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Introduction: Ciprofol is a new intravenous anesthetic with a similar chemical structure to propofol. We aimed to compare the incidence of adverse actions like injection pain and time indexes of ciprofol versus propofol on anesthesia in patients undergoing endoscopy. We also compared anesthetists' satisfaction during the procedure. Methods: Two independent researchers (Liu and Zeng) searched the Cochrane Library, Embase databases, and PubMed for controlled clinical trials. This meta-analysis of randomized controlled trials (RCTs) was performed with the Review Manager, Stata and the Cochrane Risk-of-Bias 2 tool to evaluate methodological quality. Relative risks with 95% confidence interval (CI) were calculated for outcomes. Results: Ten trials, including 1545 patients, were examined in the current meta-analysis. During anesthesia in patients undergoing endoscopy, the incidence of injection pain was significantly reduced in the research group. Compared with propofol, the pooled risk difference (RD) with the use of ciprofol for injection pain for all the procedures was − 0.34 (95% confidence interval [CI], -0.48 to 0.19), and RR for hypotension was 0.73(95% CI:0.58 to 0.92). GRADE showed this meta-analysis has moderate or low confidence. Trial sequential analysis for mortality indicated insufficient sample size for a definitive judgment for lower incidence of hypotension. Conclusion: In painless endoscopy, compared with propofol, ciprofol exhibited non-inferiority anesthesia/sedation in patients, and had a good safety profile with a lower incidence of pain on injection and may reduce the chance of hypotension. Trial sequential analysis suggested the need for more cases, and GRADE highlighted moderate certainty, emphasizing the necessity for further targeted RCTs. Systematic review registration: PROSPERO, CRD42023433627. [ABSTRACT FROM AUTHOR]

Agitated depression, also known as melancholia agitata, is a variant of depression characterized by severe symptoms of psychomotor agitation, inner unrest, anxiety, restlessness, prominent vegetative symptoms, and a high risk of suicide. This form of depression is reported to worsen with antidepressants and potentially improve with the use of ECT, lithium, antiepileptics, antipsychotics, and benzodiazepines. We describe a case of a 73‐year‐old female with a prior history of depression and generalized anxiety disorder who was maintained on flurazepam for 44 years and was admitted for severe depression with psychomotor agitation, prominent vegetative symptoms, thought perseveration, indecisiveness, and psychotic features that emerged following the discontinuation of flurazepam. Symptoms did not resolve with the use of alternative benzodiazepines such as nitrazepam and temazepam and further worsened with the use of several antidepressants. She finally had a complete resolution of these symptoms with a combination of alprazolam, zopiclone, and olanzapine. This case provides insight into this unique variant of depression and the role of GABA agonists in its pathology and management. [ABSTRACT FROM AUTHOR]

Background: As a new type of intravenous anesthetic, ciprofol has the advantages of fast onset of action, fast recovery and high clearance rate. This study aimed to investigate the effectiveness and safety of ciprofol versus traditional propofol for anesthesia and sedation in and out of the operating room. Methods: We searched the literature in PubMed, Web of Science, Cochrane Library, and Embase databases from January 2021 to December 2023. All clinical studies comparing the sedative effects of propofol and ciprofol, both inside and outside the operating room, were included in our trial. The main outcome measures were induction time and incidence of injection-site pain. Data are merged using risk ratio and standardized mean difference with 95% confidence interval. Subgroup analysis, meta-regression, sensitivity analysis, and publication bias were performed. The study protocol was prospectively registered with PROSPERO (CRD42023447747). Results: A total of 15 randomized, controlled trials involving 2002 patients were included in this study. Compared with propofol, ciprofol has a longer induction time in the operating room but a shorter induction time in non-operating room settings. Ciprofol can effectively reduce the risk of injection-site pain and respiratory depression both inside and outside the operating room. In addition, the risk of drug-related hypotension induced with ciprofol in the operating room is lower, but the awakening time is also longer. Meta-regression analysis showed that neither age nor BMI were potential sources of heterogeneity. Funnel plot, egger and begg tests showed no significant publication bias. Sensitivity analyzes indicate that our results are robust and reliable. Conclusion: Ciprofol has absolute advantages in reducing the risk of injection-site pain and respiratory depression, both in and outside operating room. Intraoperative use of ciprofol reduces the risk of drug-related hypotension and may also reduce the risk of intraoperative physical movements. However, ciprofol may have longer induction and awakening time than propofol. [ABSTRACT FROM AUTHOR]

Background Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. Aims This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. Results Acute or repeated treatment with CGP7930, GS39783, BHF177, rac -BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. Conclusions These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients. [ABSTRACT FROM AUTHOR]

After unilateral peripheral vestibular lesions, the neural activity of neurons in the ipsi-lesional medial vestibular nucleus (ipsi-MVe) are markedly decreased, resulting in static and dynamic asymmetries of the vestibulo-ocular and vestibulo-spinal reflexes. Consequently, static vestibular symptoms such as spontaneous nystagmus and postural deviation and dynamic vestibular symptoms such as oscillopsia and swaying gait are induced. However, these behavioral asymmetries gradually recover after the lesion. Progressive balance restoration is termed vestibular compensation, which is divided into two phases: static and dynamic. Static vestibular compensation is further divided into initial and late processes. In the initial process of static vestibular compensation after unilateral labyrinthectomy (UL) in rats, plastic changes in the cerebello-vestibular and vestibular commissural inhibitory pathways suppress neurons in the contra-lesional MVe (contra-MVe), resulting in the restoration of symmetrical resting activity of MVe neurons on both sides at low levels. The declining frequency of spontaneous nystagmus after UL is an index of the initial process, and short-term administration of diazepam, a GABA A receptor agonist, has been shown to accelerate the initial process in rats. Accordingly, short-term administration of diazepam is recommended for the treatment of acute vertigo in patients with unilateral vestibular dysfunction. In the late process of static vestibular compensation after UL in rats, the resting activity of ipsi-MVe neurons gradually recovers due to changes in cell membrane properties, resulting in the reinforcement of balanced intervestibular nuclear activities to nearly normal levels without the suppression of contra-MVe neurons. The declining number of MK801-induced Fos-positive neurons in contra-MVe after UL is an index of the late process, and long-term administration of betahistine, a histamine H 3 receptor antagonist, has been shown to accelerate the late process in rats. Accordingly, long-term administration of betahistine is recommended for the treatment of subacute vertigo in patients who were not compensated for unilateral vestibular dysfunction. In the process of dynamic vestibular compensation after UL, the sensitivity of ipsi-MVe neurons to head velocity and acceleration is restored due to synaptic changes such as long-term potentiation and sprouting of commissures, resulting in the restoration of the dynamic vestibulo-ocular and vestibulo-spinal reflexes. To facilitate dynamic vestibular compensation, early ambulation and subsequent vestibular rehabilitation exercise are recommended for the treatment of chronic vertigo in patients with uncompensated unilateral vestibular dysfunction. Although vestibular compensation after bilateral vestibular loss is not expected, vestibular rehabilitation with a sensory-substitution strategy can improve imbalance in patients with bilateral vestibular lesions. [ABSTRACT FROM AUTHOR]

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field. [ABSTRACT FROM AUTHOR]

Aims: To increase our understanding of which factors contribute to long‐term benzodiazepine receptor agonist (BZRA) use for insomnia in primary care, from a patients', general practitioners' (GP) and pharmacists' perspective. Design: Qualitative research following a grounded theory approach. Setting: Primary care in Belgium. Participants: Twenty‐four participants were interviewed, including nine patients, six GPs and nine pharmacists. Measurements: In‐depth, semistructured interviews with iterative cycles of data collection and analysis. Transcripts were analysed using the framework method. Thematic findings were interpreted in the context of the Theoretical Domains Framework. Findings: A reflexive relation was identified between views about hypnotic use at the level of society, healthcare and patients. Behaviour change appeared to depend strongly on context and social influence, including a need for supporting relationships by all stakeholders. Six key messages captured factors that contribute to long‐term BZRA use for insomnia in primary care: societal beliefs as a game changer, the opportunity of nonpharmacological treatment, collaborative primary care, patient‐centred goals, informed consent and self‐management. Conclusions: Long‐term BZRA use for insomnia is a complex and multifaceted public health problem that is not adequately addressed in primary care at this time. Although primary care professionals in this study found discontinuation of long‐term BZRA use relevant to the patient's health, many organisational and personal barriers were reported. Moreover, the current social and healthcare context is not empowering patients and professionals to reduce long‐term BZRA use for insomnia. Specifically, for primary care, all stakeholders reported the need for a nonmedicalised relationship between the patient and GP to lower prescribing rates. Patient or Public Contribution: The Flemish Patient Platform, a patient representative organisation, assisted with recruitment by launching a call for participants in their newsletter and volunteered to disseminate the results. The call for recruitment was also published online in social media groups regarding insomnia and via posters in public pharmacies. Patients or public were not involved in designing or conducting the interview study. [ABSTRACT FROM AUTHOR]

