity correlated with the behavior and was not merely reflective of activity in the cortex. Additionally, pharmacological activation of cAMP/PKA signaling within the LA was sufficient to mimic behavioral generalization. Together, these findings identify a neuronal and molecular basis of the transition from normal to pathological fear.
Stress-related psychiatric disorders severely affect declarative memory functions mediated by hippocampus, which is anatomically connected with amygdala. Earlier findings on differential effects of stress on the hippocampus and amygdala were based on post-mortem analysis within individual areas without any online readout of dynamic changes in the intact animal. I characterized the spatiotemporal dynamics of stress effects across the amygdala-hippocampal network using auditory evoked potentials (AEPs) in awake, behaving rats during and after chronic stress. AEPs in the hippocampus increased transiently after acute stress, but not with chronic stress. However, both acute and chronic stress caused a persistent increase in AEPs in the LA. Granger causality spectra revealed a strong directional influence from the LA to hippocampal area CA1 that persisted throughout, and even 10 days after, chronic stress. Directional coupling from hippocampal area CA3 to CA1, however, became weaker at the end of chronic stress. Thus, the growing dominance of amygdalar activity over the hippocampus during, and even after, chronic stress may contribute to stress induced enhanced emotional symptoms, alongside impaired cognitive function, seen in stress-related psychiatric disorders.
... GABA is one of the earliest and most important neurotransmitters in the brain, providing the initial excitatory drive for neural activity and establishing a balance between inhibitory and excitatory synapses. The breakdown of the GABAergic inhibitory circuit and the resulting excitatory/inhibitory imbalance has been widely reported as one of the mechanisms of anxiety [40,41]. Further studies have also proven that increasing or decreasing the synthesis of GABA to maintain the excitatory/inhibitory balance reduces or even reverses anxiety-like behavior [42]. ...
Pyridaben (PY) is a widely used organochlorine acaricide, which can be detected in the peripheral blood of pregnant women. Available evidence suggests that PY has reproductive toxicity. However, it remains uncertain whether prenatal PY exposure impacts neurobehavioral development in offspring. Here, we administered PY to pregnant mice at a dose of 0.5 and 5 mg kg⁻¹ day⁻¹ via gavage and observed anxiety-like behaviors in PY offspring aged five weeks. We then integrated the metabolome and transcriptome of the offspring's brain to explore the underlying mechanism. Metabolome data indicated that the vitamin B6 metabolism pathway was significantly affected, and the pyridoxal 5′-phosphate (PLP) concentration and the active form of vitamin B6 was significantly reduced. Moreover, the transcriptome data showed that both PLP generation-related Pdxk and anxiety-related Gad1 were significantly down-regulated. Meanwhile, there was a decreasing trend in the concentration of GABA in the hippocampal DG region. Next, we supplemented PLP at a dose of 20 mg kg⁻¹ d⁻¹ to the PY offspring via intraperitoneal injection at three weeks. We found up-regulated expression of Pdxk and Gad1 and restored anxiety-like behaviors. This study suggests that prenatal exposure to PY can disrupt vitamin B6 metabolism, reduce the concentration of PLP, down-regulate the expression levels of Pdxk and Gad1, inhibit the production of GABA, and ultimately lead to anxiety-like behaviors in offspring.
... These neuronal fluctuation and transmission of ions can control the depression and anxiety symptoms. Several studies showed that increased GABA levels in the brain can help to decrease anxiety, stress, and depression [80] and there are multiple drugs effects as alcohol and benzodiazepines which increase activity at GABA receptor [81,82]. ...
MicroRNAs are hidden players in complex psychophysical phenomena such as depression and anxiety related disorders though the activation and deactivation of multiple proteins in signaling cascades. Depression is classified as a mood disorder and described as feelings of sadness, loss, or anger that interfere with a person’s everyday activities. In this review, we have focused on exploration of the significant role of miRNAs in depression by affecting associated target proteins (cellular and synaptic) and their signaling pathways which can be controlled by the attachment of miRNAs at transcriptional and translational levels. Moreover, miRNAs have potential role as biomarkers and may help to cure depression through involvement and interactions with multiple pharmacological and physiological therapies. Taken together, miRNAs might be considered as promising novel therapy targets themselves and may interfere with currently available antidepressant treatments.
... Bahi and colleagues 13 postulate that drug alternatives acting through CB 2 receptors could become novel pharmacological therapies in the treatment of anxiety and mood disorders. Molecular research demonstrates that both the endocannabinoid and GABAergic systems are associated with the pathophysiology of anxiety and related disorders 57,58 . While αPN has not been shown to have an affinity for CB 1 or CB 2 receptors 12 , it has been demonstrated to interact with the GABA A receptor complex to prolong GABAergic synaptic transmission 21,59 , which is likely to contribute to its potential sedative and anxiolytic effects 11,20,30 . ...
Terpenes possess a wide range of medicinal properties and are potential therapeutics for a variety of pathological conditions. This study investigated the acute effects of two cannabis terpenes, β-caryophyllene and α-pinene, on zebrafish locomotion, anxiety-like, and boldness behaviour using the open field exploration and novel object approach tests. β-caryophyllene was administered in 0.02%, 0.2%, 2.0%, and 4% doses. α-pinene was administered in 0.01%, 0.02%, and 0.1% doses. As α-pinene is a racemic compound, we also tested its (+) and (−) enantiomers to observe any differential effects. β-caryophyllene had only a sedative effect at the highest dose tested. α-pinene had differing dose-dependent effects on anxiety-like and motor variables. Specifically, (+)-α-pinene and (−)-α-pinene had significant effects on anxiety measures, time spent in the thigmotaxis (outer) or center zone, in the open field test, as well as locomotor variables, swimming velocity and immobility. (+ /−)-α-pinene showed only a small effect on the open field test on immobility at the 0.1% dose. This study demonstrates that α-pinene can have a sedative or anxiolytic effect in zebrafish and may have different medicinal properties when isolated into its (+) or (−) enantiomers.
... An imbalance in the neurochemicals GABA and Glutamate, can trigger neuropsychiatric and neurodegenerative conditions [47]. Many medicinal plants have sedative and anxiolytic properties by increasing inhibitory neurotransmission or reducing excitatory neurotransmission [48]. ...
Carmoisine is a synthetic food additive which is commonly used in a wide range of food beverages. According to reports, excessive use of this coloring agent causes anxiogenic behavior in mice by inducing oxidative stress. The purpose of this study was to investigate the ameliorating effects of Vernonia Cinerea against carmoisine-induced brain injury and anxiogenic-like effects in mice. Results of behavioral studies revealed that Ethanol Extract of Vernonia Cinerea (EEVC) has anxiolytic activity. Furthermore, carmoisine administration resulted in a significant increase in neuro-chemicals such as glutamate and a depletion of Gamma-Amino Butyric Acid levels (p < 0.001) and antioxidant enzymes such as catalase, and superoxide dismutase levels (p < 0.05), confirming brain tissue damage, while EEVC administration (400 mg/kg p.o.) reversed these biochemical alterations significantly (p < 0.05) as compared to the normal control and carmoisine-treated groups. To a remarkable extent, the extract causes significant changes in neurochemicals. Furthermore, EEVC administration significantly increased the levels of various in vivo antioxidants. Furthermore, EEVC reversed hippocampus Cornu Ammonis 3 (CA3) area complications such as intense vocalization, cyanosis, and hemorrhage when compared to carmoisine groups. From the results, EEVC has shown significant anxiolytic and ameliorating potential against carmoisine-induced brain injury evidenced by a significant reversal of biochemical, neurochemical parameters along with significant improvement of antioxidant activities.
... • Hyperactivation of the amygdala is involved in the pathophysiology of SAD, 2 and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is a central regulator of anxiety 3,4 • PH94B (3β-androsta-4,16-dien-3-ol) is an investigational synthetic neuroactive pherine nasal spray that has demonstrated efficacy in two previous SAD studies 5,6 and is currently under Phase 3 development for the acute treatment of SAD and other anxiety disorders ─ It is proposed that PH94B binds to peripheral chemosensory neurons in the nasal mucosa that activate subsets of olfactory bulb neurons to modulate the olfactory-amygdala neuronal circuits of fear and anxiety 5,7 ─ When stimulated, these neural circuits regulate the release of the inhibitory neurotransmitter GABA in the amygdala, attenuating activity of the sympathetic autonomic nervous system and neural circuits underlying anxiety 7,8 ...
