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Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include changes in excitability, cellular death of hippocampal and striatal neurons, and increased inflammation and oxidative stress. Clinical presentation varies, encompassing affective disorders (anxiety, euphoria, depression), psychotic episodes, and cognitive deficits. It is crucial to note that these manifestations often go unnoticed by treating physicians, leading to delayed detection of severe symptoms, complications, and underreporting. Discontinuation of corticosteroids constitutes the cornerstone of treatment, resolving symptoms in up to 80% of cases. Although the literature on this topic is scant, isolated cases and limited studies have explored the efficacy of psychotropic medications for symptomatic control and prophylaxis. Pharmacological intervention may be warranted in situations where corticosteroid reduction or withdrawal is not feasible or beneficial for the patient. [ABSTRACT FROM AUTHOR]

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]

Background: Epilepsy is a deep rooted, partially curable brain illness that affects all individuals irrespective of ages and genders. Despite the discovery of various innovative antiepileptic drugs (AEDs), selectivity and toxicity issues remain. Materials and Methods: A series of (S)-1-(2-(substituted benzylamino)-3-methylbutanoyl)pyrrolidin-2-one analogues (5a-r) were synthesized and evaluated for their anticonvulsant activity. The analogues were screened by two gold standard methods, i.e., electroshock (MES) and chemoshock (scPTZ) seizure tests. In addition, the rotarod method was used to test motor impairment in all synthetic analogues for acute neurotoxicity. The paper also reports ADME prediction of all the 18 synthesized compounds, with each parameter discussed in detail. Furthermore, the GABA-A target protein was used in molecular docking experiments. Results: In the MES model, compounds 5e, 5h, 5k, 5l, 5o, and 5r were identified to be the most effective, while compounds 5j, 5k, 5l, 5o, and 5r were the most active against the scPTZ model. The majority of the synthesized analogues passed the neurotoxicity test, according to the findings. ADME prediction of the compounds exhibited good agreement with the in vivo outcomes. The results of molecular docking showed important interactions with TYR 62, ASN 85, ARG 114, ARG 129, and MET 115 at the active site of GABA-A and the results showed good agreement with in vivo results. Conclusion: The findings of the study indicated some of the compounds possessed excellent anticonvulsant activity without noticeable neurotoxicity. These compounds can be investigated further for the formation of newer/novel anticonvulsant agents. [ABSTRACT FROM AUTHOR]

Objective To investigate the mechanism of benzodiazepine receptor antagonist ZK93426 on promoting capacitation-associated increase in protein tyrosine phosphorylation. Methods After the mouse sperm incubated with ZK93426, changes of intracellular calcium ion concentration ([Ca2+ ]i)was measured using calcium fluorescent probe Fluo4-AM; Changes of intracellular pH (pHi)was measured using pH fluorescent probe BCECF-AM; Changes of intracellular chloride ion concentration ([Cl-]i)was measured using chloride fluorescent probe MQAE; And cell membrane potential (Em) were detected using fluorescence probe DiSC3(5). Results Compared to DMSO control group,ZK93426 promoted the capacitation-associated increase in protein tyrosine phosphorylation in mice, accompanied by the increase of [Ca2+ ]i and pHi and the decrease of [Cl-]i. Membrane hyperpolarization was inhibited by ZK93426 as well. Conclusion ZK93426 may regulate the capacitation-associated increase in tyrosine phosphorylation of mouse sperm by modulating [Ca2+ ]i, [Cl-]i, pHi and Em. [ABSTRACT FROM AUTHOR]