Previous neuroscientific research has expounded on the fundamental role played by emotion during moral decision-making. Negative emotionality has been observed to exert a general inhibitory effect towards harmful behaviors against others. Nevertheless, the downregulation of negative affects at different levels of moral processing (e.g. impersonal versus personal moral dilemmas) alongside its possible interactions with other factors (e.g. perspective taking) hasn't been directly assessed; both of which can assist in predicting future moral decision-making. In the present research, we empirically test (Study 1, N = 41) whether downregulating negative emotionality through pharmacological interventions using lorazepam (a GABA receptor agonist), modulate the permissibility of harm to others –i.e. if participants find it more morally permissible to harm others when harm is unavoidable (inevitable harm moral dilemmas), than when it may be avoided (evitable harm moral dilemmas). Furthermore, using another sample (Study 2, N = 31), we assess whether lorazepam's effect is modulated by different perspective-taking conditions during a moral dilemma task –e.g. "is it morally permissible for you to [...]?" (1st person perspective), relative to "is it morally permissible for [x individual] to [...]?" (3rd person perspective)–, where the outcome of the different scenarios is controlled. The results of both studies converge, revealing an emotion-dependent, rather than an outcome-dependent, pharmacological modulation. Lorazepam only influenced interpersonal moral judgments when not modulated by the evitable/inevitable condition. Furthermore, there was a significant interaction between perspective-taking and drug administration, as lorazepam exerted a larger effect in modulating moral choices rather than moral judgements. [ABSTRACT FROM AUTHOR]

Background: Ciprofol is a novel intravenous sedative and anesthetic. Studies have shown that it features a rapid onset of action, a fast recovery time, slight inhibition of respiratory and cardiovascular functions, and a low incidence of adverse reactions. This study aims to explore the median effective dose (ED50) and the 95% effective dose (ED95) of ciprofol in inhibiting responses to gastroscope insertion when combined with a low dose of alfentanil, and to evaluate its safety, to provide a reference for the rational use of ciprofol in clinical practices. Methods: We included 25 patients aged 18–64 years of either sex who underwent gastroscopy under intravenous general anesthesia, with a Body Mass Index (BMI) 18–28 kg/m2, and an American Society of Anesthesiologists (ASA) grade I or II. In this study, the dose-finding strategy of ciprofol followed a modified Dixon's up-and-down method with an initial dose of 0.30 mg/kg and an increment of 0.02 mg/kg. Ciprofol was administered after intravenous injection of 7 µg/kg of alfentanil, and 2 min later a gastroscope was inserted. When the insertion response of one participant was positive (including body movement, coughing, and eye opening), an escalation of 0.02 mg/kg would be given to the next participant; otherwise, a de-escalation of 0.02 mg/kg would be administered. The study was terminated when negative response and positive response alternated 8 times. A Probit model was used to calculate the ED50 and ED95 of ciprofol in inhibiting responses to gastroscope insertion when combined with alfentanil. Patients' recovery time, discharge time, vital signs and occurrence of adverse reactions were recorded. Results: The ED50 of single-dose intravenous ciprofol injection with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Patients' recovery time and discharge time were 11.04 ± 1.49 min and 9.64 ± 2.38 min, respectively. The overall incidence of adverse reactions was 12%. Conclusion: The ED50 of ciprofol combined with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Ciprofol showed a low incidence of anesthesia-related adverse events. Trial registration: http://www.chictr.org.cn (ChiCTR2200061727). [ABSTRACT FROM AUTHOR]

Administration of cocaine increases synaptic dopamine levels by blocking dopamine reuptake and leads to increased locomotor activity and compulsive drug‐seeking behaviour. It has been suggested that the lateral hypothalamus (LH) or lateral habenula (LHb) is involved in drug‐seeking behaviours. To explore the role of the LH and the LHb in cocaine‐induced psychomotor responses, we tested whether modulation of the LH or the LH‐LHb circuit affects cocaine‐induced locomotion. Cocaine‐induced locomotor activity and dopamine release were suppressed by the activation of the LH with 2‐[2,6‐difluoro‐4‐[[2‐[(phenylsulfonyl)amino]ethyl]thio]phenoxy]acetamide (PEPA), an AMPA receptor agonist. When the LH was inhibited by microinjection of a GABA receptor agonists mixture prior to cocaine injection, the cocaine's effects were enhanced. Furthermore, optogenetic activation of the LH‐LHb circuit attenuated the cocaine‐induced locomotion, while optogenetic inhibition of the LH‐LHb circuit increased it. In vivo extracellular recording found that the LH sent a glutamatergic projection to the LHb. These findings suggest that the LH glutamatergic projection to the LHb plays an active role in the modulation of cocaine‐induced psychomotor responses. [ABSTRACT FROM AUTHOR]

Background and objects: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) are often old and poor in physical fitness. The purpose of this study was to investigate the anesthetic effect of different doses of alfentanil combined with ciprofol in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Methods: In this clinical trial, 137 patients, who were candidates for ERCP were randomly divided into three groups. Group A were given 0.15 μg/kg/min of alfentanil in maintenance stage, Group B were given 0.25 μg/kg/min and Group C were given 0.35 μg/kg/min. Mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SpO2) of the patients at each time point including the entry into the operation room (T0), at the beginning of surgery(T1), 10 min after surgery(T2), 20 min after surgery(T3), 30 min after surgery(T4),endoscopy withdrawal (T5) were recorded. Adverse events(including respiratory depression, body movement and hypoxemia),the dosage of ciprofol, the time of operation time and awakening were recorded. Results: Compared with Group A, MAP and HR in Group B and Group C was decreased during T1-T5 (P < 0.05). Compared with group B, MAP and HR in group C was decreased during T1-T5 (P < 0.05). Compared with Group A and Group C,the number of adverse reactions of Group B was decreased(P < 0.05). There was no statistical difference in surgical time among the three groups(P > 0.05),but a statistically significant difference in recovery time (P < 0.05). Conclusion: The adverse events of alfentanil 0.25μg/kg/min combined with ciprofol were low, and the anesthetic effect was the best. [ABSTRACT FROM AUTHOR]

Depression is characterized by a feeling of sadness and a lack of pleasure, with impaired daily functioning and poor quality of life. The neurobiology and the pathogenesis of depression are not fully understood yet. Several hypotheses have been discussed including, monoamine theory, neurotransmission, oxidation, inflammation, glutamatergic transmission, neurotrophic factors, and others. Reviewing three decades of randomized controlled trials of antidepressants revealed that the antidepressants response rate is about 54% compared to a placebo response rate of 37%. Treatment-resistant depression (TRD) could be defined as an inadequate response to two different of antidepressants. In TRD, a combination strategy of using two FDA-approved antidepressants is used, which may predispose patients to adverse effects. Therefore, there is a compelling need to explore the potential "out of the box" adjuvants to antidepressants to provide higher and consistent response rates with high tolerability. These adjuvants could be medications available for other indications, food supplements, or even experimental drugs. This review will highlight potentially beneficial adjuvants to antidepressants such as nitric oxide modulators, NMDA antagonists, anti-inflammatory, antioxidants, mitochondrial modulators, insulin sensitizers, opioids, probiotics, and GABA agonists. [ABSTRACT FROM AUTHOR]

