GABAA Research Articles

Developmental exposure to arsenic reduces anxiety levels and leads to a depressive-like behavior in female offspring rats: Molecular changes in the prefrontal cortex

Exposure to inorganic arsenic (iAs) detrimentally affects the structure and function of the central nervous system. In-utero and postnatal exposure to iAs has been connected to adverse effects on cognitive development. Therefore, this investigation explores neurobehavioral and neurochemical effects of 0.05 and 0.10 mg/L iAs exposure during gestation and lactation periods on 90-day-old female offspring rats. The assessment of anxiety- and depressive-like behaviors was conducted through the application of an elevated plus maze and a forced swim test. The neurochemical changes were evaluated in the prefrontal cortex (PFC) through the determination of enzyme activities and α1 GABAA subunit expression levels. Our findings revealed a notable impact of iAs exposure on anxiety and the induction of depressive-like behavior in 90-day-old female offspring. Furthermore, the antioxidant status within the PFC exhibited discernible alterations in exposed rats. Notably, the activities of acetylcholinesterase and glutamate pyruvate transaminase demonstrated an increase, while glutamate oxaloacetate transaminase activity displayed a decrease within the PFC due to the iAs treatment. Additionally, a distinct downregulation in the mRNA expression of the α1GABAA receptor was observed in this neuronal region. These findings strongly suggest that iAs exposure during early stages of rat development causes significant modifications in brain oxidative stress markers and perturbs the activity of enzymes associated with cholinergic and glutamatergic systems. In parallel, it elicits a discernible reduction in the level of GABA receptors within the PFC. These molecular alterations may play a role in the diminished anxiety levels and the depressive-like behavior outlined in the current investigation.

Positive Allosteric Modulation of GABAA α5 Receptors Improves Memory performance of rats with Conditions of Hippocampal Hyperactivity

Positive Allosteric Modulation of GABAA α5 Receptors Improves Memory performance of rats with Conditions of Hippocampal Hyperactivity

Enhancing cognitive recovery in chronic traumatic brain injury through simultaneous allosteric modulation of α7 nicotinic acetylcholine and α5 GABAA receptors

Traumatic brain injury (TBI) leads to changes in the neural circuitry of the hippocampus that result in chronic learning and memory deficits. However, effective therapeutic strategies to ameliorate these chronic learning and memory impairments after TBI are limited. Two pharmacological targets for enhancing cognition are nicotinic acetylcholine receptors (nAChRs) and GABAA receptors (GABAARs), both of which regulate hippocampal network activity to form declarative memories. A promising compound, 522–054, both allosterically enhances α7 nAChRs and inhibits α5 subunit-containing GABAARs. Administration of 522–054 enhances long-term potentiation (LTP) and cognitive functioning in non-injured animals. In this study, we assessed the effects of 522–054 on hippocampal synaptic plasticity and learning and memory deficits in the chronic post-TBI recovery period. Adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 12 wk after injury, we assessed basal synaptic transmission and LTP at the Schaffer collateral-CA1 synapse of the hippocampus. Bath application of 522–054 to hippocampal slices reduced deficits in basal synaptic transmission and recovered TBI-induced impairments in LTP. Moreover, treatment of animals with 522–054 at 12 wk post-TBI improved cue and contextual fear memory and water maze acquisition and retention without a measurable effect on cortical or hippocampal atrophy. These results suggest that dual allosteric modulation of α7 nAChR and α5 GABAAR signaling may be a potential therapy for treating cognitive deficits during chronic recovery from TBI.

Selective knockdown of GABAA-α2 subunit in the dorsal dentate gyrus in adulthood induces anxiety, learning and memory deficits and impairs synaptic plasticity.

Animal studies and clinical trials suggest that maintenance of gamma-aminobutyric acid (GABA)-ergic activity may be crucial in coping with stressful conditions, anxiety and mood disorders. Drugs highly efficient in promoting anxiolysis were shown to activate this system, particularly via the α2-subunit of type A receptors (GABAA α2). Given the high expression of GABAA α2 in the dentate gyrus (DG) sub-field of the hippocampus, we sought to examine whether manipulation of the α2 subunit in this area will evoke changes in emotional behaviour, memory and learning as well as in synaptic plasticity. We found that knockdown of GABAAα2 receptor specifically in the dorsal DG of rats caused increased anxiety without affecting locomotor activity. Spatial memory and learning in the Morris water maze were also impaired in GABAAα2 receptor knocked down rats, an effect accompanied by alterations in synaptic plasticity, as assessed by long-term potentiation in the DG. Our findings provide further support to the notion that emotional information processing in the hippocampus may be controlled, at least in part, via the inhibitory GABAA α2 receptor subunit, opening a potential avenue for early interventions from pre- puberty into adulthood, as a strategy for controlling anxiety-related psychopathology.