INTRODUCTION • Social anxiety disorder (SAD) is a common and disabling condition with an estimated lifetime prevalence of 12.1% for adults in the United States 1 • Hyperactivation of the amygdala is involved in the pathophysiology of SAD, 2 and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is a central regulator of anxiety 3,4 • PH94B (3β-androsta-4,16-dien-3-ol) is an investigational synthetic neuroactive pherine nasal spray that has demonstrated efficacy in two previous SAD studies 5,6 and is currently under Phase 3 development for the acute treatment of SAD and other anxiety disorders ─ It is proposed that PH94B binds to peripheral chemosensory neurons in the nasal mucosa that activate subsets of olfactory bulb neurons to modulate the olfactory-amygdala neuronal circuits of fear and anxiety 5,7 ─ When stimulated, these neural circuits regulate the release of the inhibitory neurotransmitter GABA in the amygdala, attenuating activity of the sympathetic autonomic nervous system and neural circuits underlying anxiety 7,8 OBJECTIVE • In order to differentiate the unique mechanism of action of PH94B from other steroids, we compared the effect of intranasal PH94B administration with intranasal administration of steroidal hormones and control on the electrogram of the nasal chemosensory mucosa (EGNR) and on autonomic nervous system parameters in healthy adult subjects METHODS Study Design • This was a single-blind randomized study performed in 16 healthy adults (8 men and 8 women) age 20 to 60 years. All experimental procedures were conducted after participants signed informed consent ─ Subjects with nasal septum perforation or past/current drug or alcohol use were excluded • Each subject was invited to participate in two study sessions 2 to 3 days apart, during which test articles and control were administered intranasally ─ Subjects randomly received control (propylene glycol) and study drugs (PH94B, estradiol-β, progesterone, cortisol, and testosterone, 0.4 µg each dissolved in propylene glycol) ─ Study drugs and control were administered intranasally 30 minutes apart as a 1-second aerosolized pulse using a Multifunctional Miniprobe (MM ®) Measurements • EGNR was assessed using a recording electrode positioned on the surface of the nasal chemosensory mucosa of the medial and dorsal nasal septum • Noninvasive recording electrodes were placed on the skin surface to monitor the following autonomic reflex activity: ─ Respiratory rate was recorded with a strain gauge placed around the lower thorax ─ Heart rate was measured from the electrocardiogram (standard bipolar I) ─ Electrodermal activity was recorded as skin conductance from the palmar surface of the third and fourth finger • Autonomic parameters were recorded in 5-minute epochs before and 15-minute epochs after intranasal drug administration • Recordings were amplified, digitized, and continuously computer monitored and stored for further offline processing and analysis • The amplitude and frequency of the digitized signals were measured using ACQKnowledge software (Biopac Systems) • At the conclusion of recording for each drug, subjects provided feedback on their experience and were asked about any change in their state of well-being Statistical Analyses • The mean and standard deviations were calculated, and paired comparisons between treatments were conducted using the Student's t-test
... Moreover, gaba-a-α2 negatively correlated with reaction to social novelty, locomotor activity (vertical activity and velocity, as gad2), and anxiety levels, and positively correlated with anxiety index (animals spent more time in the closed than open arms). These results point to an inverse relationship between the activity of the GABAergic system and anxiety, social, and motor behaviors, something that is unsurprising based on the preclinical literature and current treatments in the clinical field [82][83][84]. For the cholinergic genes, the nicotinic α7 receptor negatively correlated with social exploration, and this gene, along with the muscarinic 2 receptors, chat and vacht, negatively correlated with different locomotor behaviors. ...
Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF (s.c.) from GD12.5–15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior.
... The approval of the benzodiazepines by the Food and Drug Administration for the treatment of anxiety disorders, the discovery that benzodiazepines bind to the GABA A receptor, and a number of lines of research suggest that GABA plays a critical role in regulating anxiety; GABA antagonists exhibit anxiogenic effects (Nuss 2015;Pollack et al. 2005;Durant et al. 2009;Lydiard 2003;Sanders and Shekhar 1995;Heldt et al. 2012). In humans, amygalar stimulation by electrical current presents as feelings of fear and anxiety (Lanteaume et al. 2007) and benzodiazepines reduce amygdalar activity when presented with negative emotional stimuli (Del-Ben et al. 2012;Paulus et al. 2005). ...
Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.S., and about 50,000 of them die. Persistent symptoms develop in 10–15% of the cases including neuropsychiatric disorders. Anxiety is the second most common neuropsychiatric disorder that develops in those with persistent neuropsychiatric symptoms after TBI. Abnormalities or atrophy in the temporal lobe has been shown in the overwhelming number of TBI cases. The basolateral amygdala (BLA), a temporal lobe structure that consolidates, stores and generates fear and anxiety-based behavioral outputs, is a critical brain region in the anxiety circuitry. In this review, we sought to capture studies that characterized the relationship between human post-traumatic anxiety and structural/functional alterations in the amygdala. We compared the human findings with results obtained with a reproducible mild TBI animal model that demonstrated a direct relationship between the alterations in the BLA and an anxiety-like phenotype. From this analysis, both preliminary insights, and gaps in knowledge, have emerged which may open new directions for the development of rational and more efficacious treatments.
... A rest/wake behavioral assay can be used to screen for drugs that modulate sleep (Prober et al., 2006;Rihel et al., 2010) in a high-throughput manner. Rihel et al. (2010) tested several classes of drugs that are used in anxiety and mood disorder treatment [e.g., serotonin, dopamine, GABA (Lydiard, 2003), epinephrine (Dooley, 2015) agonists and antagonists]. The drugs varied in their effects on different aspects of rest. ...
Animal models are essential for the discovery of mechanisms and treatments for neuropsychiatric disorders. However, complex mental health disorders such as depression and anxiety are difficult to fully recapitulate in these models. Borrowing from the field of psychiatric genetics, we reiterate the framework of ‘endophenotypes’ – biological or behavioral markers with cellular, molecular or genetic underpinnings – to reduce complex disorders into measurable behaviors that can be compared across organisms. Zebrafish are popular disease models due to the conserved genetic, physiological and anatomical pathways between zebrafish and humans. Adult zebrafish, which display more sophisticated behaviors and cognition, have long been used to model psychiatric disorders. However, larvae (up to 1 month old) are more numerous and also optically transparent, and hence are particularly suited for high-throughput screening and brain-wide neural circuit imaging. A number of behavioral assays have been developed to quantify neuropsychiatric phenomena in larval zebrafish. Here, we will review these assays and the current knowledge regarding the underlying mechanisms of their behavioral readouts. We will also discuss the existing evidence linking larval zebrafish behavior to specific human behavioral traits and how the endophenotype framework can be applied. Importantly, many of the endophenotypes we review do not solely define a diseased state but could manifest as a spectrum across the general population. As such, we make the case for larval zebrafish as a promising model for extending our understanding of population mental health, and for identifying novel therapeutics and interventions with broad impact.
... These results suggest that the analgesic and anxiolytic effects of GIPR are closely related to microglia and NF-kB p65 signaling. The excitatory/inhibitory (E/I) neuronal network maintains a finely tuned balance that is critical for the physiological function of the CNS (48,62). The imbalance of E/I signaling leads to a series of neurological disorders (63,64). ...
Background
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders.
Methods
The chronic inflammatory pain model was established by hind paw injection with complete Freund’s adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala ² -GIP) and antagonist (Pro ³ -GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR.
Results
In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala ² -GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro ³ -GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice.
Conclusions
GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.
... Mg may additionally balance the over activation of glutamate via increasing GABAergic availability. An imbalance between GABA and glutamate was shown to be associated with anxiety disorders [31]. ...
Introduction: Low magnesium levels have been implicated in the pathophysiology of stress, anxiety, depression, and other quality
... Further, the anxiety-like behavior of the Aβ 1-42 afflicted animals was also evaluated by the elevated plus maze task. Rodents are known to prefer dark and enclosed spaces to open areas where the number of entries in the open and (Lydiard 2003;Nemeroff 2003). Similar enhancement in anxiety levels have been linked to intracellular Aβ aggregation in GABAergic neurons in the basolateral amygdala in AD brains (España et al. 2010). ...