Background: Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including Parkinson's disease (PD). SDs during the prodromal phase could result from neurodegeneration induced in state-controlling neurons by accumulation of α-syn predominant early in the disease, and consistent with this, we reported the monomeric form of α-syn (monomeric α-syn; α-synM) caused cell death in the laterodorsal tegmental nucleus (LDT), which controls arousal as well as the sleep and wakefulness state. However, we only examined the male LDT, and since sex is considered a risk factor for the development of α-syn-related diseases including prodromal SDs, the possibility exists of sex-based differences in α-synM effects. Accordingly, we examined the hypothesis that α-synM exerts differential effects on membrane excitability, intracellular calcium, and cell viability in the LDT of females compared to males. Methods: Patch clamp electrophysiology, bulk load calcium imaging, and cell death histochemistry were used in LDT brain slices to monitor responses to α-synM and effects of GABA receptor acting agents. Results: Consistent with our hypothesis, we found differing effects of α-synM on female LDT neurons when compared to male. In females, α-synM induced a decrease in membrane excitability and heightened reductions in intracellular calcium, which were reliant on functional inhibitory acid transmission, as well as decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a concurrent reduction in action potential firing rate. Cell viability studies showed higher α-synM-mediated neurodegeneration in males compared to females that depended on inhibitory amino acid transmission. Further, presence of GABA receptor agonists was associated with reduced cell death in males. Conclusions: When taken together, we conclude that α-synM induces a sex-dependent effect on LDT neurons involving a GABA receptor-mediated mechanism that is neuroprotective. Understanding the potential sex differences in neurodegenerative processes, especially those occurring early in the disease, could enable implementation of sex-based strategies to identify prodromal PD cases, and promote efforts to illuminate new directions for tailored treatment and management of PD. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) is an essential neurotransmitter and an important regulator of neuroinflammation and disease. Microglia are important immune cells in the brain that express GABA receptors (GABAR) and respond to both GABA and GABAR agonists, yet the effect of GABA on microglial inflammatory responses is unclear. We hypothesized that GABA and GABAR agonists might modify the activation of a human microglial cell line (HMC3). We further hypothesized that Amanita muscaria extract (AME-1), which contained GABAR agonists (GABA and muscimol), would similarly stimulate HMC3. Ligand-gated GABAR (GABAAR) and G protein-coupled GABAR (GABABR) subunit expression was analyzed by qRT-PCR, metabolic activity was determined by nicotinamide adenine dinucleotide (NADH)-dependent oxidoreductase assay (XTT), reactive oxygen species (ROS) generation was analyzed by 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA), and interleukin-8 (IL-8) production was analyzed by an enzyme-linked immunosorbent assay (ELISA). HMC3 expressed several neuroreceptors such as subunits of the GABAA receptor (GABAAR). HMC3 constitutively produce IL-8 and ROS. Both muscimol and GABA stimulated HMC3 to produce more IL-8 but had no effect on constitutive ROS production. GABA and muscimol altered the morphology and Iba1 localization of HMC3. GABA, but not muscimol, increased HMC3 metabolic activity. Similarly, AME-1 induced HMC3 to produce more IL-8 but not ROS and altered cell morphology and Iba1 localization. GABA induction of IL-8 was blocked by bicuculline, an antagonist of GABAAR. AME-1-induced production of IL-8 was not blocked by bicuculline, suggesting that AME-1's effect on HMC3 was independent of GABAAR. In conclusion, these data show that GABA and GABA agonists stimulate HMC3 to increase their production of IL-8. Mixtures that contain GABA and muscimol, such as AME-1, have similar effects on HMC3 that are independent of GABAAR. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepine receptor agonists (BZRAs) are commonly prescribed in older adults despite an unfavorable risk–benefit ratio. Hospitalizations may provide a unique opportunity to initiate BZRA cessation, yet little is known about cessation during and after hospitalization. We aimed to measure the prevalence of BZRA use before hospitalization and the rate of cessation 6 months later, and to identify factors associated with these outcomes. Methods: We conducted a secondary analysis of a cluster randomized controlled trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly [OPERAM]), comparing usual care and in-hospital pharmacotherapy optimization in adults aged 70 years or over with multimorbidity and polypharmacy in four European countries. BZRA cessation was defined as taking one or more BZRA before hospitalization and not taking any BZRA at the 6-month follow-up. Multivariable logistic regression was performed to identify factors associated with BZRA use before hospitalization and with cessation at 6 months. Results: Among 1601 participants with complete 6-month follow-up data, 378 (23.6%) were BZRA users before hospitalization. Female sex (odds ratio [OR] 1.52 [95% confidence interval 1.18–1.96]), a higher reported level of depression/anxiety (OR up to 2.45 [1.54–3.89]), a higher number of daily drugs (OR 1.08 [1.05–1.12]), use of an antidepressant (OR 1.74 [1.31–2.31]) or an antiepileptic (OR 1.46 [1.02–2.07]), and trial site were associated with BZRA use. Diabetes mellitus (OR 0.60 [0.44–0.80]) was associated with a lower probability of BZRA use. BZRA cessation occurred in 86 BZRA users (22.8%). Antidepressant use (OR 1.74 [1.06–2.86]) and a history of falling in the previous 12 months (OR 1.75 [1.10–2.78]) were associated with higher BZRA cessation, and chronic obstructive pulmonary disease (COPD) (OR 0.45 [0.20–0.91]) with lower BZRA cessation. Conclusion: BZRA prevalence was high among included multimorbid older adults, and BZRA cessation occurred in almost a quarter of them within 6 months after hospitalization. Targeted BZRA deprescribing programs could further enhance cessation. Specific attention is needed for females, central nervous system-acting co-medication, and COPD co-morbidity. Registration: ClinicalTrials.gov identifier: NCT02986425. December 8, 2016. [ABSTRACT FROM AUTHOR]

Impairment of excretion and enzymatic processing of nitrogen, for example, because of liver or kidney failure, or with urea cycle and creatine synthesis enzyme defects, surprisingly leads to primarily neurologic symptoms, yet the exact mechanisms remain largely mysterious. In guanidinoacetate N‐methyltransferase (GAMT) deficiency, the guanidino compound guanidinoacetate (GAA) increases dramatically, including in the cerebrospinal fluid (CSF), and has been implicated in mediating the neurological symptoms in GAMT‐deficient patients. GAA is synthesized by arginine–glycine amidinotransferase (AGAT), a promiscuous enzyme that not only transfers the amidino group from arginine to glycine, but also to primary amines in, for example, GABA and taurine to generate γ‐guanidinobutyric acid (γ‐GBA) and guanidinoethanesulfonic acid (GES), respectively. We show that GAA, γ‐GBA, and GES share structural similarities with GABA, evoke GABAA receptor (GABAAR) mediated currents (whereas creatine [methylated GAA] and arginine failed to evoke discernible currents) in cerebellar granule cells in mouse brain slices and displace the high‐affinity GABA‐site radioligand [3H]muscimol in total brain homogenate GABAARs. While γ‐GBA and GES are GABA agonists and displace [3H]muscimol (EC50/IC50 between 10 and 40 μM), GAA stands out as particularly potent in both activating GABAARs (EC50 ~6 μM) and also displacing the GABAAR ligand [3H]muscimol (IC50 ~3 μM) at pathophysiologically relevant concentrations. These findings stress the role of substantially elevated GAA as a primary neurotoxic agent in GAMT deficiency and we discuss the potential role of GAA in arginase (and creatine transporter) deficiency which show a much more modest increase in GAA concentrations yet share the unique hyperexcitability neuropathology with GAMT deficiency. We conclude that orthosteric activation of GABAARs by GAA, and potentially other GABAAR mimetic guanidino compounds (GCs) like γ‐GBA and GES, interferes with normal inhibitory GABAergic neurotransmission which could mediate, and contribute to, neurotoxicity. [ABSTRACT FROM AUTHOR]

In the present study, long-chain acyl-CoA synthetase 6 (ACSL6), a lipid metabolizing enzyme responsible for channeling the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into neuronal membranes, was deleted exclusively in mouse dopaminergic neurons. B Front cover b Cellular memory can be defined as an inheritable cellular feature that maintains a unique gene expression pattern from a mother cell to daughter cells after cell division. We identified oligodendrocyte transcription factor2 OLIG2 as an I in vivo i bookmarking transcription factor in developing neural tubes of mice. [Extracted from the article]

[Display omitted] • Grin1 deletion in prospective parvalbumin interneurons reduces unitary GABA release. • Grin1 deletion in parvalbumin neurons impairs membrane properties and excitability. • No effect of Cav2.1 channel agonist on GABA release from Grin1 -deleted neurons. • Cav2.1-haploinsufficient parvalbumin neurons produce a similar GABA release deficit. • Grin1 deletion using parvalbumin promoter causes generally normal GABA release. N -methyl-D-aspartate receptor (NMDAR) hypofunction during brain development is likely to contribute to the manifestation of schizophrenia (SCZ) in young adulthood. The cellular targets of NMDAR hypofunction appear to be at least in part corticolimbic fast-spiking (FS) interneurons. However, functional alterations in parvalbumin (PV)-positive FS interneurons following NMDAR hypofunction are poorly understood. Paired patch-clamp recordings from murine cortical PV interneurons and pyramidal neurons revealed that genetic deletion of NMDAR subunit Grin1 in prospective PV interneurons before the second postnatal week impaired evoked- and synchronized-GABA release. Whereas intrinsic excitability and spiking characteristics were also disturbed by Grin1 deletion, neither restoring their excitability by K+ channel blockade nor increasing extracellular Ca2+ rescued the GABA release. GABA release was also insensitive to the Cav2.1 channel antagonist ω-agatoxin IVA. Heterozygous deletion of Cacna1a gene (encoding Cav2.1) in PV interneurons produced a similar GABA release phenotype as the Grin1 mutants. Treatment with the Cav2.1/2.2 channel agonist GV-58 augmented somatic Ca2+ currents and GABA release in Cacna1a -haploinsufficient PV interneurons, but failed to enhance GABA release in the Grin1 -deleted PV interneurons. Taken together, our results suggest that Grin1 deletion in prospective PV interneurons impairs proper maturation of membrane excitability and Cav2.1-recruited evoked GABA release. This may increase synaptic excitatory/inhibitory ratio in principal neurons, contributing to the emergence of SCZ-like phenotypes. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) leads to severe motor and sensory functional impairments that affect personal and social behaviors. Medical advancements have improved supportive therapeutic measures for SCI patients, but no effective neuroregenerative therapeutic options exist to date. Deficits in motor function are the most visible consequence of SCI. However, other complications, as spasticity, produce a significant impact on SCI patient's welfare. Baclofen, a GABA agonist, is the most effective drug for spasticity treatment. Interestingly, emerging data reveals that baclofen can also play a role on neuroprotection and regeneration after SCI. The goal of this study was to understand the potential of baclofen as a treatment to promote recovery after SCI. We used a pre-clinical SCI mouse model with the administration of baclofen 1 mg/Kg at different time-points after injury. Behavior analysis (locomotor and bladder function) were performed during nine weeks of the in vivo experiment. Afterwards, spinal cords were collected and processed for histological and molecular analysis. Our data showed that baclofen leads to locomotor improvements in mice when its administered acutely after SCI. Moreover, baclofen administration also led to improved bladder function control in all experimental groups. Interestingly, acute baclofen administration modulates microglia activation state and levels of circulating chemokines and cytokines, suggesting a putative role of baclofen in the modulation of the immune response. Although further studies must be performed to understand the mechanisms that underlie the functional improvements produced by baclofen, our data shed light into the pharmacological potential of baclofen to promote recovery after SCI. Our outcomes revealed that baclofen, a well-known drug used for spasticity management, improves the motor performance after SCI in a pre-clinical animal model. Our data opens new avenues for pharmacological strategies design to promote SCI recovery. [ABSTRACT FROM AUTHOR]

Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products Administration and the information of official website, indications for ciprofol include sedation and anesthesia during the surgical/procedure of nontracheal intubation, induction and maintenance of general anesthesia, and sedation during intensive care. Ciprofol is a short-acting intravenous sedative based on the structural modification of propofol. Ciprofol has high efficacy, good selectivity, and fewer adverse reactions, indicating good clinical application potential. A series of clinical studies have been conducted to evaluate the sedative effect of ciprofol in various procedures and settings, including gastroscopy and colonoscopy, fiber-optic bronchoscopy, general anesthesia in elective surgeries, and mechanical ventilation in intensive care units. This review summarizes the chemical structure, pharmacodynamics, and pharmacokinetic properties of ciprofol. We also assessed the efficacy and safety of ciprofol by synthesizing the relevant clinical trial data. [ABSTRACT FROM AUTHOR]

Ocean acidification is considered to affect fish behaviour through the disruption of GABAergic neurotransmission in controlled laboratory conditions, but less is known of the GABAergic role on fish behavioural performance in the wild. Most coral reef fishes engage in complex cleaning interactions, where they benefit from ectoparasite removal and stress relief. Here, we tested whether potential ocean acidification impairment of wild cleaning interactions, between the cleaner fish Labroides dimidiatus and its clients, can be explained by the GABA A R model. We used, the GABA A receptor agonist (muscimol) and antagonist (gabazine) for the first time in the wild and tested their effects on cleaning behaviour in Moorea Island (French Polynesia) to address natural interactions and recovery capacity. After exposure to expected ocean acidification conditions, the proportion of time spent advertising cleaning services, a measure of motivation to interact, dropped significantly relative to controls. Furthermore, the GABAergic antagonist gabazine recovered most CO 2 -induced behavioural alterations to control levels, consistent with the GABA A R model of altered Cl− flux in ocean acidification-exposed fish. However, muscimol treatment only produced the same behavioural alterations found with CO 2 exposure in time spent advertising cleaning. Our results support the evidence that ocean acidification alters some components of cleaning behaviour through GABA A receptor modulation with potential cascading effects on coral reef health and structure. • First study on ocean acidification effects on cleaning behaviour in the wild. • Ocean acidification alters some components of natural cleaning behaviour. • GABA A receptor modulation is a mechanism responsible for these alterations. [ABSTRACT FROM AUTHOR]

• Spinal disinhibition allows activation of microglia by normally innocuous stimuli. • Spinal microglia mediate the transition to a nociplastic pain state in males. • The ATP-P2X4 pathway is pivotal for the transition to male nociplastic pain. • Proinflammatory cytokines at a spinal level mediate male nociplastic pain. Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia. [ABSTRACT FROM AUTHOR]

What is already known and objective: Sedation is routinely provided for patients undergoing gastrointestinal endoscopy. Remimazolam tosilate is a novel and short‐acting sedative agent that has been used for sedation during endoscopic procedures. The optimal dose of remimazolam in gastrointestinal endoscopy for patients with liver cirrhosis has not been elucidated. Background: To determine the effective dose of remimazolam tosilate with adjuvant sufentanil for sedation in patients with liver cirrhosis undergoing oesophagogastric varices screening endoscopy. Material and Methods: Patients aged 18–65 years with liver cirrhosis undergoing screening endoscopy for oesophagogastric varices were recruited. Sufentanil 0.15 μg/kg was given intravenously at 2 min before administration of remimazolam tosilate. The initial dose of remimazolam was 0.1 mg/kg and adjusted by 0.025 mg/kg as a step size, based on the Dixon and Massay up‐and‐down sequential method. Inclusion of patients was stopped after eight crossovers and the calculated median effective dose (ED50) of remimazolam for successful endoscopy was obtained by calculating the mean of midpoint of all crossovers. Furthermore, a probit regression was applied to establish the dose–response curve of remimazolam and further assess the 95% effective dose (ED95) of remimazolam. Results: The calculated ED50 of remimazolam for successful endoscopy using the mean of midpoint of all crossovers was 0.097 mg/kg (95% CI, 0.004–0.099 mg/kg). Using the probit regression analysis, the ED50 and ED95 of remimazolam for successful endoscopy was 0.097 mg/kg (95% CI, 0.004–0.099 mg/kg) and 0.107 mg/kg (95% CI, 0.103–0.336 mg/kg), respectively. No adverse events were observed throughout the study period. Conclusions: This pilot study suggests that the ED50 and ED95 of remimazolam tosilate with adjuvant sufentanil for sedation in liver cirrhosis patients undergoing oesophagogastric varices screening endoscopy was 0.097 and 0.107 mg/kg, respectively. [ABSTRACT FROM AUTHOR]

GABA (γ-aminobutyric acid) receptors are constituents of many inhibitory synapses within the central nervous system. They are formed by 5 subunits out of 19 various subunits: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3. Two main subtypes of GABA receptors have been identified, namely GABAA and GABAB. The GABAA receptor (GABAAR) is formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel. Other subunits are γ, δ, ε, π, and ϴ. GABAAR has many isoforms, that dictate, among other properties, their differing affinities and conductance. Drugs acting on GABAAR form the cornerstone of anesthesia and sedation practice. Some such GABAAR agonists used in anesthesia practice are propofol, etomidate, methohexital, thiopental, isoflurane, sevoflurane, and desflurane. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors—mainly NMDA receptors. Inspite of its many drawbacks such as pain in injection, quick and uncontrolled conversion from sedation to general anesthesia and dose-related cardiovascular depression, propofol remains the most popular GABAR agonist employed by anesthesia providers. In addition, being formulated in a lipid emulsion, contamination and bacterial growth is possible. Literature is rife with newer propofol formulations, aiming to address many of these drawbacks, and with some degree of success. A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility. Inhalational anesthetics are also GABA agonists. The binding sites are primarily located within α+/β− and β+/α− subunit interfaces, with residues in the α+/γ− interface. Isoflurane and sevoflurane might have slightly different binding sites providing unexpected degree of selectivity. Methoxyflurane has made a comeback in Europe for rapid provision of analgesia in the emergency departments. Penthrox (Galen, UK) is the special device designed for its administration. With better understanding of pharmacology of GABAAR agonists, newer sedative agents have been developed, which utilize “soft pharmacology,” a term pertaining to agents that are rapidly metabolized into inactive metabolites after producing desired therapeutic effect(s). These newer “soft” GABAAR agonists have many properties of ideal sedative agents, as they can offer well-controlled, titratable activity and ultrashort action. Remimazolam, a modified midazolam and methoxycarbonyl-etomidate (MOC-etomidate), an ultrashort-acting etomidate analog are two such examples. Cyclopropyl methoxycarbonyl metomidate is another second-generation soft etomidate analog that has a greater potency and longer half-life than MOC-etomidate. Additionally, it might not cause adrenal axis suppression. Carboetomidate is another soft analog of etomidate with low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Alphaxalone, a GABAAR agonist, is recently formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile. [ABSTRACT FROM AUTHOR]