Pentylenetetrazole kindling induces dynamic changes in GAD65 expression in hippocampal somatostatin interneurons

IntroductionOne of the mechanisms of epileptgenesis is impairment of inhibitory neural circuits. Several studies have compared neural changes among subtypes of gamma-aminobutyric acid-related (GABAergic) neurons after acquired epileptic seizure. However, it is unclear that GABAergic neural modifications that occur during acquisition process of epileptic seizure. MethodsMale rats were injected with pentylenetetrazole (PTZ kindling: n = 30) or saline (control: n = 15) every other day to observe the development of epileptic seizure stages. Two time points were identified: the point at which seizures were most difficult to induce, and the point at which seizures were most easy to induce. The expression of GABAergic neuron-related proteins in the hippocampus was immunohistochemically compared among GABAergic subtypes at each of these time points. ResultsBimodal changes in seizure stages were observed in response to PTZ kindling. The increase of seizure stage was transiently suppressed after 8 or 10 injections, and then progressed again by the 16th injection. Based on these results, we defined 10 injections as a short-term injection period during which seizures are less likely to occur, and 20 injections as a long-term injection period during which continuous seizures are likely to occur. The immunohistochemical analysis showed that hippocampal glutamic acid decarboxylase 65 (GAD65) expression was increased after short-term kindling but unchanged after long-term kindling. Increased GAD65 expression was limited to somatostatin-positive (SOM+) cells among several GABAergic subtypes. By contrast, GAD, GABA, GABAAR α1, GABABR1, and VGAT cells showed no change following short- or long-term PTZ kindling. ConclusionPTZ kindling induces bimodal changes in the epileptic seizure stage. Seizure stage is transiently suppressed after short-term PTZ injection with GAD65 upregulation in SOM+ cells. The seizure stage is progressed again after long-term PTZ injection with GAD65 reduction to baseline level.

Quercetin increases the antidepressant-like effects of sclareol and antagonizes diazepam in thiopental sodium-induced sleeping mice: A possible GABAergic transmission intervention.

Quercetin is the most common polyphenolic flavonoid present in fruits and vegetables demonstrating versatile health-promoting effects. This study aimed to examine the effects of quercetin (QR) and sclareol (SCL) on the thiopental sodium (TS)-induced sleeping and forced swimming test (FST) mouse models. SCL (1, 5, and 10 mg/kg, p.o.) or QR (50 mg/kg, p.o.) and/or diazepam (DZP) (3 mg/kg, i.p.) were employed. After 30 min of TS induction, individual or combined effects on the animals were checked. In the FST test, the animals were subjected to forced swimming after 30 min of administration of the test and/or controls for 5 min. In this case, immobility time was measured. In silico studies were conducted to evaluate the involvement of GABA receptors. SCL (5 and 10 mg/kg) significantly increased the latency and decreased sleeping time compared to the control in the TS-induced sleeping time study. DZP (3 mg/kg) showed a sedative-like effect in animals in both sleeping and FST studies. QR (50 mg/kg) exhibited a similar pattern of activity as SCL. However, its effects were more prominent than those of SCL groups. SCL (10 mg/kg) altered the DZP-3-mediated effects. SCL-10 co-treated with QR-50 significantly (p < 0.05) increased the latency and decreased sleep time and immobility time, suggesting possible synergistic antidepressant-like effects. In silico studies revealed that SCL and QR demonstrated better binding affinities with GABAA receptor, especially α2, α3, and α5 subunits. Both compounds also exhibited good ADMET and drug-like properties. In animal studies, the both compounds worked synergistically to provide antidepressant-like effects in a slightly different fashion. As a conclusion, the combined administration of SCL and QR may be used in upcoming neurological clinical trials, according to in vivo and in silico findings. However, additional investigation is necessary to verify this behavior and clarify the potential mechanism of action.

Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression.