Alzheimer’s disease is characterized by deposition of amyloid-beta plaques in the brain. Available pharmaceuticals provide temporary symptomatic relief without affecting disease progression. Use of radiation was found effective in treating extra-cranial amyloidosis, therefore, the present study was designed to investigate the neuroprotective role of fractionated X-irradiation in Aβ1–42-based rodent model of Alzheimer’s disease. S.D. female rats were randomly divided into four groups: sham control (Group 1), Aβ1–42 injected (Group 2), cranial X-irradiated (Group 3) and Aβ1–42 injected followed by cranial X-irradiation (Group 4). A single dose of 5 µL Aβ1–42 peptide was administered through intracerebroventricular (icv) injection in Group 2 and 4 animals, while Group 1 animals were administered 5 µL of bi-distilled water (icv). The group 4 animals were further subjected to 10 Gy X-irradiation (fractionated dose, 2 Gy × 5 days) after 4 weeks of Aβ1–42 infusion of peptide. The animals in Group 3 were subjected to same dose of cranial fractionated X-irradiation (2 Gy × 5 days) only. Significant decrease in amyloid deposits were observed in the Aβ1–42 + radiation-treated animals confirmed by histopathological analysis. These finding were in concordance with neurobehavioral tests that showed a significant improvement in Aβ1–42-induced memory impairment in the animals subjected to fractionated cranial X-irradiation. Restoration of alterations in neurochemical and antioxidant defense indices further supported our results. The present study highlights the underexplored role of fractionated X-irradiation in curtailing the Aβ1–42-induced neurotoxicity, suggesting a novel treatment option for Alzheimer’s disease-associated pathologies.
... Since this neurotransmitter has a fundamental role in the regulation of excitatory and inhibitory processes in the brain, any disruption can cause CNS pathologies [3]. GABA is currently known to be involved directly or indirectly in CNS diseases including anxiety [4], cognitive [5] and sleep disorders [6], epilepsy [7], depression and bipolar disorder [8], schizophrenia [9], Alzheimer's [10] and Parkinson's diseases [11], memory impairments [12], eating disorders [13], response to anaesthesia in surgical operations [14], etc. Thus, a major aim of therapeutic approaches targeting the GABA system, on which it depends for neuronal inhibition, is to recover the neuronal balance between excitation and inhibition lost in all these pathologies. ...
Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABAA receptors (GABAARs), with sedative, anxiolytic or anti-convulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABAARs, which may act either negatively , positively, by neutralizing GABAARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABAAR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene gal-dosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.
... Mechanism of anxiety involves lowering of GABA levels in central nervous system, there by producing anxiety. Most of the anti-anxiety drugs work by the way of modulating GABA receptors 45 . ...
Life-style changes, environmental pollution, and genetic factors have resulted in a large number of diseases to human beings. Though plant extracts have been widely used to counteract these diseases wherein the combined effect of the constituents was found to be responsible for the cure of a disease, activity of individual constituent was unknown. Further, naturally obtained heterocyclic compounds have been found to possess excellent pharmacological activity. In view of improvement of pharmacological activity, synthesis of derivatized heterocyclic compounds is considered as prime importance in drug-design. It is evident that azepine derivatives have been reported to possess a wide range of pharmacological activity. Recently, the critical reviews on pharmacology of azepines have not been reported. Here, the importance of azepine analogs and azepine-related scaffolds in drug design and discovery for various diseases such as antimicrobial, anticonvulsive, analgesic, etc. has been described. Particularly, the most remarkable azepine therapeutic molecules are emphasized via structure–activity relationship. The review specially focused on disorders of central nervous system (convulsions, pain, anxiety, Alzheimer’s, and mood disorder). In this review, it is found that heterocycle-fused azepine derivatives bestowed the most promising activity. The review might be a real help to researchers in finding efficient azepine-based pharmacological agents in future.
... γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system and it is involved in the pathophysiology of many psychiatric and neurological diseases. [1][2][3] Direct GABA detection by proton magnetic resonance spectroscopy ( 1 H-MRS) is challenging due to its low concentration, complex spin system, and signal overlap with more abundant metabolites such as creatine (Cr), N-acetylaspartic acid (NAA), glutamate (Glu), and macromolecules (MMs). ...
The purposes of the study were to introduce a MEGA‐semi‐adiabatic spin‐echo full‐intensity sequence (MEGA‐sSPECIAL) with macromolecule (MM) subtraction and to compare test‐retest reproducibility of GABA measurement at 7T using the sSPECIAL and MEGA‐sSPECIAL sequences. The MEGA‐sSPECIAL editing scheme using asymmetric adiabatic and highly selective Gaussian pulses was used to compare its GABA measurement reproducibility with that of the short‐TE sSPECIAL. 1H MRS data were acquired in the motor cortex (M1) and medial prefrontal cortex (mPFC) using the sSPECIAL (TR/TE = 4000/16 ms) and MEGA‐sSPECIAL sequences (TR/TE = 4000/80 ms). The metabolites were quantified using LCModel with unsuppressed water spectra. The concentrations are reported in institutional unit. A test‐retest reproducibility was evaluated by scanning each subject twice. Between‐session reproducibility was assessed using coefficients of variation (CV), Pearson’s r correlation coefficients, and intra‐class correlation coefficient (ICC). Inter‐sequence agreement was evaluated using Pearson’s r correlation coefficients and Bland‐Altman plots. Regarding GABA measures by sSPECIAL, GABA concentrations were 0.92 ± 0.31 in the M1 and 1.56 ± 0.49 in the mPFC. It showed strong between‐session correlation across both regions (r = 0.81, p < 0.01; ICC = 0.82). CVs between two scans are 21.8% in the M1 and 10.2% in the mPFC. On the other hand, GABA measures by MEGA‐sSPECIAL were 0.52 ± 0.04 in the M1 and 1.04 ± 0.24 in the mPFC. MEGA‐sSPECIAL showed strong between‐session correlation across the two regions (r = 0.98, p < 0.001; ICC = 0.98) and lower CVs than sSPECIAL providing 4.1% in the M1 and 5.8% in the mPFC. MEGA‐editing method showed better reproducibility of GABA measures in both brain regions than the short‐TE sSPECIAL. It is a more sensitive method to detect small changes in areas with low GABA concentrations. In GABA‐rich brain regions, GABA measurement can be achieved reproducibly using both methods.
... Consequently, altered inhibition interferes with the function of neocortical neurons (Isaacson and Scanziani, 2011), leads to acute behavioral peculiarities (Engin et al., 2018) and CNS diseases ranging from epilepsy (Fritschy, 2008), anxiety disorders (Lydiard, 2003) and mood disorders (Craddock et al., 2010;Luscher et al., 2011b) to schizophrenia (Foss-Feig et al., 2017) and cognitive impairment in down syndrome (Rudolph and Möhler, 2014). The behavioral impact of GABAergic transmission is supported by pharmacologic interventions targeting GABA A Rs that are used to treat e.g. ...
Interferon-γ (IFN-γ), an important mediator of the antiviral immune response, can also act as a neuromodulator. CNS IFN-γ levels rise acutely in response to infection and therapeutically applied IFN-γ provokes CNS related side effects. Moreover, IFN-γ plays a key role in neurophysiological processes and a variety of chronic neurological and neuropsychiatric conditions. To close the gap between basic research, behavioral implications and clinical applicability, knowledge of the mechanism behind IFN-γ related changes in brain function is crucial. Here, we studied the underlying mechanism of acutely augmented neocortical inhibition by IFN-γ (1.000 IU ml–1) in layer 5 pyramidal neurons of male Wistar rats. We demonstrate postsynaptic mediation of IFN-γ augmented inhibition by pressure application of GABA and analysis of paired pulse ratios. IFN-γ increases membrane presence of GABAAR γ2, as quantified by cell surface biotinylation and functional synaptic GABAAR number, as determined by peak-scaled non-stationary noise analysis. The increase in functional receptor number was comparable to the increase in underlying miniature inhibitory postsynaptic current (mIPSC) amplitudes. Blockage of putative intracellular mediators, namely phosphoinositide 3-kinase and protein kinase C (PKC) by Wortmannin and Calphostin C, respectively, revealed PKC-dependency of the pro-inhibitory IFN-γ effect. This was corroborated by increased serine phosphorylation of P-serine PKC motifs on GABAAR γ2 upon IFN-γ application. GABAAR single channel conductance, intracellular chloride levels and GABAAR driving force are unlikely to contribute to the effect, as shown by single channel recordings and chloride imaging. The effect of IFN-γ on mIPSC amplitudes in female rats was similar as in male rats, suggesting a gender-independent mechanism of action. Collectively, these results indicate a novel mechanism for the regulation of inhibition by IFN-γ, which could impact on neocortical function and therewith behavior.
