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Metabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N -methyl- d -aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction. Fifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF). Allo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms. Both Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of the present study was to explore the impact of acute and chronic nicotine consumption on measures of intracortical inhibition and facilitation. This study involved 50 chronic heavy cigarette smokers and 40 healthy subjects matched for age, sex and educational level, with no history of chronic nicotine intake. Intracortical inhibition and facilitation were assessed using transcranial magnetic stimulation (TMS) measures of motor threshold (MT), short- and long-interval intra-cortical inhibition (SICI, LICI), cortical silent period (CSP) and intra-cortical facilitation (ICF). Basal serum levels of cotinine were measured in the healthy group and at ½ and 2 h after smoking a single cigarette in the chronic smokers. There was enhanced SICI and reduced ICF in smokers (independent of time after smoking) compared with non-smokers. The former suggests a chronic effect of increased nicotine levels on GABA-A neurotransmission whereas the latter suggests an additional effect on glutamatergic transmission. There were no significant differences between smokers and non-smokers in other TMS parameters. There was a significant negative correlation between cotinine levels at ½ h after smoking and SICI at 3 ms ISI (P < 0.001). There were no significant differences in any of the neurophysiological measures between smokers at ½ h versus 2 h after smoking a single cigarette. Chronic nicotine consumption enhances SICI, and reduces ICF, supporting the hypothesis that nicotine acts as a neuromodulator of GABA-A and glutamate neurotransmission. [ABSTRACT FROM AUTHOR]

It remains unclear whether benzodiazepines (BZDs) constitute a risk factor for Alzheimer's disease (AD). In this study, we investigated associations between chronic use of BZDs and brain amyloid load, a hallmark of AD, in 268 nondemented older individuals. F18-florbetapir positron emission tomography scans were performed to assess amyloid load as measured by standardized uptake value ratios, which were compared between chronic BZD users and nonusers using adjusted multiple linear regressions. Short- versus long-acting BZDs were also considered in the analyses. Standardized uptake value ratios were significantly lower in BZD users (n = 47) than in nonusers (n = 221), independent of multiple adjustments. The effect was stronger for short-acting BZDs than for long-acting BZDs. This is the first large clinical study showing a reduced brain amyloid load in chronic BZD users, especially with short-acting BZDs. Our results do not support the view of BZD use as a risk factor for AD and instead support the involvement of pharmacological mechanisms related to neuronal hyperactivity, neuroinflammation, and sleep quality as potential targets for blocking amyloid accumulation. • Amyloid load was significantly lower in benzodiazepine (BZD) users than in nonusers. • The effect was stronger for short-acting BZDs than for long-acting BZDs. • Our results do not support the view of BZDs as risk factors for Alzheimer's disease. • Pharmacological mechanisms related to BZDs may provide targets for blocking amyloid. [ABSTRACT FROM AUTHOR]

Benzodiazepines are one of the most commonly prescribed anxiolytic drugs in America, and between 2006 and 2015 prescription rates increased by an estimated 27.1%. Weight gain is a common side effect of these drugs and it may result from increased feeding caused by drug-enhanced food palatability. We investigated the role of specific GABA A receptor subtypes involved with benzodiazepine-induced food consumption through third ventricle injections of L-838,417, a partial agonist of GABA A α2, α3, and α5 subunits, and a full antagonist of the α1 receptor subunit. A microanalysis of the licking behavior of adult male rats to a sucrose solution was used to isolate drug effects on specific consummatory behaviors that include: hedonic taste evaluation, food approach behavior, and oromotor function. L-838,417 dose-dependently increased intake through increases in the motivation to approach the solution (shorter pause intervals between bouts of licking) and through enhancement of measures associated with hedonic taste evaluation. Oromotor depressant effects previously associated with broad-spectrum benzodiazepine receptor agonists were not observed. These results indicate that nuclei in proximity to the ventricles respond to GABA A α2, α3, or α5 activation to induce motivation to feed, absent of α1 receptor subunit activation. Furthermore, activation of the α1 subunit is not necessary for benzodiazepine hyperphagia and may instead contribute to the oromotor depressant and sedative properties of classic benzodiazepine agonists. Hypothalamic nuclei such as the paraventricular nucleus may be involved in the benzodiazepine-increased motivation to feed, while the parabrachial nucleus of the hindbrain could contribute to benzodiazepine-induced enhancement of taste palatability. • The novel compound L-838,417 is a partial agonist of GABA A α2, α3, and α5 and a full antagonist of the α1 receptor subunit. • Dose-dependent ICV injections of L-838,417 increase hedonic taste evaluation and the motivation to consume sucrose. • L-838,417 did not affect satiation or satiety-related processes. • α2/α3/α5-containing GABA A receptors play a role in benzodiazepine-induced hyperphagia. [ABSTRACT FROM AUTHOR]