Benzodiazepines (BZD), introduced into clinical practice in the 1950s, are among the most widely used medications in the world, despite their side effects. Objective: To understand the prescription profile of BZD among medical faculty and to raise awareness about the associated risks of their use. Methods: A quantitative and qualitative, exploratory, cross-sectional study with an educational component. A semi-structured questionnaire was applied, organized with alternating pages of questions and informative content about BZD. All 148 medical faculty members of a medical course were invited to respond to online questionnaire (Google Forms®). Results: 75 faculty members responded (50.7%; 43 men), the average years of medical practice were 30.9 ± 10.9 (mean ± SD). Among the respondents, there were 38 clinicians, 10 pediatricians, 8 surgeons, 6 gynecologists/obstetricians, 3 epidemiologists, 3 psychiatrists, 3 orthopedists, 2 family and community medicine doctors, 2 others. 62.6% work in the Unified Health System (SUS), 68% in the private health system, and 20% are solely engaged in academic activities. Among the participants, 75% prescribe BZD, predominantly for insomnia, anxiety, panic attacks, and chronic pain. The most recognized side effects were drowsiness (78.6%), amnesia (62.6%), and mental confusion (53.3%). 48% reported implementing a planned gradual withdrawal of BZD and providing guidance on alternative or complementary therapy. More than 80% of participants found the scientific information included in the questionnaire to be useful and important. Conclusion: Most participants prescribe BZD and acknowledge their adverse effects, with indications for other treatments. The educational research model was well-praised by the participants. [ABSTRACT FROM AUTHOR]

Background: Cupressus arizonica Greene is a coniferous tree with great importance in fragrance and pharmaceutical industries. Essential oils from C. arizonica (EC) have shown potential antioxidant, and anti-microbial activities. This study aimed at investigating the anti-nociceptive and anti-inflammatory effects/mechanisms of EC. Methods: The EC was evaluated for anti-nociceptive and anti-inflammatory activities on male Wistar rats using a formalin test and carrageenan-induced paw edema, respectively. Also, we pre-treated some of the animals with naloxone and flumazenil in the formalin test to find out the possible contributions of opioid and benzodiazepine receptors to EC anti-nociceptive effects. Finally, gas chromatography/mass spectrometry (GC/MS) analysis was used to identify the EC's constituents. Results: EC in intraperitoneal doses of 0.5 and 1 g/kg significantly decrease the nociceptive responses in both early and late phases of the formalin test. From a mechanistic point of view, flumazenil administration 20 minutes before the most effective dose of EC (1 g/kg) showed a meaningful reduction in the associated antinociceptive responses during the early and late phases of the formalin test. Naloxone also reduced the anti-nociceptive role of EC in the late phase. Furthermore, EC at the doses of 1, 0.5, and 0.25 g/kg significantly reduced paw edema from 0.5 hours after carrageenan injection to 4 hours. GC/MS analysis showed that isolated EC is a monoterpene-rich oil with the major presence of a-pinene (71.92%), myrcene (6.37%), d-3-carene (4.68%), ß-pinene (3.71%), and limonene (3.34%). Conclusions: EC showed potent anti-nociceptive and anti-inflammatory activities with the relative involvement of opioid and benzodiazepine receptors. [ABSTRACT FROM AUTHOR]

In patients with Parkinson's disease, beta (β) and gamma (γ) oscillations are altered in the basal ganglia, and this abnormality contributes to the pathophysiology of bradykinesia. However, it is unclear whether β and γ rhythms at the primary motor cortex (M1) level influence bradykinesia. Transcranial alternating current stimulation (tACS) can modulate cortical rhythms by entraining endogenous oscillations. We tested whether β- and γ-tACS on M1 modulate bradykinesia in patients with Parkinson's disease by analysing the kinematic features of repetitive finger tapping, including movement amplitude, velocity and sequence effect, recorded during β-, γ- and sham tACS. We also verified whether possible tACS-induced bradykinesia changes depended on modifications in specific M1 circuits, as assessed by short-interval intracortical inhibition and short-latency afferent inhibition. Patients were studied OFF and ON dopaminergic therapy. Results were compared to those obtained in a group of healthy subjects. In patients, movement velocity significantly worsened during β-tACS and movement amplitude improved during γ-tACS, while the sequence effect did not change. In addition, short-latency afferent inhibition decreased (reduced inhibition) during β-tACS and short-interval intracortical inhibition decreased during both γ- and β-tACS in Parkinson's disease. The effects of tACS were comparable between OFF and ON sessions. In patients OFF therapy, the degree of short-interval intracortical inhibition modulation during β- and γ-tACS correlated with movement velocity and amplitude changes. Moreover, there was a positive correlation between the effect of γ-tACS on movement amplitude and motor symptoms severity. Our results show that cortical β and γ oscillations are relevant in the pathophysiology of bradykinesia in Parkinson's disease and that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia. In conclusion, abnormal oscillations at the M1 level of the basal ganglia-thalamo-cortical network play a relevant role in the pathophysiology of bradykinesia in Parkinson's disease. [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]

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Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.

Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage 11 C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (VT), which reflects GABA-A receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, VT and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, VT-1 h was mildly reduced and only weakly predicted SNL, while VT-48 h was significantly increased and predicted SNL both individually (p < 0.01, Kendall) and across the group (p < 0.001), i.e. the higher the VT, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA-A receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h VT observed here is consistent with earlier rat studies showing early GABA-A receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications. [ABSTRACT FROM AUTHOR]

Tissue regeneration and homeostasis often require recruitment of undifferentiated precursors (adult stem cells; ASCs). While many ASCs continuously proliferate throughout the lifetime of an organism, others are recruited from a quiescent state to replenish their target tissue. A long‐standing question in stem cell biology concerns how long‐lived, non‐dividing ASCs regulate the transition between quiescence and proliferation. We study the melanocyte stem cell (MSC) to investigate the molecular pathways that regulate ASC quiescence. Our prior work indicated that GABA‐A receptor activation promotes MSC quiescence in larval zebrafish. Here, through pharmacological and genetic approaches we show that GABA‐A acts through calcium signaling to maintain MSC quiescence. Unexpectedly, we identified translocator protein (TSPO), a mitochondrial membrane‐associated protein that regulates mitochondrial function and metabolic homeostasis, as a parallel regulator of MSC quiescence. We found that both TSPO‐specific ligands and induction of gluconeogenesis likely act in the same pathway to promote MSC activation and melanocyte production in larval zebrafish. In contrast, TSPO and gluconeogenesis appear to act in parallel to GABA‐A receptor signaling to regulate MSC quiescence and vertebrate pigment patterning. [ABSTRACT FROM AUTHOR]

A insônia é um dos distúrbios do sono caracterizado pela dificuldade em iniciar ou manter o sono. Isso se reflete em um sono de baixa qualidade que pode causar problemas ao longo do dia, como cansaço e falta de energia. Sob essa condição, estão associados alguns fatores genéticos, entre eles os genes ABCC9, 5-HTT e Clock. A presente revisão de literatura tem por objetivo a explanação acerca dos fatores genéticos relacionados com o distúrbio da insônia. Trata-se de uma revisão de literatura de forma sistemática, realizada por meio de um levantamento bibliográfico que procura reunir os conhecimentos sobre as características da insônia e sua herança gênica. Encontrou-se uma relevância de achados autorais valiosos para a síntese dessa pesquisa. Portanto, a partir do estudo abordado nessa revisão, torna-se evidente a importância do conhecimento das causas genéticas do distúrbio da insônia para a melhor abordagem clínica, haja vista a relevância desse mecanismo biológico.

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 this paper, we report the synthesis of 2-[(6-substituted benzo[ d ]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothiourea derivatives ( 4a-y ) carrying active pharmacophores essential for anticonvulsant activity. The anticonvulsant activity was evaluated in vivo by maximal electroshock (MES) test and subcutaneous pentylenetetrazole (scPTZ) test in mice. Most of the compounds showed promising anticonvulsant activity. The most active compounds 4b and 4q were found active in both MES and scPTZ models, without signs of neurotoxicity. Compound 4b showed the moderate change in SGOT and alkaline phosphatase level as compared to control. Compounds 4b and 4w were also found to elevate GABA levels in the olfactory lobe, mid brain, medulla oblongata and cerebellum regions of rat brain. In molecular docking study, the title compounds exhibited good binding properties with epilepsy molecular targets such as GABA-A. Structure-activity relationships are also elaborated along with the analysis of lipophilicity. The results suggested that compound 4b is likely to have varied mechanisms of action including voltage-gated ion channel inhibition and modulating GABAergic action. [ABSTRACT FROM AUTHOR]