... Gamma-aminobutyric acid (GABA), the main inhibitor neurotransmitter in the central nervous system (CNS), plays an important role in anxiety [10]. Anxiety and related neurological disorders often result from low GABA levels in CNS [11]. ...
Anxiety and insomnia are among the most common mental health disorders and are a
major cause of disability around the world. Traditional herbal medicines are receiving significant attention in global health debates. Several Italian regions maintain rural traditions and are among the most extensively studied areas of Europe regarding medicinal plant uses. The present overview aims to highlight the use of wild and cultivated plants, specifically as sedatives and for insomnia treatment in Italy, and to collect, analyze, and summarize the available literature about their pharmacological
activity as well as clinical and pre-clinical studies concerning the most cited plants. In total, 106 wild taxa are used in Italy for sedative purposes. The plant species belong to 76 genera and 32 families, of which the most cited are Asteraceae (24.2%) and Lamiaceae (21.1%). Leaves (29%) and flowers (27%) are the plant parts mostly used as infusion (70%) and decoction (25%). Out of 106 taxa documented, only the most cited are analyzed in this overview (A. arvensis L., C. nepeta L., C. monogyna Jacq., H. lupulus L., L. nobilis L., L. angustifolia Mill., M. sylvestris L., M. chamomilla L., M. officinalis L., O.
basilicum L., P. rhoeas L., P. somniferum L., R. officinalis L., T. platyphyllus Scop., and V. officinalis L.). Among the fifteen species selected, only seven have been studied for their pharmacological activity as hypnotic-sedatives. Future pre-clinical and clinical studies are needed to better clarify the mechanism of action of bioactive compounds and confirm the potential of these alternative therapies.
... 42 Antianxiety drugs target the receptors on the GABAergic neurons to modulate the levels of GABA. 43,44,45 It was shown that GABAB receptor-deficient mice exhibited more anxiety compared to their wild-type counterparts as evaluated by multiple anxiety-related tests. 46 Benzodiazepines, an anxiolytic, achieves its pharmacological actions by specifically augmenting the effects of GABA, which are facilitated by GABAA receptors. ...
Background: Generalized anxiety disorder (GAD) and depression are the common mental health diseases affecting millions of people globally. The conventional treatment with medications causes a lot of adverse effects leading patients to seek relief from alternative systems of medicine. The alternative mode of treatment, Homeopathy, uses ultra-diluted drugs to treat GAD and Depression. Objective: This review is to narrate and assess the effectiveness of homeopathy in anxiety and depressive disorders. Also, the related animal studies and in-vitro studies have been evaluated. Methods: The search used combinations of Medical Subject Heading terms ultra-diluted, anxiety, and depression. Lists of articles under references were reviewed to identify additional studies. Results: Studies suggest that ultra diluted, dynamised medicines are used by homeopathic practitioners to treat anxiety and depression. Homeopathic physicians prescribe individualized drugs after a detailed case taking. These have a favorable effect on the patients compared to control and also to conventional medicines. In- vivo studies show encouraging results as ultra- diluted drugs act as anxiolytics without altering the motor abilities of the animal models. In-vitro studies are lacking to reach a decisive inference. Conclusion: Although there are enough preliminary studies establishing proof of the effect of homeopathy in mental health ailments, further exploration is essential and ought to embrace well premeditated controlled studies with sufficient sums of participants.
... A dysregulation of the GABA system is often associated with anxiety symptoms, usually present in human patients with AN [105,106]. For example, facilitation of GABA A receptors signaling has proven to restore feeding behavior in adult mice where hypothalamic neurons expressing the neuropeptide Y (NPY) and the agoutirelated protein AgRP were ablated leading to reduced eating [107]. ...
Background
The genesis of anorexia nervosa (AN), a severe eating disorder with a pervasive effect on many brain functions such as attention, emotions, reward processing, cognition and motor control, has not yet been understood. Since our current knowledge of the genetic aspects of AN is limited, we are left with a large and diversified number of biological, psychological and environmental risk factors, called into question as potential triggers of this chronic condition with a high relapse rate. One of the most valid and used animal models for AN is the activity-based anorexia (ABA), which recapitulates important features of the human condition. This model is generated from naïve rodents by a self-motivated caloric restriction, where a fixed schedule food delivery induces spontaneous increased physical activity.
Aim
In this review, we sought to provide a summary of the experimental research conducted using the ABA model in the pursuit of potential neurobiological mechanism(s) underlying AN.
Method
The experimental work presented here includes evidence for neuroanatomical and neurophysiological changes in several brain regions as well as for the dysregulation of specific neurochemical synaptic and neurohormonal pathways.
Results
The most likely hypothesis for the mechanism behind the development of the ABA phenotype relates to an imbalance of the neural circuitry that mediates reward processing. Evidence collected here suggests that ABA animals show a large set of alterations, involving regions whose functions extend way beyond the control of reward mechanisms and eating habits. Hence, we cannot exclude a primary role of these alterations from a mechanistic theory of ABA induction.
Conclusions
These findings are not sufficient to solve such a major enigma in neuroscience, still they could be used to design ad hoc further experimental investigation. The prospect is that, since treatment of AN is still challenging, the ABA model could be more effectively used to shed light on the complex AN neurobiological framework, thus supporting the future development of therapeutic strategies but also the identification of biomarkers and diagnostic tools.
Plain English summary
Anorexia Nervosa (AN) is a severe eating disorder with a dramatic effect on many functions of our brain, such as attention, emotions, cognition and motion control. Since our current knowledge of the genetic aspects behind the development of AN is still limited, many biological, psychological and environmental factors must be taken into account as potential triggers of this condition. One of the most valid animal models for studying AN is the activity-based anorexia (ABA). In this model, rodents spontaneously limit food intake and start performing increased physical activity on a running wheel, a result of the imposition of a fixed time schedule for food delivery. In this review, we provide a detailed summary of the experimental research conducted using the ABA model, which includes extended evidence for changes in the anatomy and function of the brain of ABA rodents. The hope is that such integrated view will support the design of future experiments that will shed light on the complex brain mechanisms behind AN. Such advanced knowledge is crucial to find new, effective strategies for both the early diagnosis of AN and for its treatment.
... GABA is the main inhibitory neurotransmitter in the body and central nervous system (CNS), functioning to reduce the activity of the neurons to which it binds, inhibiting nerve transmission and counterbalancing the action of the excitatory neurotransmitter glutamate [6][7][8]. The effects of GABA are mediated through ionotropic GABA A receptors, which exist as a number of subtypes formed by the co-assembly of different subunits (α, β, and γ subunits) and metabotropic GABA B receptors, which are G protein-coupled receptors, which consist of a heterodimer made up of two subunits (GABA B1 and GABA B2 ), whereby both are necessary for receptor functionality [9,10]. ...
Background
Of the many neurotransmitters in humans, gamma-aminobutyric acid (GABA) shows potential for improving several mental health indications such as stress and anxiety. The microbiota-gut-brain axis is an important pathway for GABAergic effects, as microbially-secreted GABA within the gut can affect host mental health outcomes. Understanding the molecular characteristics of GABA production by microbes within the gut can offer insight to novel therapies for mental health.
Results
Three strains of Levilactobacillus brevis with syntenous glutamate decarboxylase (GAD) operons were evaluated for overall growth, glutamate utilization, and GABA production in typical synthetic growth media supplemented with monosodium glutamate (MSG). Levilactobacillus brevis Lbr-6108™ (Lbr-6108), formerly known as L. brevis DPC 6108, and Levilactobacillus brevis Lbr-35 ™ (Lbr-35) had similar growth profiles but differed significantly in GABA secretion and acid resistance. Lbr-6108 produced GABA early within the growth phase and produced significantly more GABA than Lbr-35 and the type strain Levilactobacillus brevis ATCC 14869 after the stationary phase. The global gene expression during GABA production at several timepoints was determined by RNA sequencing. The GAD operon, responsible for GABA production and secretion, activated in Lbr-6108 after only 6 h of fermentation and continued throughout the stationary phase. Furthermore, Lbr-6108 activated many different acid resistance mechanisms concurrently, which contribute to acid tolerance and energy production. In contrast, Lbr-35, which has a genetically similar GAD operon, including two copies of the GAD gene, showed no upregulation of the GAD operon, even when cultured with MSG.