We describe a retrograde synaptic signal at the C. elegans GABAergic neuromuscular junction. At this synapse, GABA release is controlled by two voltage-activated calcium channels (UNC-2/CaV2 and EGL-19/CaV1), and muscle responses are mediated by a single GABA receptor (UNC-49/GABA A). Mutations inactivating UNC-49 or those preventing UNC-49 synaptic clustering cause retrograde defects in GABAergic motor neurons, whereby UNC-2/CaV2 levels at active zones, UNC-2 current, and pre-synaptic GABA release are decreased. Inactivating post-synaptic GABA A receptors has no effect on GABA neuron EGL-19/CaV1 levels nor on several other pre-synaptic markers. The effect of GABA A receptors on pre-synaptic strength is not a consequence of decreased GABA transmission and is input selective. Finally, pre-synaptic UNC-2/CaV2 levels are increased when post-synaptic GABA A receptors are increased but are unaffected by increased extra-synaptic receptors. Collectively, these results suggest that clustered post-synaptic GABA A receptors adjust the strength of their inputs by recruiting CaV2 to contacting active zones. [Display omitted] • Muscle GABA A receptors boost GABA release by recruiting CaV2 to active zones • Clustered post-synaptic GABA A receptors mediate retrograde synaptic potentiation • Extra-synaptic GABA A receptors have no retrograde effects • The C. elegans GABAergic NMJ does not exhibit pre-synaptic homeostatic plasticity Retrograde synaptic signals allow post-synaptic cells to adjust the strength and plasticity of their synaptic inputs. Zhao et al. show that clustered post-synaptic GABA A receptors stimulate release by recruiting calcium channels to contacting active zones. [ABSTRACT FROM AUTHOR]

Background Transcranial Alternating Current Stimulation (tACS) consists in delivering electric current to the brain using an oscillatory pattern that may entrain the rhythmic activity of cortical neurons. When delivered at gamma frequency, tACS modulates motor performance and GABA-A-ergic interneuron activity. Objective Since interneuronal discharges play a crucial role in brain plasticity phenomena, here we co-stimulated the primary motor cortex (M1) in healthy subjects by means of tACS during intermittent theta-burst stimulation (iTBS), a transcranial magnetic stimulation paradigm known to induce long-term potentiation (LTP)-like plasticity. Methods We measured and compared motor evoked potentials before and after gamma, beta and sham tACS-iTBS. While we delivered gamma-tACS, we also measured short-interval intracortical inhibition (SICI) to detect any changes in GABA-A-ergic neurotransmission. Results Gamma, but not beta and sham tACS, significantly boosted and prolonged the iTBS-induced after-effects. Interestingly, the extent of the gamma tACS-iTBS after-effects correlated directly with SICI changes. Conclusions Overall, our findings point to a link between gamma oscillations, interneuronal GABA-A-ergic activity and LTP-like plasticity in the human M1. Gamma tACS-iTBS co-stimulation might represent a new strategy to enhance and prolong responses to plasticity-inducing protocols, thereby lending itself to future applications in the neurorehabilitation setting. [ABSTRACT FROM AUTHOR]