Rapid and reflexive responses to threats are present across phylogeny. The neural circuitry mediating reflexive defense reactions has been well-characterized in a variety of species, for example, in rodents and cats, the detection of and species-typical response to threats is mediated by a network of structures including the midbrain tectum (deep and intermediate layers of the superior colliculus [DLSC]), periaqueductal gray (PAG), and forebrain structures such as the amygdala and hypothalamus. However, relatively little is known about the functional architecture of defense circuitry in primates. We have previously reported that pharmacological activation of the DLSC evokes locomotor asymmetry, defense-associated vocalizations, cowering behavior, escape responses, and attack of inanimate objects (Holmes et al., 2012; DesJardin et al., 2013; Forcelli et al., 2016). Here, we sought to determine if pharmacological activation of the PAG would induce a similar profile of responses. We activated the PAG in three awake, behaving macaques by microinfusion of GABA-A receptor antagonist, bicuculline methiodide. Activation of PAG evoked defense-associated vocalizations and postural/locomotor asymmetry, but not motor defense responses (e.g., cowering, escape behavior). These data suggest a partial dissociation between the role of the PAG and the DLSC in the defense network of macaques, but a general conservation of the role of PAG in defense responses across species. [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]

The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system ( CNS) of vertebrates. Signalling of the transmitter γ-aminobutyric acid ( GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/ GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research. [ABSTRACT FROM AUTHOR]

A recent experimental study ( Mizuseki, Sirota, Pastalkova, & Buzsaki, 2009 ) has shown that the temporal delays between population activities in successive entorhinal and hippocampal anatomical stages are longer (about 70–80 ms) than expected from axon conduction velocities and passive synaptic integration of feed-forward excitatory inputs. We investigate via computer simulations the mechanisms that give rise to such long temporal delays in the hippocampus structures. A model of the dentate gyrus (DG), CA3 and CA1 microcircuits is presented that uses biophysical representations of the major cell types including granule cells, CA3 and CA1 pyramidal cells (PCs) and six types of interneurons: basket cells (BCs), axo-axonic cells (AACs), bistratified cells (BSCs), oriens lacunosum-moleculare cells (OLMs), mossy cells (MCs) and hilar perforant path associated cells (HC). Inputs to the network came from the entorhinal cortex (EC) (layers 2 and 3) and the medial septum (MS). The model simulates accurately the timing of firing of different hippocampal cells with respect to the theta rhythm. The model shows that the experimentally reported long temporal delays in the DG, CA3 and CA1 hippocampal regions are due to theta modulated somatic and axonic inhibition. The model further predicts that the phase at which the CA1 PCs fire with respect to the theta rhythm is determined primarily by their increased dendritic excitability caused by the decrease of the axial resistance and the A-type K + conductance along their dendritic trunk. The model predicted latencies by which the DG, CA3 and CA1 principal cells fire are inline with the experimental evidence. Finally, the model proposes functional roles for the different inhibitory interneurons in the retrieval of the memory pattern by the DG, CA3 and CA1 networks. The model makes a number of predictions, which can be tested experimentally, thus leading to a better understanding of the biophysical computations in the hippocampus. [ABSTRACT FROM AUTHOR]

Aim The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. γ-aminobutyric acid ( GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells ( PBMCs) was influenced by gender, pregnancy or mental health. Methods We used RT- qPCR to determine the mRNA expression level in PBMCs from men ( n = 16), non-pregnant women ( n = 19), healthy pregnant women ( n = 27) and depressed pregnant women ( n = 15). Results The ρ2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The δ and ρ2 subunits were up-regulated by pregnancy, whereas the ε subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs. Conclusion The results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs. [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]

Characteristic changes in brain activity accompany the paradoxical increase in alertness observed in some patients with severe brain injury when they are treated with the sleeping pill zolpidem.

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6–10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7–0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6–10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors.