The serotonin (5-hydroxytryptamine (5-HT))-mediated system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous studies showed that stress and drug exposure can modulate the dorsal raphe nucleus (DRN)-5-HT system via γ-aminobutyric acid (GABA)A receptors. Moreover, GABAA receptor-mediated inhibition of serotonergic DRN neurons is required for stress-induced reinstatement of opioid seeking. To further test the role of GABAA receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABAA α1 subunit to manipulate GABAA receptors in either the DRN or the entire population of 5-HT neurons. The GABAA α1 subunit is a constituent of the most abundant GABAA subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons. Our results showed that mice with DRN-specific knockout of α1-GABAA receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABAA receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety. Our data suggest that GABAA receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.

Positive allosteric modulation of α5 GABAA receptors effects on binge eating and hyperactivity in two-hit model

Positive allosteric modulation of α5 GABAA receptors effects on binge eating and hyperactivity in two-hit model

Sclareol exerts synergistic antidepressant effects with quercetin and caffeine, possibly suppressing GABAergic transmission in chicks

This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student–Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABAA receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABAA (α2 and α5) subunits than QUR with α2, α3, and α5. All these compounds showed stronger interactions with the GABAA receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABAA receptor subunits.

Electrophysiological and molecular changes following neuroprotective placental protein administration on tinnitus-induced rats.

Despite 6%-20% of the adult population suffering from tinnitus, there is no standard treatment for it. Placenta extract has been used for various therapeutic purposes, including hearing loss. Here, we evaluate the effect of a novel neuroprotective protein composition (NPPC) extract on electrophysiological and molecular changes in the medial geniculate body (MGB) of tinnitus-induced rats. To evaluate the protein analysis by western blot, the rats were divided into three groups: (1) saline group (intraperitoneal injection of 200 mg/kg saline twice a day for 28 consecutive days, (2) chronic Na-Sal group received sodium salicylate as in the first group, and (3) chronic treatment group (received salicylate 200 mg/kg twice daily for 2 weeks, followed by 0.4 mg NPPC daily from day 14 to day 28). Single-unit recordings were performed on a separate group that was treated as in group 4. Gap-prepulse inhibition of the acoustic startle (GPIAS) and pre-pulse inhibition (PPI) was performed to confirm tinnitus in all groups at the baseline, 14th and 28th days. Western blot analysis showed that the expression of γ-Aminobutyric acid Aα1 subunit (GABA Aα1), N-methyl-d-aspartate receptor subtype 2B (NR2B or NMDAR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR1 (GluR1), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR2 (GluR2) decreased after Na-Sal injection, while NPPC upregulated their expression. MGB units in rats with tinnitus showed decreased spontaneous firing rate, burst per minute, and a spike in a burst. After NPPC administration, neural activity patterns showed a significant positive effect of NPPC on tinnitus. NPPC can play an effective role in the treatment of tinnitus in salicylate-induced rats, and MGB is one of the brain areas involved in these processes. NA.

Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAAR α1 Expression.

Imbalance between excitation and inhibition is an important cause of epilepsy. Salt-inducible kinase 1 (SIK1) gene mutation can cause epilepsy. In this study, we first found that the expression of SIK3 is increased after epilepsy. Furthermore, the role of SIK3 in epilepsy was explored. In cultured hippocampal neurons, we used Pterosin B, a selective SIK3 inhibitor that can inhibit epileptiform discharges induced by the convulsant drug cyclothiazide (a positive allosteric modulator of AMPA receptors, CTZ). Knockdown of SIK3 inhibited epileptiform discharges and increased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). In mice, knockdown of SIK3 reduced epilepsy susceptibility in a pentylenetetrazole (a GABAA receptor antagonist, PTZ) acute kindling experiment and increased the expression of GABAA receptor α1. In conclusion, our results suggest that blockade or knockdown of SIK3 can inhibit epileptiform discharges and that SIK3 has the potential to be a novel target for epilepsy treatment.