Background: Gamma-aminobutyric acid (GABA) analogs are being used by an increasing number of reproductive-age women. However, there is concern regarding the teratogenic potential of GABA analogs. Methods: We performed this systematic review and meta-analysis to assess the relationship between GABA analog exposure and risk of adverse neonatal outcomes. Results: Eight cohort studies were included in the meta-analysis. Exposure to a GABA analog during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 1.19, 95% confidence interval [CI] 0.96–1.46, P = 0.106) or a small for gestational age (SGA) infant (OR 1.99, 95% CI 0.78–5.1, P = 0.152) compared to no exposure. However, exposure to a GABA analog was associated with an increased risk of preterm birth (PB) (OR 1.56, 95% CI 1.04–2.35, P = 0.033), spontaneous abortion (SA) (OR 1.64, 95% CI 1.14–2.38, P = 0.008), or termination of pregnancy (TOP) (OR 3.02, 95% CI 2–4.56, P < 0.001). Conclusion: Exposure to GABA analogs during pregnancy does not appear to be associated with congenital malformation, although there was some evidence of a higher risk of several other negative neonatal outcomes. Given the few studies included, larger prospective studies controlling for important confounders are needed to verify our findings. [ABSTRACT FROM AUTHOR]

• L. augustifolia is a proven anticonvulsant, anxiolytic, and antidepressant plant. • Computational screening was performed for the plant bioactive compounds. • Swertianolin was found to be the potent drug against three target enzymes. • Swertianolin also clears druglikeliness and pharmacokinetic evaluations. In the present study, we evaluate the pharmacological significance of phytoconstituents derived from Lavandula angustifolia with respect to anticonvulsant, antidepressant, and anxiolytic activities using in silico approach against human GABA A R-beta3 receptor, human serotonin transporter, and human potassium channel KCSA-FAB, respectively. Through in silico approach we performed molecular docking simulations, molecular dynamics simulations, binding free energy calculations, and ADMET analysis. In the context, swertianolin, a xanthone heterocyclic compound proved to be an efficient agonist of human GABA A R-beta3 receptor, and inhibitor of both human serotonin transporter, and human potassium channel KCSA-FAB. During molecular docking simulation, swertianolin showed lower binding affinities compared to all the three standard drug controls (methaqualone, paroxetine, and diazepam) used. It also proved its stability to remain in the binding pocket to induce the pharmacological action for extended period of time compared to the standard control drugs. Binding free energy calculations reveal that binding complex of swertianolin was stronger than the respective standard drug controls of the three target proteins. In addition, ADMET analysis of swertianolin predicted zero toxic activity and no negative effect on body metabolism. Therefore, being a site-specific, functionally stable, and null toxic effects on body metabolism, swertianolin could be a better neuromodulator in near future. [ABSTRACT FROM AUTHOR]

Background: Ciprofol is a recently developed, short-acting γ-aminobutyric acid receptor agonist sedative that is more potent than propofol, but there have been few clinical studies of this agent to date. Here, we sought to examine the safety and efficacy of ciprofol use for the induction of general anesthesia in individuals undergoing gynecological surgery. Methods: Women between the ages of 18 and 60 years (ASA physical status 1 or 2) who were scheduled to undergo elective gynecological surgery under general anesthesia were randomly assigned to two equally sized groups in which anesthesia induction was performed using either ciprofol or propofol. General anesthesia induction success rates were the primary outcome for this study, while secondary outcomes included changes in BIS during the 10 min following the first administration of the study drug, the duration of successful induction, and adverse event incidence. Results: A total of 120 women were included in the study. A 100% rate of successful induction was achieved in both the ciprofol and propofol groups, with no significant differences between these groups with respect to the duration of successful induction (34.8 ± 15.5 s vs 35.4 ± 9.5 s, P = 0.832), the time to the disappearance of the eyelash reflex (33.7 ± 10.6 s vs 34.0 ± 6.5 s, P = 0.860), or tracheal intubation (58.2 ± 31.1 s vs 53.9 ± 25.4 s, P = 0.448). Adverse event rates, including intubation responses, were significantly lower in the ciprofol group as compared to the propofol group(20% vs 48.33%, P = 0.0019). Ciprofol was associated with reduced injection pain relative to propofol (16.7% vs 58.3%, P < 0.001). Conclusions: Ciprofol exhibits comparable efficacy to that of propofol when used for the induction of general anesthesia in individuals undergoing gynecological surgery and is associated with fewer adverse events. [ABSTRACT FROM AUTHOR]

Introduction: Long‐term benzodiazepine receptor agonist (BZRA) use persists in healthcare settings worldwide and poses risks of patient harm. Objective: This study aimed to develop an intervention to support discontinuation of long‐term BZRA use among willing individuals. Methods: The intervention development process aligned with the UK Medical Research Council's complex intervention framework. This involved a previous systematic review of brief interventions targeting long‐term BZRA use in primary care and qualitative interviews based on the Theoretical Domains Framework that explored barriers and facilitators to discontinuing long‐term BZRA use. A codesign approach was used involving an active partnership between experts by experience, researchers and clinicians. Intervention content was specified in terms of behaviour change techniques (BCTs). Results: The SAFEGUARDING‐BZRAs (Supporting sAFE and GradUAl ReDuctIon of loNG‐term BenZodiazepine Receptor Agonist uSe) toolkit comprises 24 BCTs and includes recommendations targeted at primary care‐based clinicians for operationalizing each BCT to support individuals with BZRA discontinuation. Conclusion: The SAFEGUARDING‐BZRAs toolkit has been developed using a systematic and theory‐based approach that addresses identified limitations of previous research. Further research is needed to assess its usability and acceptability by service users and clinicians, as well as its potential to effectively support safe and gradual reduction of long‐term BZRA use. Patient or Public Contribution: The qualitative interview phase included patients as participants. The codesign process included 'experts by experience' with either current or previous experience of long‐term BZRA use as collaborators. [ABSTRACT FROM AUTHOR]

GABAA receptors are a major contributor to fast inhibitory neurotransmission in the brain. The receptors are activated upon binding the transmitter GABA or allosteric agonists including a number of GABAergic anesthetics and neurosteroids. Functional receptors can be formed by various combinations of the nineteen GABAA subunits cloned to date. GABAA receptors containing the ε subunit exhibit a significant degree of constitutive activity and have been suggested to be unresponsive to allosteric agents. In this study, we have characterized the functional properties of the rat α1β2ε GABAA receptor. We confirm that the α1β2ε receptor exhibits a higher level of constitutive activity than typical of GABAA receptors and show that it is inefficaciously activated by the transmitter and the allosteric agonists propofol, pentobarbital, and allopregnanolone. Manipulations intended to alter ε subunit expression and receptor stoichiometry were largely without effect on receptor properties including sensitivity to GABA and allosteric agonists. Surprisingly, amino acid substitutions at the conserved 9' and 6' positions in the second transmembrane (TM2) domain in the ε subunit did not elicit the expected functional effects of increased constitutive activity and resistance to the channel blocker picrotoxin, respectively. We tested the accessibility of TM2 residues mutated to cysteine using the cysteine-modifying reagent 4-(hydroxymercuri)benzoic acid and found a unique pattern of water-accessible residues in the ε subunit. [ABSTRACT FROM AUTHOR]

• α4βδ GABA A receptors increase at puberty in layer 3 male prelimbic cortex. • Targeting these receptors with drugs or by knock-out alters spine pruning. • α4 knock-out increases spines and impairs temporal order memory. • An α4βδ agonist decreases spines and impairs temporal order memory. • These findings may be relevant for ASD and SCZ where spine density/recency memory are abnormal. Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4βδ GABA A receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4βδ receptors also increase at puberty in L3 PL (P < 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4βδ, reduced L3 spine density by half (P < 0.0001), while α4 knock-out increased spine density ∼ 40 % (P < 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: −0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; −0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P < 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4βδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders. [ABSTRACT FROM AUTHOR]

North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3–5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABA A receptors. This suggests that GABA A could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies. • Progressive Myoclonus Epilepsies (PME) are notoriously difficult to treat. • This study evaluates ASMs in a validated North Sea-PME (NS-PME) Drosophila model. • GABA A agonists significantly suppress seizures in a NS-PME Drosophila model. • A new GABA A agonist ganaxolone effectively suppresses seizures in NS-PME Drosophila. • Ganaxolone could be a potential new treatment for NS-PME and other PMEs. [ABSTRACT FROM AUTHOR]