The macrolide antibiotic clarithromycin can enhance central nervous system excitability, possibly by antagonism of GABA-A receptors. Enhancement of GABA signaling has recently been demonstrated in a significant proportion of patients with central nervous system hypersomnias, so we sought to determine whether clarithromycin might provide symptomatic benefit in these patients. We performed a retrospective review of all patients treated with clarithromycin for hypersomnia, in whom cerebrospinal fluid enhanced GABA-A receptor activity in vitro in excess of controls, excluding those with hypocretin deficiency or definite cataplexy. Subjective reports of benefit and objective measures of psychomotor vigilance were collected to assess clarithromycin’s effects. Clinical and demographic characteristics were compared in responders and non-responders. In total, 53 patients (38 women, mean age 35.2 (SD 12.8 years)) were prescribed clarithromycin. Of these, 34 (64%) reported improvement in daytime sleepiness, while 10 (19%) did not tolerate its side effects, and nine (17%) found it tolerable but without symptomatic benefit. In those who reported subjective benefit, objective corroboration of improved vigilance was evident on the psychomotor vigilance task. Twenty patients (38%) elected to continue clarithromycin therapy. Clarithromycin responders were significantly younger than non-responders. Clarithromycin may be useful in the treatment of hypersomnia associated with enhancement of GABA-A receptor function. Further evaluation of this novel therapy is needed. [ABSTRACT FROM PUBLISHER]

The aim of this study was to evaluate the time-dependent effect of progesterone-only contraceptives on the brain and to obtain an improved understanding of mood disorders experienced under this medication. A total of 66 Wistar albino rats were divided into three groups: etonogestrel (ENG) implant (group 1, n = 30); depot medroxyprogesterone acetate (MPA)-injectable (group 2, n = 30); and control (group 3, n = 6) groups. Groups 1 and 2 were each divided into five subgroups, which were examined every 10 d for up to 50 d after medication administration, to evaluate its time-dependent effect. There was no difference in terms of gamma-aminobutyric acid (GABA) and serotonin immunohistochemical staining in white and gray matter among the subgroups of group 1. In group 2, there was a significant decrease in serotonin receptor staining intensity in white and gray matter on day 50, when compared to the control group ( p = 0.041). When the subgroups of group 2 were compared, there was a significant decrease in serotonin receptor staining intensity in white and gray matter on days 40 and 50 when compared to day 10. In conclusion, we showed that ENG and MPA have no effect on apoptosis and GABA-A receptors in the brain. We also showed that MPA has time-dependent effects on serotonin receptors, which may be a possible mechanism involved in mood disorders during long-term usage of injectable progesterone-only contraceptives. [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]

In recent years, it has become clear that there is an extensive cross-talk between the nervous and the immune system. Somewhat surprisingly, the immune cells themselves do express components of the neuronal neurotransmitters systems. What role the neurotransmitters, their ion channels, receptors and transporters have in immune function and regulation is an emerging field of study. Several recent studies have shown that the immune system is capable of synthesizing and releasing the classical neurotransmitter GABA (γ-aminobutyric acid). GABA has a number of effects on the immune cells such as activation or suppression of cytokine secretion, modification of cell proliferation and GABA can even affect migration of the cells. The immune cells encounter GABA when released by the immune cells themselves or when the immune cells enter the brain. In addition, GABA can also be found in tissues like the lymph nodes, the islets of Langerhans and GABA is in high enough concentration in blood to activate, e.g., GABA-A channels. GABA appears to have a role in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis and may modulate the immune response to infections. In the near future, it will be important to work out what specific effects GABA has on the function of the different types of immune cells and determine the underlying mechanisms. In this review, we discuss some of the recent findings revealing the role of GABA as an immunomodulator. [ABSTRACT FROM AUTHOR]

