Side Effects Of Benzodiazepines Research Articles

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse.

Benzodiazepines have been in use for over half a century. While they remain highly prescribed, their unfavorable side-effect profile and abuse liability motivated a search for alternatives. Most of these efforts focused on the development of benzodiazepine-like drugs that are selective for specific GABAA receptor subtypes. While there is ample evidence that subtype-selective GABAA receptor ligands have great potential for providing symptom relief without typical benzodiazepine side-effects, it is less clear whether subtype-selective targeting strategies can also reduce misuse and abuse potential. This review focuses on the three benzodiazepine properties that are relevant to the DSM-5-TR criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder, namely, reinforcing properties of benzodiazepines, maladaptive behaviors related to benzodiazepine use, and benzodiazepine tolerance and dependence. We review existing evidence regarding the involvement of different GABAA receptor subtypes in each of these areas. The reviewed studies suggest that α1-containing GABAA receptors play an integral role in benzodiazepine-induced plasticity in reward-related brain areas and might be involved in the development of tolerance and dependence to benzodiazepines. However, a systematic comparison of the contributions of all benzodiazepine-sensitive GABAA receptors to these processes, a mechanistic understanding of how the positive modulation of each receptor subtype might contribute to the brain mechanisms underlying each of these processes, and a definitive answer to the question of whether specific chronic modulation of any given subtype would result in some or all of the benzodiazepine effects are currently lacking from the literature. Moreover, how non-selective benzodiazepines might lead to the maladaptive behaviors listed in DSM and how different GABAA receptor subtypes might be involved in the development of these behaviors remains unexplored. Considering the increasing burden of benzodiazepine abuse, the common practice of benzodiazepine misuse that leads to severe dependence, and the current efforts to generate side-effect free benzodiazepine alternatives, there is an urgent need for systematic, mechanistic research that provides a better understanding of the brain mechanisms of benzodiazepine misuse and abuse, including the involvement of specific GABAA receptor subtypes in these processes, to establish an informed foundation for preclinical and clinical efforts.

Deprescribing Benzodiazepines in Older Adults

Benzodiazepines are well established as having the ability to produce rapid relief of anxiety and sleep disorders. However, despite their association with harm and often-short therapeutic effects, they continue to be prescribed often. Through the process of aging, the accumulation of medications needed to treat various disease states contributes to polypharmacy among the elderly. Older adults have unique factors that position them at a higher susceptibility of the anticholinergic side effects of benzodiazepines, which can result in falls, cognitive impairments and depression. Given these concerns, multiple professional organizations have identified the deprescribing of benzodiazepines as a national public health priority and have strongly recommended the pursuit of alternative shared decision-making approaches. While non- pharmacologic techniques are widely recognized to safely manage the common reasons clinicians provide when choosing to prescribe benzodiazepine’s, there is a mounting need for prescriber education regarding these practical approaches as well as evidence-based clinical practice guidelines to support successful deprescribing [1]. The purpose of this DNP project was to improve prescriber knowledge of deprescribing approaches and present alternative prescribing decisions through participation of an evidence-based education program at a geriatric specialized, primary care practice in Pennsylvania. The study participants consisted of Physicians, Nurse Practitioners and Physician Assistants who prescribe benzodiazepines. The results indicated an improvement in the participant’s knowledge of deprescribing approaches and alternative prescribing choices, as evidenced by how they rated their attitudes, knowledge and practices after participating in the evidence-based education.

Design, Synthesis and Pharmacological Activity of New Pyrrolo[1,2-A] Pyrazine Translocator Protein (TSPO) Ligands

Background: Translocator protein 18 kDa (TSPO) is a promising target for the creation of effective and safe neuropsychotropic drugs. The ligands of TSPO exhibit anxiolytic, antidepressant, neuroprotective and other activities without the side effects of benzodiazepines. Methods: New TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives were designed using calculated pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out by two schemes using [3+3]-cycloaddition reaction of 2-azidoacrylic acid derivatives with pyrrolphenylketone as a key stage. The anxiolytic activity of new substances has been established using open field test with flash. Results: Several synthesized N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives significantly increased the total motor activity of Balb/c mice compared to the control. The structureactivity relationship was investigated. The most effective compound was found to be GML-11 (Nbenzyl- N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamide), which had anxiolytic action in the dose range from 0.001 to 0.100 mg/kg (Balb/c, i.p.). This compound is two orders of magnitude higher in dose activity than all other pyrrolo[1,2-a]pyrazine TSPO ligands. Conclusion: Molecular modelling methods allowed us to create new TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides with high anxiolytic activity.