Conclusions
This study is the first to evaluate whole transcriptome changes in Levilactobacillus brevis during GABA production in different growth phases. The concurrent expression of multiple acid-resistance mechanisms reveals niche-specific metabolic functionality between common human commensals and highlights the complex regulation of GABA metabolism in this important microbial species. Furthermore, the increased and rapid GABA production of Lbr-6108 highlights the strain’s potential as a therapeutic and the overall value of screening microbes for effector molecule output.
... Additionally, nicotine stimulates the release of glutamate, an excitatory neurotransmitter, which is associated with learning and memory [58,59]. Nicotine also indirectly stimulates the release of GABA, which is associated with a modulatory reduction of anxiety [59][60][61]. Not only does the use of nicotine promote these positive responses with continued use, it also promotes an increase in the number of high-affinity nicotine binding sites in the brain [57]. ...
Both stroke and smoking continue to be major public health crises in the United States, with stroke being the third and fourth leading cause of death among women and men, respectively. The goal of this review will be to provide clinicians a succinct overview regarding the epidemiology, economics, and biology of stroke in the setting of smoking and electronic cigarette use. Special attention will be given to the escalating public health crisis of electronic cigarette use, emphasizing mechanistic relationships of stroke and lung injury. Readers will be made aware of the need for continued scientific advancement and study regarding these relationships, as well as the need for improved governmental and public health efforts to curb these ongoing public health crises.
... GABA neurotransmission is considered as the cornerstone modulator of epilepsy pathology, considering the GABAergic pathway as the main inhibitory pathway in the brain. Benzodiazepines are the drug class of choice for attenuating anxiety, by activating GABAA receptor and mediating an inhibitory state [69]. The effect of Citrus aurantium L. EOs was examined on anxiety and its correlation with the GABAergic pathway. ...
Limonene is a monoterpene confined to the family of Rutaceae, showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its mitigating effect on oxidative stress and inflammation and regulating apoptotic cell death. There are several available studies demonstrating the neuroprotective role of limonene in neurodegenerative diseases, including Alzheimer’s disease, multiple sclerosis, epilepsy, anxiety, and stroke. The high abundance of limonene in nature, its safety profile, and various mechanisms of action make this monoterpene a favorable molecule to be developed as a nutraceutical for preventive purposes and as an alternative agent or adjuvant to modern therapeutic drugs in curbing the onset and progression of neurodegenerative diseases. This manuscript presents a comprehensive review of the available scientific literature discussing the pharmacological activities of limonene or plant products containing limonene which attribute to the protective and therapeutic ability in neurodegenerative disorders. This review has been compiled based on the existing published articles confined to limonene or limonene-containing natural products investigated for their neurotherapeutic or neuroprotective potential. All the articles available in English or the abstract in English were extracted from different databases that offer an access to diverse journals. These databases are PubMed, Scopus, Google Scholar, and Science Direct. Collectively, this review emphasizes the neuroprotective potential of limonene against neurodegenerative and other neuroinflammatory diseases. The available data are indicative of the nutritional use of products containing limonene and the pharmacological actions and mechanisms of limonene and may direct future preclinical and clinical studies for the development of limonene as an alternative or complementary phytomedicine. The pharmacophore can also provide a blueprint for further drug discovery using numerous drug discovery tools.
... CNS-GABA dysfunction is associated with anxiety [182][183][184][185] and depression [186][187][188][189]. In previous reports, assessment of GABA concentration in depression patients showed reduced levels in the cortical brain [190,191], CSF [192] and plasma [193,194]. ...
Novel therapeutic strategies are needed to address depression, a major neurological disorder affecting hundreds of millions of people worldwide. Cannabinoids and their synthetic derivatives have demonstrated numerous neurological activities and may potentially be developed into new treatments for depression. This review highlights cannabinoid (CB) receptors, monoamine oxidase (MAO), N-methyl-D-aspartate (NMDA) receptor, gamma-aminobutyric acid (GABA) receptor, and cholecystokinin (CCK) receptor as key molecular targets of cannabinoids that are associated with depression. The anti-depressant activity of cannabinoids and their binding modes with cannabinoid receptors are discussed, providing insights into rational design and discovery of new cannabinoids or cannabimimetic agents with improved druggable properties.
... In anxiety disorders, the neurotransmitter gamma aminobutyric acid (GABA), (the main restrictor of the activity of the CNS), is known to influence mental symptomatology. Indeed, a large number of anxiolytics are effective in modulating GABA receptors [78]. The most important parts of the brain involved in anxiety are the amygdala and the hippocampus. ...
Nowadays, gluten and FODMAP food components (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) are increasingly studied due to their possible relation with extraintestinal-associated conditions. In recent years, gluten-free diets (GFD) and low-FODMAP diets (LFD) are becoming more popular not only in order to avoid the food components that cause intolerances or allergies in some people, but also due to the direct influence of marketing movements or diet trends on feeding habits. Likewise, neurological and psychiatric diseases are currently of increasing importance in developed countries. For this reason, a bibliographic systematic review has been carried out to analyse whether there is a pathophysiological relationship between the dietary intake of gluten or FODMAPs with mental disorders. This review collects 13 clinical and randomized controlled trials, based on the PRISMA statement, which have been published in the last ten years. Based on these results, limiting or ruling out gluten or FODMAPs in the diet might be beneficial for symptoms such as depression, anxiety (7 out of 7 articles found any positive effect), or cognition deficiency (improvements in several cognition test measurements in one trial), and to a lesser extent for schizophrenia and the autism spectrum. Nevertheless, further studies are needed to obtain completely reliable conclusions.
Enduring loneliness is associated with mental disorders and physical diseases. Although genome-wide association studies (GWAS) have identified risk loci associated with loneliness, how these loci confer the risk remains largely unknown. In the current study, we aimed to investigate key proteins underlying loneliness in the brain by integrating human brain proteomes and transcriptomes with loneliness GWAS to perform a discovery proteome-wide association study (PWAS), followed by a confirmatory PWAS, transcriptome-wide association analysis (TWAS), Mendelian randomization (MR), Steigering filtering analysis and Bayesian colocalization analysis. Moreover, given the fact that loneliness is associated with mental disorders, we explored the shared genetic architecture between loneliness and mental disorders. Totally, we identified 18 genes to be associated with loneliness via their cis-regulated brain protein abundance. Eleven of the 18 genes (61.1%) were replicated in the confirmatory PWAS, and mRNA levels of 4 genes were further validated to be associated with loneliness.MR and genetic colocalization analysis further confirmed that the increased protein abundance of ALDH2 and ICA1L was protective against loneliness, while the increased protein abundance of GPX1 was a risk for developing loneliness. Furthermore, we found genetic correlations, bidirectional causal associations and overlapping phenotype-associated protein profiles between loneliness and mental disorders including major depression and schizophrenia. In summary, our findings provided clues about the brain-related molecular basis underlying loneliness, which warrants further investigation.
Anxiety disorders are currently a major psychiatric and social problem, the mechanisms of which have been only partially elucidated. The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation. Yet so far, its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation. Recent advances in imaging, virus tracking, and optogenetics/chemogenetics have permitted elucidation of the activity, connectivity, and function of specific cell types within the hippocampus and its connected brain regions, providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety. Studies of hippocampal neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic systems, have contributed to the interpretation of the underlying neural mechanisms of anxiety. Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation. This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation, based on molecular, cellular, and circuit properties, to provide tailored targets for future anxiety treatment.
Background
Anxiety is one of the psychiatric disorders that disturbs routine life including moods and motivation. Excessive anxiety causes mental illnesses or anxiety disorders, which are commonly treated by synthetic medicines. Recently, there is a substantial increase in the studies of phytochemicals as alternatives to first-line conventional anxiolytic drugs. Yet there is insufficient information about the mechanisms of how these bioactive constitutes from plants manage anxiety disorders. This systematic review aims to answer the following research questions: 1) Which plant extracts and phytochemicals have anxiolytic effect? what is the mechanism of action? 2) Have human trials been conducted to confirm their anxiolytic effect? 3) If not, which plants/phytochemicals are recommended for further human trials?
Methodology
To define and summarize such information, this systematic review consolidated in vitro, preclinical, and clinical studies that examine the anti-anxiety activity of plant extracts via oral administration, conducted through three scientific databases including PubMed, Scopus, and Google Scholar following the PRISMA protocol.