Cannabinoid system plays an important role in controlling neuronal excitability and brain function. On the other hand, modulation of gamma-aminobutyric acid (GABA) transmission is one of the initial strategies for the treatment of seizure. The aim of the present study was to evaluate possible interaction between cannabinoidergic and GABAergic systems in pentylenetetrazole (PTZ)-induced acute seizure in rat. Drugs were administered by intracerebroventricular (i.c.v.) administration 20 min before a single intraperitoneal (i.p.) injection of PTZ and the latency to the first generalized tonic-clonic seizure was measured. Both the cannabinoid receptor agonist WIN55212-2 (10, 30, 50 and 100 μg/rat) and the GABA-A receptor agonist isoguvacine (IGN; 10, 30 and 50 μg/rat) significantly increased the latency of seizure occurrence. Moreover, the fatty acid amide hydrolase inhibitor URB597 showed no anticonvulsive effect while the monoacyl glycerol lipase (MAGL) inhibitor URB602 (10, 50 and 100 μg/rat) protected rats against PTZ-induced seizure. Moreover, co-administration of IGN and cannabinoid compounds attenuated the anticonvulsant action of both WIN55212-2 and IGN in this model of seizure. Our data suggests that exogenous cannabinoid WIN55212-2 and MAGL inhibitor URB602 imply their antiseizure action in part through common brain receptorial system. Moreover, the antagonistic interaction of cannabinoids and IGN in protection against PTZ-induced seizure could suggest the involvement of GABAergic system in their anticonvulsant action. [ABSTRACT FROM AUTHOR]

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the α5-subtype (α5IA). We demonstrate that α5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, α5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with α5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with α5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant α5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals. [ABSTRACT FROM PUBLISHER]

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]

Objective We aimed to probe for regional cerebral effects of S-ketamine on in vivo GABA-A-receptor binding in healthy human subjects. Methods We investigated I-123-iomazenil SPECT before, during and after administration of S-ketamine in a blinded placebo-controlled study design (n = 12 in both groups). Analyses of SPECT were performed with voxel-based statistical parametric mapping (SPM), and statistical comparisons were made between the groups. We also assessed biochemical and behavioural changes during S-ketamine infusion. Results S-ketamine induced positive and negative symptoms measured by the Brief Psychiatric Rating scale (BPRS). It increased the cortisol and prolactin levels. Image analysis revealed significantly decreased I-123-iomazenil binding in bilateral dorsomedial prefrontal cortex during S-ketamine administration when compared to placebo. Conclusion Our study delivers preliminary evidence for an in vivo interaction of S-ketamine with GABA-A-receptors in human dorsomedial prefrontal cortex. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Characterized by burning and painful oral sensations in absence of clinically significant mucosal abnormalities, the burning mouth syndrome is, despite numerous researches made, basically idiopathic and, consequently, difficult to treat effectively. Therapy with tricyclic antidepressants and benzodiazepines has been proposed, although the exact pathomechanism is not clear. The objective of this study is to define the possible reasons for the efficacy of benzodiazepines in the treatment of the burning mouth syndrome. Starting from the report of eight cases successfully treated with prazepam, the present authors examined the clinical features and the evidence from literature that support the possibility of a role of neuroinflammation in the pathogenesis of the burning mouth syndrome. Available data suggest that the nervous system could be crucial in the pathogenesis of the syndrome (altered perception of pain, disturbance of neural transmission, increased excitability, negative involvement of trigeminal-vascular system), and the present authors’ experience lets them suppose a role for neuroinflammation. This hypothesis could also explain the positive response to benzodiazepines in some patients. The important role of neuroinflammation in dermatologic and oral diseases has been only recently investigated and acknowledged. Further studies on the connection between neuroinflammation and burning mouth syndrome could open interesting perspectives in the understanding and management of this difficult clinical condition. [ABSTRACT FROM AUTHOR]

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical γ-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type–specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value. [ABSTRACT FROM PUBLISHER]

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]

This study aimed to identify variables associated to the consumption of benzodiazepine among workers of a private company in the VIII Region, Chile. This is a cross-sectional and correlative study. Study population: 40 employees of a private company. The instruments included a questionnaire on socio-demographic variables and a benzodiazepine questionnaire. There was no record of benzodiazepine consumption at the moment of the study. Twenty percent (20%) of the interviewees had already used benzodiazepine in the past, whereas, half of them (10%) in the last year. The bivariate analysis of the last year consumption of benzodiazepine with work hours variables showed no significant relation (p=0.073). No association was found between benzodiazepine consumption and socio-demographic variables among the study participants. [ABSTRACT FROM AUTHOR]