Can the use of benzodiazepines increase the risk of dementia?

Objective. This study aims to provide up-to-date data on the possible relationship between the use of benzodiazepines and the subsequent occurrence of dementia. Literature review. Benzodiazepines (BDA) have been used in medicine for over half a century. Initially, they were considered very safe, especially when compared to older generation drugs. Over time, more and more information about possible side effects became available and the problem of abuse and addiction was growing. One of the side effects of BDA is possible deterioration of cognitive functions, particularly relevant in elderly population. In recent years, numerous studies have been published, the results of which indicate the possible impact of using this group of drugs on the risk of developing dementia. The possibility of reverse causality, i.e. when BDA is included in the prodromal phase of dementia to alleviate such symptoms as anxiety or insomnia, is also discussed. Conclusions. Although numerous studies confirm a higher incidence of dementia in BDA users, this relationship has not been clearly confirmed due to methodological problems and possible influence of many additional factors.

The impact of in hospital patient-education intervention on older people's attitudes and intention to have their benzodiazepines deprescribed: a feasibility study.

Background:Long-term benzodiazepine use in the older population is common and is associated with significant harm. The provision of a patient-educational booklet during hospitalization may encourage patients to discuss review and possible deprescribing of benzodiazepine therapy with their health professionals. The aim of this study was to assess the feasibility and effect of a patient empowerment intervention in hospital inpatients on patient initiation of a discussion about deprescribing benzodiazepines versus usual care.Methods:A feasibility interventional study using a patient-empowerment education intervention was conducted at a Sydney teaching hospital. Patients aged ⩾ 65 years, prescribed a benzodiazepine, and able to provide consent were invited to participate in the study. Participants were randomly allocated to intervention or control group (1:1). Intervention participants received the patient-empowerment booklet and control received usual care. All participants received 1-month follow-up phone interviews to assess medication and attitudinal changes.Results:A total of 42 participants were recruited (20 intervention and 22 control). The average age was 71.5 (interquartile range: 69.0–80.3) and 54.8% were females. There was no difference in baseline characteristics between intervention and control groups (p > 0.05). At baseline, 65.0% of participants (53.0% intervention, 86.0% control) were not concerned about the potential benzodiazepine side effects. Twenty-nine participants (15 intervention and 14 control) completed 1-month follow up; 22 participants (11 intervention and 11 control) were discharged on the benzodiazepine. Among these, 13 (59.1%) had ceased benzodiazepine at 1-month follow up [46.2% (n = 6) intervention; 53.8% (n = 7) control]. In the intervention group, 33.3% (n = 5) of participants had initiated a discussion with their doctor or pharmacist about stopping the benzodiazepine compared with 35.7% (n = 5) in the control group.Conclusion:Cessation of benzodiazepines 1 month following discharge was common. Future larger studies are required to confirm the effectiveness of providing a patient-empowerment booklet on reducing benzodiazepine use and other potentially inappropriate medications.

Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling

BackgroundBenzodiazepines are widely used for anesthesia and sedation and have immunomodulatory properties that may negatively influence clinical outcomes; however, the cellular targets and intermediary signaling pathways involved are unclear. We examined the immunomodulatory effects of the benzodiazepine midazolam on human macrophages and associated molecular mechanisms. MethodsWe analyzed effects of midazolam pretreatment on lipopolysaccharide (LPS)-induced upregulation of the costimulatory molecule CD80 and secretion of the pro-inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α, interleukin-10, and nitric oxide (NO) in the human monocyte–macrophage cell line THP-1 and in peripheral monocyte-derived macrophages (PMDMs). The effects of midazolam on NF-κB, IκBα protein, and mitogen-activated protein kinase (MAPK) activation were analyzed in THP-1 cells. We analyzed the involvement of translocator protein (TSPO) in the immunomodulatory effects of midazolam using TSPO ligands. The role of TSPO was investigated using THP-1 cells overexpressing TSPO and THP-1 cells with TSPO knockdown through transfection with small interfering RNA for TSPO. ResultsMidazolam suppressed LPS-induced upregulation of CD80 and release of IL-6 and NO in THP-1 cells and PMDMs. Additionally, midazolam suppressed the activation of NF-κB/AP-1 and MAPKs in human THP-1 cells. The assessed synthetic TSPO ligands showed the same inhibitory effects on macrophage activation as midazolam. Macrophages overexpressing TSPO exhibited enhanced susceptibility to immunosuppression by midazolam, and macrophages lacking TSPO expression exhibited reduced effects of midazolam. ConclusionMidazolam inhibits LPS-stimulated immune responses in human macrophages by activating TSPO signaling. Suppression of macrophage activity may contribute to deleterious side effects of benzodiazepines reported in critically ill patients.