Results and conclusion
Similar to synthetic drugs, most bioactive phytochemical compounds modulate anxiolytic activity through six main neurotransmitter pathways including acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate, serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These bioactive compounds mainly belong to phenolics, alkaloids, and terpenoids, and they demonstrated effective therapeutic benefits against anxiety symptoms. Four plants, including Aloysia polystachya, Lavandula angustifolia, Matricaria chamomilla L. and Humulus lupulus, have been evaluated in human trials. However, studies on majority plants were performed using animal models, and among them, Tanacetum parthenium L. Schultz-Bip (Asreraceae), demethoxysudachitin, Albizzia julibrissin, Nelumbo nucifera Gaertn. leaves, Zizyphi spinosi semen seed extract, obovatol, Mangifera indica stem barks, Nectandra grandiflora Ness and Lavandula angustifolia, Bupleurum yinchowense roots, Citrus aurantium L. and Foeniculum vulgare exhibited the most significant anxiolytic effect at dosage of 30 mg/kg/day or lower. Further human trials are recommended to validate the efficacy and safety of these plants/plant extracts/phytochemicals in managing psychiatric disorders.
With the range of psychotropic drugs expanding and the usages of existing medications diversifying, we are pleased to present the Seventh Edition of the world's best-selling formulary in psychopharmacology. The new edition features nine new compounds as well as information about several new formulations of existing drugs. Many important new indications are covered for existing drugs, as are updates to the profiles of the entire content and collection, including new injectable and transdermal formulations, as well as updated warnings and indications. The Pearls have all been refreshed and the antipsychotics section has been completely revised. With its easy-to-use, full-colour template-driven navigation system, Prescriber's Guide combines evidence-based data with clinically informed advice to support everyone who is prescribing in the field of mental health.
Chronic sleep deficiency, a public health epidemic, triggers an elevated risk for physical and mental disorders and may cause unpleasant sensations or experiences in daily life. Importantly, sleep-associated skin diseases attract public attention because most people have anxiety about their facial appearance in modern society. Amounts of health food, especially derived from edible and efficient plant extracts, have been developed for skincare via improvement of sleep quality. Mechanisms of good sleep and healthy skin have been studied, however, the relationship between sleep-promoting herbs and skincare is less elucidated. In this review, we summarize the main signaling pathways of neurotransmitter-mediated skin beauty and list dozens of functional plant extracts for sleep assistance. We conclude several plant candidates for oral cosmetics application through sleep-related neurotransmitters regulation. This review provides pieces of evidence for the application of oral cosmetic food derived from plant extracts in sleep-related beauty.
The gastrointestinal microbiome plays a crucial role in maintaining an individual’s health. Although the gastrointestinal microbiome is commonly perceived as facilitating gastrointestinal functions including digestion, current studies demonstrated that it is able to influence one’s health in the neurological aspect. Emerging findings show that the gut microbiome is highly correlated with anxiety. Here, this review aims to discuss the interaction between the gut microbiome and anxiety. This review shows the significant role of the gut microbiome in gut-brain communication. To better understand how the gut microbiome influences anxiety, this paper discusses the experimental results of the gut microbiome impacting anxiety behaviourally and neurochemically. In addition, several potential pathways between the gut microbiome and the brain are reviewed to investigate the possible mechanisms behind microbiome-anxiety interaction. These studies together may be crucial for future treatments of anxiety disorders via intervening in the gut microbiome.
Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy, and abstinence duration interact to generate anxiety-like behavior.
Male and female human subjects show contrasting propensities to misuse drugs of addiction, including alcohol. These differences lead to different psychological and neurological consequences, such as the likelihood of developing dependence. The pattern and extent of brain damage in alcohol‐use disorder cases also varies with comorbid disease. To explore mechanisms that might underlie these outcomes, we used autopsy tissue to determine mRNA transcript expression in relation to genotype for two GABAA receptor subunit genes. We used quantitative Real‐Time PCR to measure GABRA6 and GABRA2 mRNA concentrations in dorsolateral prefrontal and primary motor cortices of alcohol‐use disorder subjects and controls of both sexes with and without liver disease who had been genotyped for these GABAA receptor subunit genes. Cirrhotic alcohol‐use disorder cases had significantly higher expression of GABRA6 and GABRA2 transcripts than either controls or non‐cirrhotic alcohol‐use disorder cases. Differences were observed between sexes, genotypes and brain regions. We show that sex differences in subjects with GABRA6 and GABRA2 variants may contribute to differences in susceptibility to alcohol‐use disorder and alcohol‐induced cirrhosis. The pattern and extent of brain damage in alcohol‐use disorder cases also varies with comorbid disease. We used quantitative real‐time PCR to measure GABRA6 and GABRA2 mRNA concentrations in dorsolateral prefrontal and primary motor cortices of alcohol‐use disorder subjects and controls of both sexes with and without liver disease who had been genotyped for these GABAA receptor subunit genes.
The human microbiota is influenced by the immune and nervous systems of the host. Gamma-aminobutyric acid (GABA) is known as bioactive compound and it has important physiological functions, such as anti-hypertensive and antidepressant activities. Lactic acid bacteria (LAB), especially Lactobacillus species are known as the most important GABA producers because of the food-grade nature. The purpose of this study is to develop a functional chocolate using microencapsulated GABA producer Lacticaseibacillus rhamnosus NRRL B-442 strain for patients having an anxiety disorder.
Water-in-oil emulsion technique was conducted for microencapsulation using whey-pullulan complex. Microencapsulated and free L. rhamnosus cell counts were 6.75 and 7.20 log CFU/g in chocolates, respectively, at the end of 60 days. During simulated in vitro digestion analysis, survival rate of microencapsulated bacteria in chocolate samples was found at higher percentage (87%) than free bacteria (75%). Furthermore, microencapsulated L. rhamnosus did not affect the physical, chemical, and sensory properties of chocolate.
Consequently, L. rhamnosus with the highest GABA producing capability may provide insight for an anxiety disorder patient, since this strain has been thought as having a therapeutic effect. A new functional food model was developed for “GutBrain Axis” phenomena since the chocolate could be accepted as a good carrier for GABA producer bacteria.
Background:
Post-traumatic stress disorder (PTSD) is a severe and debilitating condition. Several pharmacological interventions have been proposed with the aim to prevent or mitigate it. These interventions should balance efficacy and tolerability, given that not all individuals exposed to a traumatic event will develop PTSD. There are different possible approaches to preventing PTSD; universal prevention is aimed at individuals at risk of developing PTSD on the basis of having been exposed to a traumatic event, irrespective of whether they are showing signs of psychological difficulties.
Objectives:
To assess the efficacy and acceptability of pharmacological interventions for universal prevention of PTSD in adults exposed to a traumatic event.
Search methods:
We searched the Cochrane Common Mental Disorders Controlled Trial Register (CCMDCTR), CENTRAL, MEDLINE, Embase, two other databases and two trials registers (November 2020). We checked the reference lists of all included studies and relevant systematic reviews. The search was last updated on 13 November 2020.
Selection criteria:
We included randomised clinical trials on adults exposed to any kind of traumatic event. We considered comparisons of any medication with placebo or with another medication. We excluded trials that investigated medications as an augmentation to psychotherapy.
Data collection and analysis:
We used standard Cochrane methodological procedures. In a random-effects model, we analysed dichotomous data as risk ratios (RR) and number needed to treat for an additional beneficial/harmful outcome (NNTB/NNTH). We analysed continuous data as mean differences (MD) or standardised mean differences (SMD).
Main results:
We included 13 studies which considered eight interventions (hydrocortisone, propranolol, dexamethasone, omega-3 fatty acids, gabapentin, paroxetine, PulmoCare enteral formula, Oxepa enteral formula and 5-hydroxytryptophan) and involved 2023 participants, with a single trial contributing 1244 participants. Eight studies enrolled participants from emergency departments or trauma centres or similar settings. Participants were exposed to a range of both intentional and unintentional traumatic events. Five studies considered participants in the context of intensive care units with traumatic events consisting of severe physical illness. Our concerns about risk of bias in the included studies were mostly due to high attrition and possible selective reporting. We could meta-analyse data for two comparisons: hydrocortisone versus placebo, but limited to secondary outcomes; and propranolol versus placebo. No study compared hydrocortisone to placebo at the primary endpoint of three months after the traumatic event. The evidence on whether propranolol was more effective in reducing the severity of PTSD symptoms compared to placebo at three months after the traumatic event is inconclusive, because of serious risk of bias amongst the included studies, serious inconsistency amongst the studies' results, and very serious imprecision of the estimate of effect (SMD -0.51, 95% confidence interval (CI) -1.61 to 0.59; I2 = 83%; 3 studies, 86 participants; very low-certainty evidence). No study provided data on dropout rates due to side effects at three months post-traumatic event. The evidence on whether propranolol was more effective than placebo in reducing the probability of experiencing PTSD at three months after the traumatic event is inconclusive, because of serious risk of bias amongst the included studies, and very serious imprecision of the estimate of effect (RR 0.77, 95% CI 0.31 to 1.92; 3 studies, 88 participants; very low-certainty evidence). No study assessed functional disability or quality of life. Only one study compared gabapentin to placebo at the primary endpoint of three months after the traumatic event, with inconclusive evidence in terms of both PTSD severity and probability of experiencing PTSD, because of imprecision of the effect estimate, serious risk of bias and serious imprecision (very low-certainty evidence). We found no data on dropout rates due to side effects, functional disability or quality of life. For the remaining comparisons, the available data are inconclusive or missing in terms of PTSD severity reduction and dropout rates due to adverse events. No study assessed functional disability.