Anxiolytic-like effect of succinic acid: A possible GABAergic intervention

In the modern era, physical and mental stress lead to anxiety at an alarming rate. Therefore, searching for new lead compounds that deal with anxiety has a practical demand. Our study aimed to evaluate succinic acid's (SUC) possibility of managing anxiety through in vivo and in silico studies. For this, SUC (5, 10, and 15) mg/kg were administered orally (p.o.) to the adult male Swiss mice, followed by several studies like open field, swing, hole cross, and light-dark residence tests. The GABAergic agonist diazepam (DZP-2 mg/kg) and an antagonist such as caffeine (CAF-10 mg/kg) were also studied in combination with the SUC group. In contrast to the DZP group, SUC significantly (p < 0.0001) increased the amount of time that animals spent in the light, suggesting that it may have relaxing impacts on mice. Additionally, in silico studies were carried out to understand the interaction between SUC and GABAA (α1, β2, and γ2) receptor subunits. Furthermore, pharmacokinetic and drug-like properties were examined by pkCSM and SwissADME online servers and found to be supportive of considering SUC as a potential drug candidate. Our experiment found that SUC-10 had an anxiolytic-like effect on the animals. SUC-10, when combined with DZP, produced more significant (p < 0.0001) anxiolytic effects than their individual groups, suggesting possible synergistic effects with this commonly used anxiolytic drug. SUC-10 also altered CAF-mediated effects in mice. An in silico study demonstrates that SUC has good interaction capacity with GABAA receptor subunits. Taken together, SUC-10 exerted anxiolytic-like effects in Swiss mice. It may act synergistically with DZP while acting antagonistically with CAF, possibly through GABAergic interaction pathways.

Quercetin Antagonizes the Sedative Effects of Linalool, Possibly through the GABAergic Interaction Pathway.

Sedatives promote calmness or sleepiness during surgery or severely stressful events. In addition, depression is a mental health issue that negatively affects emotional well-being. A group of drugs called anti-depressants is used to treat major depressive illnesses. The aim of the present work was to evaluate the effects of quercetin (QUR) and linalool (LIN) on thiopental sodium (TS)-induced sleeping mice and to investigate the combined effects of these compounds using a conventional co-treatment strategy and in silico studies. For this, the TS-induced sleeping mice were monitored to compare the occurrence, latency, and duration of the sleep-in response to QUR (10, 25, 50 mg/kg), LIN (10, 25, 50 mg/kg), and diazepam (DZP, 3 mg/kg, i.p.). Moreover, an in silico investigation was undertaken to assess this study's putative modulatory sedation mechanism. For this, we observed the ability of test and standard medications to interact with various gamma-aminobutyric acid A receptor (GABAA) subunits. Results revealed that QUR and LIN cause dose-dependent antidepressant-like and sedative-like effects in animals, respectively. In addition, QUR-50 mg/kg and LIN-50 mg/kg and/or DZP-3 mg/kg combined were associated with an increased latency period and reduced sleeping times in animals. Results of the in silico studies demonstrated that QUR has better binding interaction with GABAA α3, β1, and γ2 subunits when compared with DZP, whereas LIN showed moderate affinity with the GABAA receptor. Taken together, the sleep duration of LIN and DZP is opposed by QUR in TS-induced sleeping mice, suggesting that QUR may be responsible for providing sedation-antagonizing effects through the GABAergic interaction pathway.

3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors.

Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3', 4'-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3', 4'-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving KATP channels, adenosine and GABAA receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3', 4'-dihydroxyflavone at the above targets were also carried out. The test compound 3', 4'-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3', 4'-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of KATP channels, adenosine and GABAA receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3', 4'-dihydroxyflavone at these targets. The findings of the present study suggests that, 3', 4'-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve KATP channels, adenosine (A3) and GABAA (α2 subunit) receptors.

Alcohol and Ganaxolone Suppress Tremor via Extra-Synaptic GABAA Receptors in the Harmaline Model of Essential Tremor.

A long-standing question is why essential tremor often responds to non-intoxicating amounts of alcohol. Blood flow imaging and high-density electroencephalography have indicated that alcohol acts on tremor within the cerebellum. As extra-synaptic δ-subunit-containing GABAA receptors are sensitive to low alcohol levels, we wondered whether these receptors mediate alcohol's anti-tremor effect and, moreover, whether the δ-associated GABAA receptor α6 subunit, found abundantly in the cerebellum, is required. We tested the hypotheses that low-dose alcohol will suppress harmaline-induced tremor in wild-type mice, but not in littermates lacking GABAA receptor δ subunits, nor in littermates lacking α6 subunits. As the neurosteroid ganaxolone also activates extra-synaptic GABAA receptors, we similarly assessed this compound. The harmaline mouse model of essential tremor was utilized to generate tremor, measured as a percentage of motion power in the tremor bandwidth (9-16 Hz) divided by background motion power at 0.25-32 Hz. Ethanol, 0.500 and 0.575 g/kg, and ganaxolone, 7 and 10 mg/kg, doses that do not impair performance in a sensitive psychomotor task, reduced harmaline tremor compared to vehicle-treated controls in wild-type mice but failed to suppress tremor in littermates lacking the δ or the α6 GABAA receptor subunit. As cerebellar granule cells are the predominant brain site intensely expressing GABAA receptors containing both α6 and δ subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target α6βδ-containing GABAA receptors may be effective and well-tolerated for treating essential tremor. How does alcohol temporarily ameliorate essential tremor? This study with a mouse model found that two specific kinds of GABA receptor subunits were needed for alcohol to work. As receptors with both these subunits are found mainly in cerebellum, this work suggests this is where alcohol acts to suppress tremor.