Fear generalization occurs when a response, previously acquired with a threatening stimulus, is transferred to a similar one. However, it could be maladaptive when stimuli that do not represent a real threat are appraised as dangerous, which is a hallmark of several anxiety disorders. Stress exposure is a major risk factor for the occurrence of anxiety disorders and it is well established that it influences different phases of fear memory; nevertheless, its impact on the generalization of contextual fear memories has been less studied. In the present work, we have characterized the impact of acute restraint stress prior to contextual fear conditioning on the generalization of this fear memory, and the role of the GABAergic signaling within the basolateral amygdala complex (BLA) on the stress modulatory effects. We have found that a single stress exposure promoted the generalization of this memory trace to a different context that was well discriminated in unstressed conditioned animals. Moreover, this effect was dependent on the formation of a contextual associative memory and on the testing order (i.e., conditioning context first vs generalization context first). Furthermore, we observed that increasing GABA-A signaling by intra-BLA midazolam administration prior to the stressful session exposure prevented the generalization of fear memory, whereas intra-BLA administration of the GABA-A antagonist (Bicuculline), prior to fear conditioning, induced the generalization of fear memory in unstressed rats. We concluded that stress exposure, prior to contextual fear conditioning, promotes the generalization of fear memory and that the GABAergic transmission within the BLA has a critical role in this phenomenon. [ABSTRACT FROM AUTHOR]

In view of their expected anticonvulsant activity, some novel derivatives of 2,3-dihydrophthalazine-1,4-dione 4 – 22 were designed, synthesized and evaluated using pentylenetetrazole (PTZ) and picrotoxin as convulsion-inducing models. Moreover, the most active compounds were tested against electrical induced convulsion using maximal electroshock (MES) models of seizures. Most of the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 13 and 14g were proved to be the most potent compounds of this series with relatively low toxicity in the median lethal dose test when compared with the reference drug. Molecular modeling studies were done to verify the biological activity. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogues. [ABSTRACT FROM AUTHOR]

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S -DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c , 5e , and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c , and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c , 5e , and 5f , which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype. [Display omitted] • In silico and in vivo studies of pyrimidine thioether derivatives. • Three compounds exhibited anxiolytic, performance enhancing, and nootropic properties. • Molecular docking suggests GABA-A, melatonin, and sigma-1 receptors as targets. • 3-D QSAR studies led to useful SAR for the design of new derivatives. [ABSTRACT FROM AUTHOR]

Objective: It is inconclusive as to whether benzodiazepines (BZDs) are related to cognitive deterioration in the elderly populations. Animal studies suggest that γ-aminobutyric acid A receptor agonists, such as BZDs, may prevent Aβ-neurotoxicity and reduce β-amyloid (Aβ). However, no studies have investigated the effects of BZD use on Aβ in humans.Methods: This cross-sectional, prospective study using Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada on nondemented elderly adults between 55 and 90 years of age assessed cortical Aβ levels by positron emission tomography radiotracer F18-Florbetapir. Changes in global cognitive function and verbal memory performance over 2 years were assessed using scores on Montreal Cognitive Assessment and five domains of Rey Auditory Verbal Learning Test, respectively.Results: Previous BZD users (N = 15) had lower cortical Aβ levels in frontal (F(1, 26) = 8.82, p = 0.006), cingulate (F(1, 26) = 8.58, p = 0.007), parietal (F(1, 26) = 7.31, p = 0.012), and temporal (F(1, 26) = 7.67, p = 0.010) regions compared with matched BZD nonusers (N = 15), after controlling for history of psychiatric disorders and antidepressant use. Also, no differences were found in global cognitive function and changes in cortical Aβ over 2 years between continuous BZD users (N = 15) andthe matched nonuser group (N = 15).Conclusion: Previous BZD use was associated with lower cortical Aβ levels in nondemented elderly control subjects. Future studies with larger samples are required to replicate our findings. [ABSTRACT FROM AUTHOR]