This review gives an overview of what we see as the key issues in the human pharmacology of drugs of addiction. We review evidence of efficacy and mechanisms by which treatments act and point out areas where further work is needed. The role of agonist, partial agonist and antagonist treatments for opioid addiction is detailed and current issues relating to the mechanisms of actions at the receptor level and how to improve on compliance are discussed. The role of the brain dopamine and GABA-A systems in drug dependence is considered in relation to the growing pharmacology of these receptor systems, and the current status of novel preclinical targets reviewed. In addition, the different roles of dynamic and kinetic factors in both addiction and its treatment are discussed in relation to the underlying neuropharmacology of the disorders as defined from human and preclinical studies. Finally, some pointers to future research and especially to drug development by pharma are elaborated. [ABSTRACT FROM AUTHOR]

This study aimed to identify variables associated to the consumption of benzodiazepine among workers of a private company in the VIII Region, Chile. This is a cross-sectional and correlative study. Study population: 40 employees of a private company. The instruments included a questionnaire on socio-demographic variables and a benzodiazepine questionnaire. There was no record of benzodiazepine consumption at the moment of the study. Twenty percent (20%) of the interviewees had already used benzodiazepine in the past, whereas, half of them (10%) in the last year. The bivariate analysis of the last year consumption of benzodiazepine with work hours variables showed no significant relation (p=0.073). No association was found between benzodiazepine consumption and socio-demographic variables among the study participants. [ABSTRACT FROM AUTHOR]

An automated solid phase extraction, utilizing a 96-well plate format, was used to isolate a selective GABA-A α2,3 partial agonist (I) and internal standard (II) from human plasma. Following the isolation procedure, the analyte and internal standard were separated and detected using reversed phase HPLC coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry operated in the positive ionization mode. Based upon the peak area ratio (analyte:internal standard), the analyte was quantified over a concentration range of 0.1 to 50 ng/mL. The absolute and relative matrix effects from different sources of human plasma on the ionization efficiency were examined and the absence of these effects was confirmed. Assay validation results including parameters such as intra- and inter-day precision and accuracy are presented. The validated method was subsequently used to support human pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Rationale: GABA-A receptor ligands, including benzodiapines, may induce disinhibitory effects that increase the probability of risky decision making. To date, few laboratory studies have examined the acute, dose-related effects of benzodiazepines on human risk-taking behavior. Recent data indicate that in the United States alprazolam is the benzodiazepine most frequently misused for recreational purposes. Objectives: The present study was designed to demonstrate a dose-response relationship between acute alprazolam administration and human risk taking. Furthermore, this investigation sought to examine: (1) the behavioral mechanisms that may be involved in changes in the probability of risky decision making related to alprazolam administration and (2) risk seeking-related personality variables that may predict drug effects on risk taking. Methods: Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.5, 1.0, and 2.0 mg alprazolam in a within-subject repeated-measures design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, trial-by-trial response probabilities, and personality correlates related to drug effects at the 2.0-mg dose. Results: Alprazolam administration produced dose-related changes in subjective effects, response rates, and, most importantly, dose-dependently increased selection of the risky response option. The 2.0-mg dose increased the probability of making consecutive risky responses following a gain on the risky response option. Increases at 2.0 mg were related to a combination of personality scales that included high venturesomeness and novelty seeking and low harm avoidance. Conclusions: Alprazolam administration produced increases in human risk taking under laboratory conditions. In union with previous studies, the observed shift in trial-by- trial response probabilities suggests that sensitivity to consequences (e.g., oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may be predictive of acute drug effects on risk-taking behavior. [ABSTRACT FROM AUTHOR]