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Para-Chlorophenyl Alanine Induces Aggressive Behavior by Serotonin Depletion in Male Rats and Increases Tryptophan Hydroxylase two and GABAA α1 mRNA Expression in the Olfactory Bulb

Profiling GABA(A) Receptor Subunit Expression in the Hippocampus of PMDD Rat Models Based on TCM Theories.

γ-Aminobutyric acid type A receptors (GABAARs) play an important role in cognitive and emotional regulation and are related to the hippocampus. However, little is known regarding patterns of hippocampal GABAAR subunit expression in rat models of premenstrual dysphoric disorder (PMDD). This study investigated the above changes by establishing two PMDD rat models based on Traditional Chinese Medicine (TCM) theories, namely, PMDD liver-qi invasion syndrome (PMDD-LIS) and PMDD liver-qi depression syndrome (PMDD-LDS). Behavioral tests were used to detect depression and irritability emotion. Western blot analysis was used to investigate protein levels of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits, whereas ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis was performed to determine gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the hippocampus across each group. Concurrently, behavioral data indicated that the PMDD-LDS and PMDD-LIS rat models had been successfully established. GABAAR α2, α5, β2, and δ subunit was significantly upregulated, whereas α4 was significantly downregulated (P < 0.05) in PMDD-LDS rat models relative to controls. On the other hand, GABAAR α1, α2, and β3 were significantly downregulated while α4 and β2 were significantly upregulated in PMDD-LIS rat models relative to the control group (P < 0.05). Moreover, GABA levels significantly decreased, while Glu and the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conversely, GABA and Glu levels significantly decreased, whereas the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conclusively, our results revealed differential expression of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits between PMDD-LIS and PMDD-LDS rat models, suggesting that they may be biomarkers in the pathogenesis of PMDD.

Phase 1 Trial of Darigabat for the Reduction of Acute Psychological and Physiological Panic and Fear Symptoms Following CO2 Inhalation in Healthy Participants (S8.005)

<h3>Objective:</h3> To evaluate the panicolytic effect of 2 dose strengths of darigabat in reducing panic and fear symptoms following carbon dioxide (CO₂) inhalation by healthy participants. <h3>Background:</h3> Panic disorder is associated with subjective and physiological symptoms which no single drug class adequately addresses. Darigabat, in development for neurological and psychiatric disorders, was designed to have nonsedative panicolytic potential by selectively enhancing the effect of GABA at α2/3/5, while sparing activity at α1 GABA_A receptor subtypes. <h3>Design/Methods:</h3> This phase 1 randomized, double-blind, crossover, placebo- and active-controlled trial (NCT04592536) enrolled adults sensitive to anxiogenic effects of 35% CO₂ double-breath inhalation. Participants were randomized to receive placebo and either 1 of 3 active treatments in 3 separate cohorts for 8 days: darigabat 7.5 or 25 mg twice daily (BID) or alprazolam 1 mg BID. Target darigabat doses were achieved following a 4-day titration. After each crossover period, CO₂ challenge was performed 3 hours post-dose. Panic and fear symptoms were measured before and immediately after CO₂ inhalation using the Panic Symptom List-IV total score (PSL-IV; primary endpoint) and fear visual analog scale (VAS Fear; secondary endpoint). Each participant’s placebo treatment served as their own control. <h3>Results:</h3> Fifty-six participants were randomized. On Day 8, darigabat 7.5-mg and 25-mg BID groups demonstrated a 3.9-point (nominal <i>P</i>=0.036) and 4.5-point (nominal <i>P</i>=0.008) improvement on the PSL-IV versus placebo, respectively. Darigabat groups demonstrated a 12.8-point (nominal <i>P</i>=0.026) and 7.8-point (nominal <i>P</i>=0.282) improvement on the VAS Fear versus placebo, respectively. The positive control (alprazolam 1 mg BID) exhibited panicolytic effect compared with placebo, in line with expectations. Darigabat was generally well tolerated, with no serious adverse events and no discontinuations in darigabat cohorts. <h3>Conclusions:</h3> The panicolytic potential of darigabat was validated, warranting further evaluation in patients with panic disorder. <b>Disclosure:</b> Dr. Gurrell has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Gurrell has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Cerevel Therapeutics. Dr. Gurrell has stock in Pfizer Ltd. Ms. Chang has received personal compensation for serving as an employee of Cerevel. Ms. Chang has stock in Cerevel Therapeutics. Dr. Dandurand has received personal compensation for serving as an employee of Cerevel. Dr. Dandurand has received personal compensation for serving as an employee of Otsuka. Dr. Dandurand has stock in Cerevel Therapeutics. An immediate family member of Dr. Dandurand has stock in Velocit . An immediate family member of Dr. Dandurand has stock in Cerebus. Dr. Duvvuri has received personal compensation for serving as an employee of Cerevel. Dr. Duvvuri has stock in Cerevel Therapeutics. Dr. Duvvuri has stock in Pfizer. Amy Guigliano has nothing to disclose. Dr. Pastino has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Pastino has received personal compensation for serving as an employee of PRA Health Sciences. Dr. Pham has nothing to disclose. Dr. Versavel has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Versavel has received stock or an ownership interest from Cerevel Therapeutics. Dr. Jacobs has nothing to disclose. Mr. Pour has nothing to disclose. Dr. Zuiker has nothing to disclose. Dr. Sanchez has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Sanchez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Coleman Research. Dr. Sanchez has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Cerevel Therapeutics. Dr. Sanchez has received stock or an ownership interest from Cerevel Therapeutics. Dr. Sanchez has received personal compensation in the range of $500-$4,999 for serving as a Consultant with GLG. Dr. Renger has received personal compensation for serving as an employee of Cerevel Therapeutics.