Authors' conclusions:
This review provides uncertain evidence only regarding the use of hydrocortisone, propranolol, dexamethasone, omega-3 fatty acids, gabapentin, paroxetine, PulmoCare formula, Oxepa formula, or 5-hydroxytryptophan as universal PTSD prevention strategies. Future research might benefit from larger samples, better reporting of side effects and inclusion of quality of life and functioning measures.
In the present study we measured the concentrations of cortisol, thyroid hormones, testosterone, and GABA (gamma aminobutyric acid) in blood plasma samples of combatants with an at least 10 year history of military psychological trauma (N = 74) divided in groups that either suffer from post-traumatic stress disorder (PTSD) (N = 37) or are resistant (N = 37) as well as in a control group without traumatic experience (N = 34). PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS).
The results show that the blood cortisol levels of individuals that were exposed to war zone experiences irrespective susceptibility for or resistance to PTSD were significantly higher than the values observed in the controls. Testosterone levels in PTSD patients differed neither from that observed in PTSD resistant nor control groups. In the resistant group testosterone levels were however significantly higher than in controls. The level of all thyroid hormones did not differ between the study groups. GABA level was significantly lower in the PTSD group compared with healthy controls. In the resistant group blood GABA levels were not significantly different from either PTSD patients or controls.
In conclusion, the current data show that cortisol and to some extent testosterone may serve as biomarker of war zone stress per se, even if trauma was experienced at least ten years before, rather than of only PTSD or resistance to PTSD. GABA, in contrast, can be considered a potential marker of the protracted nature of PTSD.
With the range of psychotropic drugs expanding and the usages of existing medications diversifying, we are pleased to present the Seventh Edition of the world's best-selling formulary in psychopharmacology. The new edition features nine new compounds as well as information about several new formulations of existing drugs. Many important new indications are covered for existing drugs, as are updates to the profiles of the entire content and collection, including new injectable and transdermal formulations, as well as updated warnings and indications. The Pearls have all been refreshed and the antipsychotics section has been completely revised. With its easy-to-use, full-colour template-driven navigation system, Prescriber's Guide combines evidence-based data with clinically informed advice to support everyone who is prescribing in the field of mental health.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the request of the authors as they recently discovered that some of the procedures conducted as part of the experiments in the published manuscript were not approved by their animal research committee. The manuscript reports that "all animal experimental procedures were approved by the Committees of Weifang People's Hospital", however, procedures specifically related to the cannula implantation and the use of isoflurane as an anesthetic in the surgical procedures were not approved. As a result, Dr. Shiqiang Wang has requested that the manuscript be withdrawn.
Behavioural Brain Research appreciate Dr. Wang's honesty and agree with retraction of this article due to serious violations of animal use in research.
Essential oils (EOs) absorbed via inhalation are consistently reported to produce anxiolytic effects. The underlying neurochemical mechanisms, however, are not well understood. High concentrations of ascorbate in the human brain (∼10 mM in neurons) implicates this compound as a key signaling molecule and regulator of oxidative stress. In this study, we demonstrate the significant in vitro capacity of ascorbate to produce H2O2 in the presence of oxygen at physiological pH values, peaking at ∼400 μM for ascorbate levels of 1.0 mg/mL. In comparison, individual EOs and selected neurotransmitters at similar concentrations produced <100 μM H2O2. Systematic studies with binary and ternary mixtures containing ascorbate indicated that EOs and neurotransmitters could variably enhance (pro-oxidant, POX) or suppress (anti-oxidant, AOX) the production of H2O2 versus the ascorbate control, depending on the concentration ratios of the components in the mixture. Moreover, the AOX/POX chemistry observed with binary mixtures did not necessarily predict effects with ternary mixtures, where the POX ascorbate chemistry tended to dominate. A model is proposed to account for the ability of compounds with electron-donating capacity to catalytically regenerate ascorbate from intermediate oxidized forms of ascorbate, thus driving H2O2 production and exerting a net POX effect; whilst compounds that irreversibly reacted with oxidized forms of ascorbate suppressed the production of H2O2 and produced an overall AOX effect. Since the anxiolytic effects of different EOs, including extracts of Lavendula angustifolia (lavender) and Salvia rosmarinus (rosemary), were associated with AOX regulation of H2O2 production by ascorbate, it can be concluded that these anxiolytic effects are potentially related to the AOX properties of EOs. In contrast, EOs driving POX effects (eg, Junipenus communis (Juniper) berry EO) are proposed to be more useful for their potential anti-microbial or cancer cytotoxic applications.
It is well known that the central nervous system (CNS) is a complex neuronal network and its function depends on the balance between excitatory and inhibitory neurons. Disruption of the excitatory/inhibitory (E/I) balance is the main cause for the majority of the CNS diseases. In this review, we will discuss roles of the inhibitory system in the CNS diseases. The GABAergic system as the main inhibitory system, is essential for the appropriate functioning of the CNS, especially as it is engaged in the formation of learning and memory. Many researchers have reported that the GABAergic system is involved in regulating synaptic plasticity, cognition and long-term potentiation. Some clinical manifestations (such as cognitive dysfunction, attention deficits, etc.) have also been shown to emerge after abnormalities in the GABAergic system accompanied with concomitant diseases, that include Alzheimer’s disease, Parkinson’s disease, Autism spectrum disorders, Schizophrenia, etc. The GABAergic system consists of GABA, GABA transporters, GABAergic receptors and GABAergic neurons. Changes in any of these components may contribute to the dysfunction of the CNS. In this review, we will synthesize studies which demonstrate how the GABAergic system participates in the pathogenesis of the CNS disorders, which may provide a new idea that might be used to treat the CNS diseases.
Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. In this study we investigated the relation of fecal microbiome diversity and composition with depression in 1,054 from the Rotterdam Study cohort and validated these findings in the Amsterdam HELIUS cohort in 1,539 subjects. Using supervised and unsupervised machine learning approaches, we identified and replicated the association of several microbial genera. We confirm the association of genus Eggerthella, Subdoligranulum, Coprococcus and family Ruminococcaceae and identify novel bacteria including Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002,UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup associated with depression. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests the gut microbiome composition may play a key role in depression.
Corticotropin-releasing factor (CRF), a 41 amino acid-containing neuropeptide, acts both as a hypothalamic releasing factor, controlling ACTH and corticosteroid secretion, and at extrahypothalamic CNS sites to modulate mammalian organisms' responses to stress. In this article, the evidence that CRF-containing neurons within the CNS are hyperactive in patients with depression is reviewed. The evidence, taken together, suggests that during depressive episodes, CRF is hypersecreted, resulting in both pituitary-adrenal axis hyperactivity and certain of the signs and symptoms of depression, including decreased appetite, decreased libido and disturbed sleep. There is also evidence that treatments for depression, including antidepressant medications and electroconvulsive therapy, reduce CRF hypersecretion within the CNS. Finally, evidence suggests that alterations in CRF-containing neurons and receptors are responsible for the widely held observation that early untoward life events increase an individual's vulnerability for affective disorders. These findings have a number of implications for treatment of the mood disorders, including the suggestion that the pharmacological manipulation of CRF receptors may provide a novel avenue for the treatment of depression.
Evidence from preclinical and clinical studies suggests a role for alterations in the benzodiazepine/GABAA receptor complex in stress and anxiety. Flumazenil is a relatively pure benzodiazepine/GABAA antagonist with limited intrinsic activity. In panic disorder patients, but not healthy controls, flumazenil has been demonstrated to provoke panic attacks.