Context Adaptations in γ-aminobutyric acid type A (GABAA)–benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal. Objective To study GABAA-benzodiazepine receptor adaptations in subjects with alcohol dependence over the first month of sobriety. Design Inpatients who were not receiving medication, were either smokers or nonsmokers, and had alcohol dependence completed 2 iodine I 123–labeled iomazenil single-photon emission computed tomographic scans: 1 scan at a mean ± SD of 4.9 ± 2.5 days of sobriety (n = 23) and 1 scan at a mean ± SD of 29.8 ± 7.6 days of sobriety (n = 20). Participants in a matched group of healthy subjects (n = 15) completed 1 single-photon emission computed tomographic scan. Participants Men with alcohol dependence (n = 27) and a matched healthy comparison group (n = 15). Main Outcome Measures 123I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free 123I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between 123I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated. Results 123I-iomazenil uptake was elevated in several cortical regions, with a more prominent increase in nonsmokers with alcohol dependence as compared with smokers with alcohol dependence at 1 week of abstinence from alcohol. No significant differences were observed at 4 weeks of abstinence. At 1 week of abstinence, frontal 123I-iomazenil uptake correlated with the severity of alcohol withdrawal and the number of days since the last alcoholic drink was consumed. No significant associations were observed for smokers with alcohol dependence. Conclusions These data demonstrate time-dependent regulation of cortical GABAA-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABAA-benzodiazepine receptor levels during acute withdrawal may reflect a compensation for reduced receptor function, which is thought to contribute to alcohol tolerance and withdrawal. The subsequent decline may reflect “normalization” of GABAA receptor function with sobriety. Smoking may attenuate GABAA receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) has been shown to increase the extracellular concentrations of both dopamine (DA) and glutamate (GLU) in the striatum. Dopamine, glutamate, or their combined effects have been hypothesized to mediate striatal DA nerve terminal damage. Although it is known that METH releases DA via reverse transport, it is not known how METH increases the release of GLU. We hypothesized that METH increases GLU indirectly via activation of the basal ganglia output pathways. METH increased striatonigral GABAergic transmission, as evidenced by increased striatal GAD65 mRNA expression and extracellular GABA concentrations in substantia nigra pars reticulata (SNr). The METH-induced increase in nigral extracellular GABA concentrations was D1 receptor-dependent because intranigral perfusion of the D1 DA antagonist SCH23390 (10 µM) attenuated the METH-induced increase in GABA release in the SNr. Additionally, METH decreased extracellular GABA concentrations in the ventromedial thalamus (VM). Intranigral perfusion of the GABA-A receptor antagonist, bicuculline (10 µM), blocked the METH-induced decrease in extracellular GABA in the VM and the METH-induced increase in striatal GLU. Intranigral perfusion of either a DA D1 or GABA-A receptor antagonist during the systemic administrations of METH attenuated the striatal DA depletions when measured 1 week later. These results show that METH enhances D1-mediated striatonigral GABAergic transmission (l), which in turn activates GABA-A receptors in the SNr (2), leading to a decrease in GABAergic nigrothalamic activity (3), an increase in corticostriatal GLU release (4), and a consequent long-term depletion of striatal DA content (5). [ABSTRACT FROM AUTHOR]

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]

Post-training administration of the GABA-A and GABA-B receptor agonists muscimol and baclofen dose-dependently impaired retention of an inhibitory avoidance response in C57 mice, while improving memory consolidation in the DBA strain. By contrast, picrotoxin (blocker of GABA-activated ionophores), bicuculline (GABA-A antagonist) and CGP 35348 (GABA-B antagonist) dose-dependently improved retention in C57 mice and impaired it in DBA mice. These effects cannot be ascribed to non-specific actions of the drugs on retention performance, as the latencies during the retention test of those mice that had not received footshock during the training were not lengthened by the post-training drug administration. The effects on retention performance induced by GABA agonists and antagonists are probably due to an effect on memory consolidation, since they are observed when the drugs are given at short, but not at long, intervals after training. These results are discussed in terms of possible interaction of GABA systems with endogenous opioid and dopamine systems, whose activation has been shown to produce strain-dependent effects on memory processes. The possible utilization of these results for a genetic behavioral approach with recombinant inbred (RI) mice is also considered. [ABSTRACT FROM AUTHOR]