In addition to their well-known anxiolytic functions, benzodiazepines produce hyperphagia. Previously, we reported that the benzodiazepine, chlordiazepoxide (CDP), increased consumption of both normally-preferred and normally-avoided taste stimuli during long-term (1 h) tests, primarily through changes in licking microstructure patterns associated with hedonic taste evaluation, whereas there was little effect on licking microstructure measures associated with post-ingestive feedback. In this study, we further examined the hedonic and motivational specificity of CDP effects on ingestive behavior. We tested brief access (15 s) licking responses for tastants spanning all taste qualities after treatment with either CDP (5 or 10 mg/kg) or the non-benzodiazepine anxiolytic, buspirone (1.5 or 3 mg/kg). A between-subjects, counterbalanced design compared the CDP or buspirone effects on licking responses for water and a range of weak to strong concentrations of NaCl, Q-HCl, citric acid, MSG, saccharin, and capsaicin under water-restricted (23 h) conditions; and sucrose, saccharin, and MSG under water-replete conditions. In a dose dependent manner, CDP increased licking for taste stimuli that were normally-avoided after saline treatment, with a notable exception observed for the trigeminal stimulus, capsaicin, which was not affected at any concentration or drug dose, suggesting a taste-specific effect of CDP on orosensory processing. Under water-replete conditions, CDP dose-dependently increased licking to normally-accepted concentrations of sucrose, saccharin, and MSG. There was no effect of either drug on licks for water under either water-restricted or water-replete conditions. Buspirone slowed oromotor coordination by increasing brief interlick intervals, but it did not affect licking for any concentrations of the tastants. Overall, these results indicate that benzodiazepines selectively enhance the hedonic acceptance of gustatory orosensory stimuli, independent of general anxiolytic or oromotor coordination effects, or physiological states such as thirst. [ABSTRACT FROM AUTHOR]

Highlights: [•] Psychopathy arises mainly out of genetic contributions to emotional hyporesponsivity. [•] Sociopathy arises out of interactive gene–environment effects on emotional dysregulation. [•] Enhanced versus dampened serotonergic functionality may define these profiles respectively. [•] High testosterone can increase emotional dysfunctions and the risk for aggression. [Copyright &y& Elsevier]

Salvia limbata C. A. Mey. (Persian name: Maryam Goli-e-labeh dar) has been used for treating central nervous disorders such as insomnia, anxiety and depression in Persian traditional medicine. S. limbata is known for its pharmacological activities which could be at least in a part, upon the presence of rosmarinic acid (RA). However, the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extract has not yet been examined. In the current study the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extracts were evaluated. Besides, the effects of altitude and phenological stage on the RA content of S. limbata were investigated. Sedative-hypnotic and anxiolytic effects were evaluated through the pentobarbital induced loss of righting reflex test and open field test, respectively. Flumazenil was used to reveal the mechanism of action. Possible side effects were investigated in the passive avoidance and grip strength tests. Besides, the effects of altitude and phenological stage (vegetative, flowering, and seed setting) on the RA content of S. limbata were evaluated using reversed-phase high-performance liquid chromatography (RP-HPLC). Following behavioral tests, sedative-hypnotic and anxiolytic effects were observed. Since the observed effects were reversed by flumazenil and no side effect on the memory and muscle strength was reported, modulation of the α1-containing GABA-A receptors could be proposed as one of the involved mechanisms. According to the RP-HPLC analysis, harvesting S. limbata in the vegetative stage at the altitude of 2500 m led to the highest content of RA (8.67 ± 0.13 mg/g dry matter). Among different extract of the plant samples collected in the vegetative stage at the altitude of 2500 m, the hydroalcoholic extract showed the highest rosmarinic acid content. The obtained results help to find the optimum situation to gain the highest content of RA as well as the pharmacological activity that could be economically important for the pharmaceutical industries. [Display omitted] • Salvia limbata possess sedative-hypnotic and anxiolytic activities. • α1-containing GABA-A receptors are involved in the observed effects. • The highest content of rosmarinic acid is obtained in the vegetative stage. • Altitude has a great impact on the rosmarinic acid content of Salvia limbata. [ABSTRACT FROM AUTHOR]