Vietnam combat veterans with PTSD (n = 14) received 90-second intravenous infusions of flumazenil 2 mg or placebo in a double-blind, crossover study design. PTSD symptomology was assessed using the PTSD Symptom Scale, and anxiety symptoms were measured with visual analogue rating scales.
There was no significant difference in PTSD and anxiety symptoms between administration of flumazenil and placebo.
Flumazenil administration does not produce an increase in anxiety and PTSD symptoms in patients with PTSD. This suggests that PTSD and panic disorder are dissimilar in terms of benzodiazepine/GABAA system function.
Flumazenil is a benzodiazepine receptor antagonist that has been reported to provoke panic attacks in patients with panic disorder. This study was undertaken to compare the effects of flumazenil and sodium lactate, the most widely studied panic provocation agent.
Ten patients with panic disorder were given infusions of saline, sodium lactate, and flumazenil in randomized order. Panic attacks, psychopathological changes, heart rate, and cortisol and ACTH secretion were recorded.
Eight of the 10 patients experienced a panic attack after sodium lactate, but none did after flumazenil or saline. Cortisol and ACTH secretion were not enhanced by any of the treatments. Sodium lactate increased heart rate, whereas flumazenil had the opposite effect.
These findings do not lend support to the view that the benzodiazepine receptors of lactate-susceptible patients with panic disorder are hypersensitive and that flumazenil can therefore act as an inverse agonist.
Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects.
A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96).
A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex.
Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.
Low levels of γ-aminobutyric acid (GABA) in plasma have been associated with the presence of mood disorders in patients with major depressive disorder. We examined plasma GABA in patients with panic disorder, a disorder that is often comorbid with major depression, and in a group of control subjects. Patients with panic disorder had plasma GABA levels that did not differ significantly from levels in controls subjects. These data support the specificity of low plasma GABA as a marker for mood disorders.
The authors provide an overview of the current state of knowledge with regards to the neurobiological mechanisms involved in normal and pathological anxiety. A brief review of the classification and cognitive psychology of anxiety is followed by a more in-depth look at the neuroanatomical and neurochemical processes and their relevance to our understanding of the modes of action of anxiolytic drugs. The serotonergic, noradrenergic, and γ-aminobutyric acidergic systems are reviewed. The numerous physiological and pharmacological methods of anxiety provocation and the increasing importance of functional neuroimaging are also examined. The review provides an overview of the biology and basic pharmacology of anxiolytic drugs, and compliments the more clinically oriented companion review.
In rodents, the effect of the beta-carboline derivative isopropyl-6- benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarrnil), a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties, was evaluated on the function of central gamma-aminobutyric acid (GABA)A receptor complex, both in vitro and in vivo. Added in vitro to rat cortical membrane preparation, abecarnil increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS). These effects were similar to those induced by diazepam, whereas the partial agonist Ro 16-6028 (tert-butyl-(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H- imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate) showed very weak efficacy in these biochemical tests. After i.p. injection to rats, abecarnil and diazepam decreased in a time-dependent and dose-related (0.25-20 mg/kg i.p.) manner [35S]TBPS binding measured ex vivo in the cerebral cortex. Moreover, both drugs at the dose of 0.5 mg/kg antagonized completely the convulsant activity and the increase of [35S]TBPS binding induced by isoniazide (350 mg/kg s.c.) as well as the increase of [35S]TBPS binding induced by foot-shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of abecarnil on [35S]TBPS binding, exploratory motility and on isoniazid-induced biochemical and pharmacological effects in mice. In these animals, abecarnil produced a paralleled dose-dependent (0.05-1 mg/kg i.p.) reduction of both motor behavior and cortical [35S]TBPS binding. Moreover, 0.05 mg/kg of this beta-carboline reduced markedly the increase of [35S]TBPS binding and the convulsions induced by isoniazid (200 mg/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)
The acute effects of diazepam on plasma GABA were determined in 18 patients with panic disorder, 13 patients with generalized anxiety disorder and 20 healthy controls. All subjects were benzodiazepine-naive. Four logarithmically increasing doses of diazepam/placebo were administered intravenously at 15-min intervals on 2 separate days. Plasma GABA was measured at baseline and 3 min after the highest dose of diazepam/placebo. There was an overall decrease in plasma GABA that was significantly greater following diazepam compared with placebo, but no group differences in response. In a separate group of 18 panic disorder patients receiving chronic benzodiazepine treatment with alprazolam, the same diazepam infusion procedure (no placebo day) produced decreases in plasma GABA similar to those seen in the untreated panic disorder patients. The clinical and physiologic implications of these findings are discussed.
To evaluate the possibility that abnormal regulation of benzodiazepine receptor (BZR) function may relate to the pathophysiology of anxiety disorders, two doses of the BZR antagonist flumazenil (Ro 15-1788) and placebo were administered to panic disorder patients in a double-blind, randomized, crossover design. All 11 patients received flumazenil (600 mg). Ten of the 11 also received flumazenil (200 mg), and 8 of the 11 were given matching placebo capsules orally on separate test days. Neither dose of flumazenil showed significant anxiolytic effects or significantly altered heart rate, blood pressure, or levels of plasma cortisol or 3-methoxy-4-hydroxyphenylglycol in comparison to placebo. On 200 mg days, anxiety ratings on a visual analog scale significantly increased compared to placebo at 30 min and then returned to baseline levels. Panic attacks occurred on placebo, 200 mg, and 600 mg days in 0/8, 4/10, and 0/11, respectively. Failure to observe anxiolytic effects suggests that flumazenil at these doses does not antagonize a tonic increased interaction of BZRs with an endogenous BZR inverse agonist in panic patients.
Gamma aminobutyric acid (GABA), an inhibitory neurotransmitter, may play an important role in anxiety. We studied changes in plasma GABA levels in nine healthy subjects before and after infusions of sodium lactate and dextrose. Plasma GABA significantly decreased during infusions of sodium lactate (109.3 +/- 4.4 versus 91.6 +/- 5.1 pmol/ml; P = 0.0001) but not during infusions of dextrose.
Cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in 11 patients with panic disorder (PD) prior to and following 7 months of treatment with alprazolam or imipramine and in six neurological control patients. Although a clear treatment response was observed in patients with PD, neither alprazolam nor imipramine significantly changed CSF GABA during the treatment period. A negative correlation was demonstrated between baseline CSF GABA and posttreatment overt psychopathology. Low pretreatment level of CSF GABA correlated significantly with poor therapeutic outcome, judged by the amount of anxiety and depression as well as by the frequency of panic attacks at the end of follow-up.
1. Pharmacological actions of a novel benzodiazepine receptor ligand, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano+ ++[4,3-b] pyridine monophosphate monohydrate), were examined in in vitro and in vivo studies. 2. S-8510 was characterized as a partial inverse agonist with a modest GABA ratio and low efficacy. 3. S-8510 ameliorated memory impairment induced by cholinergic deficit in the water maze paradigm of Wistar rats. 4. S-8510 augmented LTP of the Schaffer collateral/commissural fiber-CA1 synapses in the hippocampal slice preparations of SD rat. 5. S-8510 increased the extracellular levels of acetylcholine and noradrenaline in the hippocampus of Wistar rat. 6. S-8510 selectively potentiated pentylenetetrazol-induced convulsion without affecting minimal electroconvulsive shock- or strychnine-induced convulsion in ddY mice. 7. S-8510 failed to induce any sign of anxiety in the Wistar rat pro-conflict test. 8. S-8510 showed antidepressant-like pharmacological actions in ddY mice. 9. These results suggest that S-8510 can be used as a therapeutic drug for senile dementia, including Alzheimer's disease with little risk for inducing anxiety or convulsion.
This paper reviews the preclinical literature related to the effects of stress on neurobiological and neuroendocrine systems. Preclinical studies of stress provide a comprehensive model for understanding neurobiological alterations in post-traumatic stress disorder (PTSD). The pathophysiology of stress reflects long-standing changes in biological stress response systems and in systems involved in stress responsivity, learning, and memory. The neural circuitry involved includes systems mediating hypothalamic-pituitary-adrenal (HPA) axis, norepinephrine (locus coeruleus), and benzodiazepine, serotonergic, dopaminergic, neuropeptide, and central amino acid systems. These systems interact with brain structures involved in memory, including hippocampus, amygdala, and prefrontal cortex. Stress responses are of vital importance in living organisms; however excessive and/or repeated stress can lead to long-lasting alterations in these circuits and systems involved in stress responsiveness. Intensity and duration of the stressor, and timing of the stressor in life, have strong impact in this respect.