GABAA receptor subunit modulation reversed electrophysiological network alterations after blast exposure in rat organotypic hippocampal slice cultures

Throughout training and deployment, some military service members are frequently exposed to shock waves due to blasts, and some complain of myriad neurological symptoms. In rat organotypic hippocampal slice cultures (OHSCs), blast-induced traumatic brain injury (bTBI) causes deficits in some electrophysiological measures, like long term potentiation, a neuronal correlate for learning and memory. In this study, we further characterized the alterations in the hippocampal network of OHSCs following a single moderate blast exposure. Connectivity and clustering coefficients were reduced across the hippocampal network following bTBI, despite the lack of changes in the firing rate, spike amplitude, spike duration, or inter-spike interval. However, interrogation with the GABAA receptor antagonist, bicuculline, revealed additional significant differences between injured and control slices in measures of spike amplitude, spike duration, connectivity, and clustering. bTBI also significantly reduced expression of the α1 and α5 GABAA receptor subunits. Treatment with the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) restored the α1 subunit and attenuated deficits in network measures, like connectivity and clustering coefficients. These findings suggest that GABAA receptors may be implicated in neuronal network changes in OHSCs following bTBI, and their recovery may be a viable therapeutic intervention to mitigate injury-induced neurological symptoms.

Exposure to chlorpyrifos during pregnancy differentially affects social behavior and GABA signaling elements in an APOE- and sex-dependent manner in a transgenic mouse model

The massive use of chlorpyrifos (CPF) has been associated with an increased prevalence of neurodevelopmental disorders. Some previous studies have shown that prenatal, but not postnatal, CPF exposure causes social behavior deficits in mice depending on sex while others have found that in transgenic mice models carrying the human apolipoprotein E (APOE) ε3 and ε4 allele confer different vulnerabilities to either behavioral or metabolic disorders after CPF exposure. This study aims to evaluate, in both sexes, how prenatal CPF exposure and APOE genotype impact on social behavior and its relation to changes in GABAergic and glutamatergic systems. For this purpose, apoE3 and apoE4 transgenic mice were exposed through the diet to 0 or 1 mg/kg/day of CPF, between gestational day 12 and 18. A three-chamber test was used to assess social behavior on postnatal day (PND) 45. Then, mice were sacrificed, and hippocampal samples were analyzed to study the gene expression of GABAergic and glutamatergic elements. Results showed that prenatal exposure to CPF impaired social novelty preference and increased the expression of GABA-A α1 subunit in females of both genotypes. In addition, the expression of GAD1, the ionic cotransporter KCC2 and the GABA-A α2 and α5 subunits were increased in apoE3 mice, whereas CPF treatment only accentuated the expression of GAD1 and KCC2. Nevertheless, future research is needed to evaluate whether the influences detected in the GABAergic system are present and functionally relevant in adults and old mice.