Abstract: This study is the first one to construct the reliable structure of the α1/γ2 interface of Gamma aminobutyric acid type A (GABA-A) receptor by homology modeling and refined every loop of the whole protein structure. The modeling GABA-A receptor was validated by docking the control compounds in binding site, checking the key residue in α1/γ2 interface, probability density function (PDF) value, and Ramachandran plot. This paper is also the first one to propose that jujubogenin is the effective component in suanzaoren decoction, neither jujuboside A nor jujuboside B by chemoinformatics and pharmacoinformatics approach. In addition, pharmacophore analysis showed that the oxygens on jujubogenin approached α1-TYR160 and γ2-LYS184, respectively. The comparative molecular field analysis (CoMFA) model yielded a value of 0.731 and an r 2 of 0.942 at 5 components. Comparative molecular similarity indices analysis (CoMSIA) produced a of 0.617 and an r 2 of 0.921 at 5 components. The CoMFA and CoMSIA models showed statistically significant results. Hence, based on the results of docking, ADMET descriptor, pharmacophore, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies, the jujubogenin was suggested to be the effective GABA-A agonist in suanzaoren decoction. [Copyright &y& Elsevier]

Abstract: The mechanisms by which the inhalation of carbon dioxide (CO2) produces anxiety and panic are not fully understood, although more recently there is evidence to suggest the involvement of a neural ‘fear circuit’. We have suggested that this neural fear circuit is partly mediated by the brain noradrenaline network [ Does the brain noradrenaline network mediate the effects of the CO2 challenge? J Psychopharmacol 17(3): 252–259.]. However, we now review evidence that GABA-A may also play an important role in the modulation of CO2-induced anxiety. The review of this evidence starts with a key publication showing that 1 min of 35% CO2/65% air produced anxiogenic effects in a rat model of anxiety, to a similar extent to the anxiogenic betacarboline derivative FG7142, a benzodiazepine receptor inverse agonist. The effects of both anxiogenic stimuli were abolished with pre-treatment with alprazolam (0.5 mg/kg), but only those of FG7142, not CO2, was blocked by a benzodiazepine antagonist [Cuccheddu, T., Floris, S., Serra, M., Porceddu, L., Sanna, E., Biggio, G., (1995) Proconflict effect of carbon dioxide inhalation in rats. Life Sci 56: PL 321–324.]. Although the evidence from this study did not conclusively prove that CO2 had an action to reduce GABA function, it was an experiment designed to be translational to compare what was known about CO2-induced anxiety in patients, and to also to explore if GABA mechanisms are involved. Additional evidence from the literature is found in the association between GABA and chemoreceptors, both in laboratory and human studies and GABA and anxiety disorders. Evidence of this association is found across species from stress-induced change in GABA levels in plants and insects to humans, where there is now much evidence of abnormalities in GABA/benzodiazepine receptors in anxiety and other psychiatric disorders. This paper reviews some of the evidence and attempts to relate and compare these findings across species from the human to the Drosophila. [Copyright &y& Elsevier]

The aim of the present study was to test the hypothesis that allopregnanolone infused into the lateral septal nuclei will reduce conflict-like behavior in ovariectomized rats. The interaction with systemic administration of several agonists and antagonists of the GABA-A receptor was assessed. Results showed that intralateral septal doses of allopregnanolone (1.0 μg, P<.05; 2.0 μg, P<.05) or systemic injections of allopregnanolone (1.0 mg/kg sc, P<.05; 2.0 mg/kg sc, P<.05), diazepam (2.0 mg/kg ip, P<.05), or muscimol (0.3 mg/kg ip, P<.05; 0.6 mg/kg ip, P<.05) reduced conflict-like behavior. Subthreshold doses of intralateral septal infusions of allopregnanolone (0.5 μg/side) synergized with systemic subthreshold doses of GABA-A agonists: allopregnanolone (0.5 mg/kg, P<.05), diazepam (1.5 mg/kg, P<.05), or muscimol (0.1 mg/kg, P<.05). The GABA-A antagonists, flumazenil (0.1 mg/kg ip) and bicuculline (2.0 mg/kg ip) attenuated the synergism between intralateral septal infusions of allopregnanolone and diazepam or muscimol, respectively. Conversely, neither flumazenil (P<.05) nor bicuculline (P<.05) attenuated the synergism of the combination allopregnanolone (intralateral septum nuclei; 0.5 μg/side) plus systemic injections of allopregnanolone. In conclusion, allopregnanolone reduced conflict-like behavior probably acting at the GABA-A receptors found in the lateral septal nuclei. [Copyright &y& Elsevier]