Abl2/Arg (ABL-related gene) is a member of the Abelson family of nonreceptor tyrosine kinases, known for its role in tumor progression, metastasis, tissue injury responses, inflammation, neural degeneration, and other diseases. In this study, we developed Abl2/Arg knockout (abl2 -/- ) mice to explore its impact on sensory/motor functions and emotion-related behaviors. Our findings show that abl2 -/- mice exhibit normal growth and phenotypic characteristics, closely resembling their wild-type (WT) counterparts. Behavioral tests, including the elevated plus maze, marble-burying behavior test, and open field test, indicated pronounced anxiety-like behaviors in abl2 -/- mice compared to WT mice. Furthermore, in the tail suspension test, abl2 -/- mice showed a significant decrease in mobility time, suggesting depressive-like behavior. Conversely, in the Y-maze and cliff avoidance reaction tests, no notable differences were observed between abl2 -/- and WT mice, suggesting the absence of working memory deficits and impulsivity in abl2 -/- mice. Proteomic analysis of the hippocampus in abl2 -/- mice highlighted significant alterations in proteins related to anxiety and depression, especially those associated with the GABAergic synapse in inhibitory neurotransmission. The expression of Gabbr2 was significantly reduced in the hippocampus of abl2 -/- compared to WT mice, and intraperitoneal treatment of GABA receptor agonist Gaboxadol normalized anxiety/depression-related behaviors of abl2 -/- mice. These findings underscore the potential role of Abl2/Arg in influencing anxiety and depressive-like behaviors, thereby contributing valuable insights into its broader physiological and pathological functions. [ABSTRACT FROM AUTHOR]

Summary: Objective: Stiripentol (STP; Diacomit®) is an antiepileptic drug indicated for Dravet syndrome that has been identified as a γ‐aminobutyric acid (GABAergic) positive allosteric modulator. Dravet syndrome is characterized by multiple seizure types: generalized tonic–clonic, focal, myoclonic, and absence seizures. In addition to its antiepileptic effects on tonic–clonic seizures, STP has also been reported to reduce the frequency of atypical absence seizures in patients. Our study focused on STP potential effects on absence seizures, to better characterize its full spectrum of mechanisms of action. Methods: STP effects on absence seizures were quantified by electroencephalographic recording in two animal models: rats treated with a low dose of pentylenetetrazol (20 mg/kg ip) and rats from the WAG/Rij strain. In addition, we characterized STP effects on T‐type calcium channel activity. Peak currents were recorded with manual patch clamp on cells transfected with cDNA encoding for the human isoform for Cav3.1, Cav3.2, and Cav3.3. Results: STP administered before pentylenetetrazol almost completely abolished the generation of spike‐and‐wave discharges (SWDs) at the dose of 300 mg/kg. At this dose, STP also statistically significantly decreased SWD cumulated duration and number in WAG/Rij rats. Its antiepileptic effect was maintained in WAG/Rij rats, whose seizures were aggravated by the GABA agonist THIP (gaboxadol hydrochloride). Furthermore, electrophysiological recordings showed that STP inhibits T‐type calcium channel peak activity, with a higher specificity for the Cav3.3 subtype. Significance: In addition to its previously characterized anticonvulsive properties, these data highlight a new mechanism of action of STP on abnormal thalamocortical activity. This strong antiabsence effect on seizures is correlated with an inhibition of T‐type calcium channels. This new mechanism of action could be implicated in the specificity of STP therapeutic effects in Dravet syndrome. [ABSTRACT FROM AUTHOR]

The medial orbitofrontal cortex (mOFC) regulates a variety of cognitive functions, including re→ning action selection involving reward uncertainty. This region sends projections to numerous subcortical targets, including the ventral and dorsal striatum, yet how these corticostriatal circuits differentially regulate risk/reward decision-making is unknown. The present study examined the contribution of mOFC circuits linking the nucleus accumbens (NAc) and dorsomedial striatum (DMS) to risk/ reward decision-making using pharmacological disconnections. Male rats were well trained on a probabilistic discounting task involving choice between small/certain or large/risky rewards, with the probability of obtaining the larger reward decreasing or increasing over a session. Disconnection of mOFC-striatal pathways was achieved using infusions of GABA agonists inactivating the mOFC in one hemisphere, combined with NAc or DMS inactivation in the contralateral or ipsilateral hemisphere. Perturbing mOFC → NAc circuits induced suboptimal, near-random patterns of choice that manifested as a flattening of the discounting curve. Animals were equally likely to stay or shift following rewarded/nonrewarded choices, suggesting this pathway mediates use of information about reward history to stabilize decision biases. In contrast, mOFC → DMS disconnection impaired adjustments in decision biases, causing opposing changes in risky choice depending on how probabilities varied over time. This was driven by alterations in lose-shift behavior, suggesting mOFC → DMS circuits track volatility in nonrewarded actions to adjust choice in accordance with changes in pro→tability. Thus, separate mOFC-striatal projection pathways regulate dissociable processes underlying decision-making, with mOFC → NAc circuits aiding in establishing and stabilizing tasks states and mOFC → DMS circuits facilitating transitions across states to promote flexible reward seeking. [ABSTRACT FROM AUTHOR]

Background: Difficulty using the upper-limb is a major barrier to independence for many patients post-stroke or brain injury. High dose rehabilitation can result in clinically significant improvements in function even years after the incident; however, there is still high variability in patient responsiveness to such interventions that cannot be explained by age, sex, or time since stroke. Methods: This retrospective study investigated whether patients prescribed certain classes of central nervous system-acting drugs—γ-aminobutyric acid (GABA) agonists, antiepileptics, and antidepressants—differed in their outcomes on the three-week intensive Queen Square Upper-Limb program. For 277 stroke or brain injury patients (167 male, median age 52 years (IQR: 21), median time since incident 20 months (IQR: 26)) upper-limb impairment and activity was assessed at admission to the program and at six months post-discharge, using the upper limb component of the Fugl-Meyer, Action Research Arm Test, and Chedoke Arm and Hand Activity Inventory. Drug prescriptions were obtained from primary care physicians at referral. Specification curve analysis was used to protect against selective reporting results and add robustness to the conclusions of this retrospective study. Results: Patients with GABA agonist prescriptions had significantly worse upper-limb scores at admission but no evidence for a significant difference in program-induced improvements was found. Additionally, no evidence of significant differences in patients with or without antiepileptic drug prescriptions on either admission to, or improvement on, the program was found in this study. Although no evidence was found for differences in admission scores, patients with antidepressant prescriptions experienced reduced improvement in upper-limb function, even when accounting for anxiety and depression scores. Conclusions: These results demonstrate that, when prescribed typically, there was no evidence that patients prescribed GABA agonists performed worse on this high-intensity rehabilitation program. Patients prescribed antidepressants, however, performed poorer than expected on the Queen Square Upper-Limb rehabilitation program. While the reasons for these differences are unclear, identifying these patients prior to admission may allow for better accommodation of differences in their rehabilitation needs. [ABSTRACT FROM AUTHOR]

Background: Enteric neurons undergo to functional changes during aging. We investigated the possible age‐associated differences in enteric γ‐aminobutyric acid (GABA)ergic transmission evaluating function and distribution of GABAergic receptors in human colon. Methods: Mechanical responses to GABA and GABA receptor agonists on slow phasic contractions were examined in vitro as changes in isometric tension in colonic muscle strips from young (<65 years old) and aged patients (>65 years old). GABAergic receptor expression was assessed by quantitative RT‐PCR. Key Results: In both preparations GABA induced an excitatory effect, consisting in an increase in the basal tone, antagonized by the GABAA receptor antagonist, bicuculline, and potentiated by phaclofen, GABAB receptor antagonist.Tetrodotoxin (TTX) and atropine‐sensitive contractile responses to GABA and GABAA receptor agonist, muscimol, were more pronounced in old compared to young subjects. Baclofen, GABAB receptor agonist, induced a TTX‐sensitive reduction of the amplitude of the spontaneous. Nω–nitro‐l‐arginine methyl ester (L‐NAME), nitric oxide (NO) synthase inhibitor abolished the inhibitory responses in old preparations, but a residual responses persisted in young preparations, which in turn was abolished by suramin, purinergic receptor antagonist. α3–GABAA receptor subunit expression tends to change in an age‐dependent manner. Conclusions and inferences: Our results reveal age‐related differences in GABAergic transmission in human colon. At all the age tested GABA regulates muscular contractility modulating the activity of the intrinsic neurons. Activation of GABAA receptor, through acetylcholine release, induces contraction, which increases in amplitude with age. GABAB receptor activation leads to neural release of NO and purines, being a loss of purinergic‐component in aged group. [ABSTRACT FROM AUTHOR]

Gabapentinoids are centrally active GABA agonists whose use has increased substantially in the past decade. The current study aimed to provide a comprehensive clinical profile of a national case series of fatal poisonings related to gabapentinoids. Retrospective study of all deaths due to drug toxicity in Australia in which gabapentinoids were a contributory mechanism, retrieved from the National Coronial Information System (2000–2020). Information was collected on case characteristics, toxicology and major organ pathology. A total of 887 cases were identified, with a mean age of 45.7 years and 55.2% being male. Death was due to accidental toxicity in 81.3% of cases and intentional in 18.7%. Pre-existing disease was co-contributory to drug toxicity in 19.5%. Pregabalin was present in 92.9% of cases, with a median blood concentration of 7.6 mg/L (range 0.1–850.0 mg/L). Gabapentin was present in 7.2%, with a median blood concentration of 9.5 mg/L (range 0.5–1940.0 mg/L). Both pregabalin and gabapentin were present in five cases. No other gabapentinoids were detected. Drugs other than gabapentinoids were present in 99.8%, most frequently opioids (90.1%), hypnosedatives (76.9%) and antidepressants (60.5%). A body mass index in the obese range was seen in 45.4%. Clinically significant pre-existing disease was common, notably cardiomegaly (24.9%), emphysema (20.2%), nephrosclerosis (18.7%) and severe hepatic steatosis (11.7%). The concomitant use of other drugs was close to universal, with CNS depressants predominating. Mental health problems, chronic pain and substance misuse were prominent. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis (JE) is a potentially fatal viral infection with a wide range of manifestations and can also present with a variety of movement disorders (MD) including dystonia. Dystonic features in JE are uncommon. Here, we have tried to summarize the clinical features and management of dystonia among JE patients with a comprehensive literature search. Methods: Various databases, including PubMed, Embase, and Google Scholar, were searched against the predefined criteria using suitable keywords combination and boolean operations. Relevant information from observational and case studies was extracted according to the author, dystonic features, radiological changes in the brain scans, treatment options, and outcome wherever provided. Result: We identified 19 studies with a total of 1547 JE patients, the diagnosis of which was confirmed by IgM detection in serum and/or cerebrospinal fluid in the majority of the patients (88.62%). 234 (15.13%) of JE patients had dystonia with several types of focal dystonia being present in 131 (55.98%) either alone or in combination. Neuroimaging showed predominant involvement of thalami, basal ganglia, and brainstem. Oral medications including anticholinergics, GABA agonists, and benzodiazepines followed by botulinum toxin were the most common treatment modalities. Conclusion: Dystonia can be a disabling consequence of JE, and various available medical therapies can significantly improve the quality of life. Owing to insufficient studies on the assessment of dystonia associated with JE, longitudinal studies with a larger number of patients are warranted to further clarify the clinical course, treatment, and outcome of dystonia. [ABSTRACT FROM AUTHOR]

In the present research, the production potential of gamma aminobutyric acid (GABA) using Lactobacillus brevis PML1 was investigated. In addition, the microorganism viability was examined in MAN, ROGOSA, and SHARPE (MRS) after undergoing high hydrostatic pressure at 100, 200, and 300 MPa for 5, 10, and 15 min. Response surface methodology (RSM) was applied to optimize the production conditions of GABA as well as the bacteria viability. Analysis of variance (ANOVA) indicated that both the independent variables (pressure and time) significantly influenced the dependent ones (GABA and bacteria viability) (P < 0.05). The optimum extraction conditions to maximize the production of GABA included the pressure of 300 MPa and the time of 15 min. The amount of the compound was quantified using thin-layer chromatography (TLC) and spectrophotometry. For the process optimization, a central composite design (CCD) was created using Design Expert with 5 replications at the center point, whereby the highest content of GABA was obtained to be 397.73 ppm which was confirmed by high performance liquid chromatography (HPLC). Moreover, scanning electron microscopy (SEM) was utilized to observe the morphological changes in the microorganism. The results revealed that not only did have Lactobacillus brevis PML1 the potential for the production of GABA under conventional conditions (control sample) but also the content of this bioactive compound could be elevated by optimizing the production parameters. [ABSTRACT FROM AUTHOR]

• Olfactory defects in preclinical Alzheimer's disease (AD) can be targeted for effective therapies • Reduced presynaptic inhibitory transmissions in the olfactory bulb (OB) cause olfactory deficits • Increase in GABA A receptor activity rescues inhibitory transmission • Local GABAergic microcircuits in the OB are potential therapeutic targets for AD Olfactory damage develops at the early stages of Alzheimer's disease (AD). While amyloid-β (Aβ) oligomers are shown to impair inhibitory circuits in the olfactory bulb (OB), its underlying mechanisms remain unclear. Here, we investigated the olfactory dysfunction due to impaired inhibitory transmission to mitral cells (MCs) of the OB in APP/PS1 mice. Using electrophysiological studies, we found that MCs exhibited increased spontaneous firing rates as early as 3 months, much before development of Aβ deposits in the brain. Furthermore, the frequencies but not amplitudes of MC inhibitory postsynaptic currents decreased markedly, suggesting that presynaptic GABA release is impaired while postsynaptic GABA A receptor responses remain intact. Notably, muscimol, a GABA A receptor agonist, improved odor identification and discrimination behaviors in APP/PS1 mice, reduced MC basal firing activity, and rescued inhibitory circuits along with reducing the Aβ burden in the OB. Our study links the presynaptic deficits of GABAergic transmission to olfactory dysfunction and subsequent AD development and implicates the therapeutic potential of maintaining local inhibitory microcircuits against early AD progression. [ABSTRACT FROM AUTHOR]

Aging is associated with cognitive impairment, but there are large individual differences in these declines. One neural measure that is lower in older adults and predicts these individual differences is moment-to-moment brain signal variability. Testing the assumption that GABA should heighten neural variability, we examined whether reduced brain signal variability in older, poorer performing adults could be boosted by increasing GABA pharmacologically. Brain signal variability was estimated using fMRI in 20 young and 24 older healthy human adults during placebo and GABA agonist sessions. As expected, older adults exhibited lower signal variability at placebo, and, crucially, GABA agonism boosted older adults' variability to the levels of young adults. Furthermore, poorer performing older adults experienced a greater increase in variability on drug, suggesting that those with more to gain benefit the most from GABA system potentiation. GABA may thus serve as a core neurochemical target in future work on aging- and cognition-related human brain dynamics. [ABSTRACT FROM AUTHOR]

Cough is a common symptom which makes the patient to address for medical attention when it no longer improves and becomes annoying. Cough lasting more than 8 weeks is evaluated as chronic, refractory, idiopathic or unexplained, that does not respond to classic antitussive preparations and requires a differentiated and thorough approach. Cough and non-cough stimuli, including subtreshold, through a series of biological peptides, mediators of inflammation and immune processes, can generate a series of nonspecific mechanisms. In these cases, new strategies are needed based on the elucidation of peripheral and central mechanisms of hypersensitivity to cough. Research on centrally acting neuromodulators – GABA agonists (baclofen), antidepressants (amitriptyline), antiepileptics (gabepentin, pregabalin), potential transient receptor channel antagonists, new tachykin antagonists, P2X3 purinergic receptor blockers (gefapixant), H1-antihistamines and opioids – opens new perspectives in the pharmacotherapy of chronic refractory cough. [ABSTRACT FROM AUTHOR]

Insomnia is a pervasive sleep disorder affecting numerous patients across diverse demographical populations and comorbid disease states. Contributing factors are often a complex interaction of biological, psychological, and social components, requiring a multifaceted approach in terms of both diagnosis and management. In the setting of Alzheimer's disease, insomnia is an even more complicated issue, with a higher overall prevalence than in the general population, greater complexity of contributing etiologies, and differences in diagnosis (at times based on caregiver observation of sleep disruption rather than subjective complaints by the individual with the disorder), and requiring more discretion in terms of treatment, particularly in regard to adverse effect profile concerns. There also is growing evidence of the bidirectional nature of sleep disruption and Alzheimer's disease, with insomnia potentially contributing to disease progression, making the condition even more paramount to address. The objective of this review was to provide the clinician with an overview of treatment strategies that may have value in the treatment of disturbed sleep in Alzheimer's disease. Nonpharmacological approaches to treatment should be exhausted foremost; however, pharmacotherapy may be needed in certain clinical scenarios, which can be a challenge for clinicians given the paucity of evidence and guidelines for treatment in the subpopulation of Alzheimer's disease. Agents such as sedating antidepressants, melatonin, and site-specific γ-aminobutyric acid agonists are often employed based on historical usage but are not necessarily supported by high-quality trials. Newer agents such as dual orexin receptor antagonists have demonstrated some promise but still need further evaluation. [ABSTRACT FROM AUTHOR]

The investigational drug zuranolone improved depressive symptoms relative to placebo for women with postpartum depression, a Phase 3 trial has found. Improvement was seen by day 3 of treatment in the 2‐week trial, and the antidepressant effects persisted through day 45 of follow‐up, the researchers reported. Study results were published online June 30, 2021, in JAMA Psychiatry. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sevoflurane mainly targets GABA receptors while ketamine targets NMDA receptors. • Early-life ketamine resulted in anxiety and depression-like behavior later in life. • Early-life sevoflurane, not ketamine, reduced hippocampal GABAergic inhibition. • Early-life sevoflurane, not ketamine, enhanced induced seizure activity later in life. • Anesthetic receptor targets may determine long-term effects after early-life treatment. Understanding the different mechanisms associated with different anesthetic targeted receptors is critical towards identifying accurate long-term outcome measures as a result of early-life anesthetic exposure. We examined changes in GABA A receptor mediated neurotransmission by a predominately GABA A receptor targeted anesthetic, sevoflurane or a predominately NMDA receptor targeted anesthetic, ketamine. Postnatal day 7 male mice were exposed to sevoflurane or ketamine and examined as adults for changes in inhibitory neurotransmission and its associated change in induced seizure activity. Paired pulse stimulation experiment showed that early-life sevoflurane treated mice had significantly less hippocampal CA1 inhibition later in life. There was significantly increased CA1 excitatory output in the sevoflurane treated group compared to the no sevoflurane treated group after the GABA agonist muscimol. Similar to our previously established data for early-life sevoflurane, here we established early-life ketamine administration resulted in neurodevelopmental behavioral changes later in life. However, muscimol did not produce a significant difference on the excitatory CA1 output between early-life ketamine group and saline group. While sevoflurane treated mice showed significantly higher induced seizure intensities and shorter latency periods to reach seizure intensity stage 5 (Racine score) compared with no sevoflurane treated mice, this phenomenon was not observed in the ketamine vs. saline treated groups. Early-life sevoflurane, but not ketamine, exposure reduced GABAergic inhibition and enhanced seizure activity later in life. The results indicate that early-life exposure to different anesthetics lead to distinct long-term effects and their unique pathways require mechanistic studies to understand induced long-lasting changes in the brain. [ABSTRACT FROM AUTHOR]

Background: Perioperative neurocognitive disorder (PND) is a long-term postoperative complication in elderly surgical patients. The underlying mechanism of PND is unclear, and no effective therapies are currently available. It is believed that neuroinflammation plays an important role in triggering PND. The secreted glycoprotein myeloid differentiation factor 2 (MD2) functions as an activator of the Toll-like receptor 4 (TLR4) inflammatory pathway, and α5GABAA receptors (α5GABAARs) are known to play a key role in regulating inflammation-induced cognitive deficits. Thus, in this study, we aimed to investigate the role of MD2 in PND and determine whether α5GABAARs are involved in the function of MD2.Methods: Eighteen-month-old C57BL/6J mice were subjected to laparotomy under isoflurane anesthesia to induce PND. The Barnes maze was used to assess spatial reference learning and memory, and the expression of hippocampal MD2 was assayed by western blotting. MD2 expression was downregulated by bilateral injection of AAV-shMD2 into the hippocampus or tail vein injection of the synthetic MD2 degrading peptide Tat-CIRP-CMA (TCM) to evaluate the effect of MD2. Primary cultured neurons from brain tissue block containing cortices and hippocampus were treated with Tat-CIRP-CMA to investigate whether downregulating MD2 expression affected the expression of α5GABAARs. Electrophysiology was employed to measure tonic currents. For α5GABAARs intervention experiments, L-655,708 and L-838,417 were used to inhibit or activate α5GABAARs, respectively.Results: Surgery under inhaled isoflurane anesthesia induced cognitive impairments and elevated the expression of MD2 in the hippocampus. Downregulation of MD2 expression by AAV-shMD2 or Tat-CIRP-CMA improved the spatial reference learning and memory in animals subjected to anesthesia and surgery. Furthermore, Tat-CIRP-CMA treatment decreased the expression of membrane α5GABAARs and tonic currents in CA1 pyramidal neurons in the hippocampus. Inhibition of α5GABAARs by L-655,708 alleviated cognitive impairments after anesthesia and surgery. More importantly, activation of α5GABAARs by L-838,417 abrogated the protective effects of Tat-CIRP-CMA against anesthesia and surgery-induced spatial reference learning and memory deficits.Conclusions: MD2 contributes to the occurrence of PND by regulating α5GABAARs in aged mice, and Tat-CIRP-CMA is a promising neuroprotectant against PND. [ABSTRACT FROM AUTHOR]

• Higher GABA receptor expression by skin than masticatory muscle ganglion neurons. • GABA receptor agonists attenuate sensory transmission through the trigeminal ganglion. • Muscle afferent conduction velocity determines response to GABA receptor agonists. • There is a sex-related difference in sensory gating through the ganglion. While the trigeminal ganglion is often considered a passive conduit of sensory transmission, neurons and satellite glial cells (SGCs) within it can release neurotransmitters and express neuroreceptors. Some trigeminal ganglion neurons contain the neurotransmitter γ-aminobutyric acid (GABA) and express GABA receptors. There is behavioral evidence that increased GABA levels in the trigeminal ganglion decreases nociception, while a loss of GABA receptors results in hyperalgesia, although the neural mechanisms for this remain to be investigated. In this study, the expression of GABA receptors by trigeminal ganglion neurons that innervate rat labial skin and masseter muscle was compared using immunohistochemistry. The effect of intraganglionic administration of GABA receptor agonists was investigated by single unit recording of trigeminal brainstem and ganglion neuron responses to stimulation of the labial skin and/or masseter muscle in anesthetized rats. The mean frequency of expression of GABA A and GABA B receptors by masseter and labial skin ganglion neurons was 62.5% and 92.7%, and 55.4% and 20.3%, respectively. The expression of both GABA receptors was significantly greater in skin ganglion neurons. Masticatory muscle evoked brainstem trigeminal neuron responses were significantly attenuated by intraganglionic injection of muscimol (GABA A) but not baclofen (GABA B). The mechanical sensitivity of slow and fast conducting masticatory muscle afferent fibers was decreased and increased, respectively, by intraganglionic injection of both muscimol and baclofen. Activation of GABA A receptors may exert a gating effect on sensory transmission through the trigeminal ganglion by decreasing putative nociceptive input and enhancing innocuous sensory input. [ABSTRACT FROM AUTHOR]

Pentameric ligand-gated ion channels (pLGICs) are crucial mediators of electrochemical signal transduction in various organisms from bacteria to humans. Lipids play an important role in regulating pLGIC function, yet the structural bases for specific pLGIC-lipid interactions remain poorly understood. The bacterial channel ELIC recapitulates several properties of eukaryotic pLGICs, including activation by the neurotransmitter GABA and binding and modulation by lipids, offering a simplified model system for structure-function relationship studies. In this study, functional effects of noncanonical amino acid substitution of a potential lipid-interacting residue (W206) at the top of the M1-helix, combined with detergent interactions observed in recent X-ray structures, are consistent with this region being the location of a lipid-binding site on the outward face of the ELIC transmembrane domain. Coarse-grained and atomistic molecular dynamics simulations revealed preferential binding of lipids containing a positive charge, particularly involving interactions with residue W206, consistent with cation-π binding. Polar contacts from other regions of the protein, particularly M3 residue Q264, further support lipid binding via headgroup ester linkages. Aromatic residues were identified at analogous sites in a handful of eukaryotic family members, including the human GABAA receptor ε subunit, suggesting conservation of relevant interactions in other evolutionary branches. Further mutagenesis experiments indicated that mutations at this site in ε-containing GABAA receptors can change the apparent affinity of the agonist response to GABA, suggesting a potential role of this site in channel gating. In conclusion, this work details type-specific lipid interactions, which adds to our growing understanding of how lipids modulate pLGICs. [ABSTRACT FROM AUTHOR]

• Inhibitory plasticity induction enhances tonic current in CA1 pyramidal neurons. • Induction of iLTP increases the pool of the extrasynaptic α5-containing GABAARs. • NMDA-iLTP does not affect δ-GABAARs population mediating tonic current. It is known that besides synaptic inhibition, there is a persistent component of inhibitory drive mediated by tonic currents which is believed to mediate majority of the total inhibitory charge in hippocampal neurons. Tonic currents, depending on cell types, can be mediated by a variety of GABA A receptor (GABA A R) subtypes but in pyramidal neurons, α5-subunit containing receptors were found to be predominant. Importantly, α5-GABA A Rs were implicated in both inhibitory and excitatory synaptic plasticity as well as in a variety of cognitive tasks. In the present study, we asked whether the protocol that evokes NMDAR-dependent GABAergic inhibitory long-term potentiation (iLTP) also induces the plasticity of tonic inhibition in hippocampal pyramidal neurons. Our whole-cell patch-clamp recordings revealed that the induction of this type of iLTP is associated with a marked increase in tonic current. By using the specific inverse agonist of α5-containing GABA A Rs (L-655,709) we provide evidence that this plastic change in tonic current is correlated with an increased proportion of this type of GABA A Rs. On the contrary, the iLTP induction did not affect the tonic current potentiated by THIP, indicating that the pool of δ subunit-containing GABA A Rs receptors remains unaffected. We conclude that the α5-GABA A Rs-dependent plasticity of tonic inhibition is a novel dimension of the neuroplasticity of the inhibitory drive in the hippocampal principal neurons. Overall, α5-containing GABA A Rs emerge as key players in a variety of plasticity mechanisms operating over a large span of time and spatial scales. [ABSTRACT FROM AUTHOR]