Characterization of 6-methoxyflavanone as a novel anxiolytic agent: A behavioral and pharmacokinetic approach

Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABAA receptors implicated in anxiolytic-like activity in rodents, but are devoid of the unwanted side effects of benzodiazepines. In this study, 6-methoxyflavanone (6-MeOF), a positive allosteric modulator of γ-amino butyric acid (GABA) responses at human recombinant GABAA receptors, was evaluated for its behavioral profile in the elevated plus-maze as well as the staircase- plus and open-field tests in mice. In addition, the distribution of 6-MeOF in selected brain areas involved in anxiety (amygdala and cerebral cortex) was also examined using a validated high performance liquid chromatography ultraviolet detection (HPLC/UV) method. 6-MeOF (10, 30 and 50mg/kg) exerted an anxiolytic-like effect, increasing entries and time spent in the open arm and the central platform, as well as head-dipping frequency in the mouse elevated plus-maze assay. It also decreased rearing incidence without suppressing the number of steps ascended in the staircase test. Whereas, in the open-field anxiety test, 6-MeOF had no effect on locomotor activity at lower doses, a decrease was observed at the highest dose (100mg/kg). 6-MeOF additionally produced an anxiolytic-like increase in the time spent at the center of the open-field apparatus. These effects were preferentially antagonized by pentylenetetrazole (15mg/kg). Furthermore, pharmacokinetic studies disclosed a rapid appearance of 6-MeOF in the plasma and discrete brain areas. Taken together, our findings suggest that 6-MeOF readily crosses the blood brain barrier (BBB) generating anxiolytic activity, mediated through the GABAergic system.

Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset

IntroductionThe primary objective of this study was to determine if second generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first generation (FGA) in schizophrenia (SZ). The secondary objective was to determine if antidepressants, mood stabilizers and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications.MethodsThree hundred and thirty-one patients with schizophrenia (n = 255) or schizoaffective disorder (n = 76) (mean age = 32.5 years, 75.5% male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders and validated scales for psychotic symptomatology, insight and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded.ResultsPatients who received SGA had lower BPAQ scores than patients who did not (P = 0.01). On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (P = 0.04). These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder and daily cannabis consumption.ConclusionThe results of the present study are in favor of the choice of SGA in SZ patients with aggressiveness, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Inhibition of soluble epoxide hydrolase as a novel approach to high dose diazepam induced hypotension.

Hypotension is one of the dose limiting side effects of benzodiazepines (BZDs), in particular of diazepam (DZP) which is still widely used in the clinic. Currently, only one FDA approved antidote exists for BZD overdose and novel approaches are needed to improve management of DZP overdose, dependency and withdrawal. Here, we hypothesized that increasing bioactive lipid mediators termed epoxy fatty acids (EpFAs) will prevent hypotension, as was shown previously in a murine model of LPS-induced hypotension. Therefore, we first characterized the time and dose dependent profile of DZP induced hypotension in mice, and then investigated the reversal of the hypotensive effect by inhibiting the soluble epoxide hydrolase (sEH), an enzyme that regulates the levels of EpFAs. Following baseline systolic BP recording using tail cuffs, mice were administered a sEH inhibitor (TPPU) before DZP and BP was monitored. Blood and brain levels of DZP and TPPU were quantified to examine distribution and metabolism. Plasma EpFAs levels were quantified to determine TPPU target engagement. In this murine model, DZP induced dose dependent hypotension which was more severe than midazolam. The temporal profile was consistent with the reported pharmacokinetics/pharmacodynamics of DZP. Treatment with TPPU reversed the hypotension resulting from high doses of DZP and decreased the sEH metabolites of EpFAs in the plasma demonstrating target engagement. Overall, these findings demonstrate the similarity of a murine model of DZP induced hypotension to clinical observations in humans. Furthermore, we demonstrate that stabilization of EpFAs by inhibiting sEH is a novel approach to overcome DZP-induced hypotension and this beneficial effect can be enhanced by an omega three diet probably acting through epoxide metabolites of the fatty acids.

Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset

The primary objective of this study was to determine if second generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first generation (FGA). The secondary objective was to determine if antidepressants, mood stabilizers and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications. 331 patients with schizophrenia (n = 255) or schizoaffective disorder (n = 76) (mean age = 32.5 years, 75.5 % male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders and validated scales for psychotic symptomatology, insight and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded. Patients who received SGA had lower BPAQ scores than patients who did not (p = 0.01). More specifically, these patients had lower physical and verbal aggression scores. On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (p = 0.04). No significant difference was found between BPAQ scores of patients respectively being administered mood stabilizers (including valproate), antidepressant, and the patients who were not. These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder and daily cannabis consumption. The results of the present study are in favor of a superior efficacy of second-generation antipsychotics in aggressiveness in patients with schizophrenia, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior.

Diazepam effect during early neonatal development correlates with neuronal Cl(.).

Although benzodiazepines and other GABAA receptors allosteric modulators are used to treat neonatal seizures, their efficacy may derive from actions on subcortical structures. Side effects of benzodiazepines in nonseizing human neonates include myoclonus, seizures, and abnormal movements. Excitatory actions of GABA may underlie both side effects and reduced anticonvulsant activity of benzodiazepines. Neocortical organotypic slice cultures were used to study: (1) spontaneous cortical epileptiform activity during early development; (2) developmental changes in [Cl(-)]i and (3) whether diazepam's anticonvulsant effect correlated with neuronal [Cl(-)]i. Epileptiform activity in neocortical organotypic slice cultures was measured by field potential recordings. Cl(-) changes during development were assessed by multiphoton imaging of neurons transgenically expressing a Cl-sensitive fluorophore. Clinically relevant concentrations of diazepam were used to test the anticonvulsant effectiveness at ages corresponding to premature neonates through early infancy. (1) Neocortical organotypic slices at days in vitro 5 (DIV5) exhibited spontaneous epileptiform activity. (2) Epileptiform event duration decreased with age. (3) There was a progressive decrease in [Cl(-)]i over the same age range. (4) Diazepam was ineffective in decreasing epileptiform activity at DIV5-6, but progressively more effective at older ages through DIV15. (5) At DIV5-6, diazepam worsened epileptiform activity in 50% of the slices. The neocortical organotypic slice is a useful model to study spontaneous epileptiform activity. Decreasing [Cl(-)]i during development correlates with decreasing duration of spontaneous epileptiform activity and increasing anticonvulsant efficacy of diazepam. We provide a potential explanation for the reports of seizures and myoclonus induction by benzodiazepines in newborn human neonates and the limited electrographic efficacy of benzodiazepines for the treatment of neonatal seizures.

Effect of benzodiazepines on thyroglobulin, anti-thyroglobulin, anti-thyroid peroxidase, and thyroid stimulating hormone in rat

Background: Benzodiazepines are widely used as psychoactive agents and the side effects of benzodiazepines to the endocrine system are reported. Objective: This study was designed to explore the effects of the benzodiazepines - lorazepam and clonazepam - on thyroglobulin (Tg), anti-thyroglobulin (aTg), anti-thyroid peroxidase (aTPO), and thyroid stimulating hormone (TSH). Materials and Methods: Eighteen male Wistar rats were randomly divided into three groups: control (C), lorazepam-treated, and clonazepam-treated groups. The changes in Tg, aTg, aTPO, and TSH in these three groups were compared after 4 weeks. Results: The levels of Tg and aTg in the lorazepam-treated and clonazepam-treated rats significantly increased compared to the control group. But there was no significant difference in the levels of TSH and aTPO between lorazepam-treated and clonazepam-treated rats in comparison with the control group rats. Conclusion: The thyroid gland is affected by lorazepam and clonazepam, which are used in epilepsy, bruxism, anxiety, insomnia, and other psychic disorders.

Benefits and risks of benzodiazepines and Z-drugs: comparison of perceptions of GPs and community pharmacists in Germany.

Objective: Newer non-benzodiazepines zolpidem and zopiclone (“Z-drugs”) are often prescribed instead of benzodiazepine hypnotics, although there is no evidence of differences in effectiveness and safety. Aim was to compare perceptions on benefits and harms of benzodiazepines and Z-drugs between general practitioners (GPs) and community pharmacists (CPs).Methods: A questionnaire was mailed to a random sample of 1,350 GPs and 600 CPs in 2012. They were asked to rate perceptions on a five-point Likert scale used for both benzodiazepines and Z-drugs. Wilcoxon signed rank test was performed for the comparison of perceptions between GPs and CPs. Due to multiple testing, only p-values ≤0.01 were considered statistically significant.Results: 458 GPs and 202 CPs returned questionnaires (response 33.9% and 33.7%). Mean age of GPs was 53.3 years (40.6% female) and 48.8 years for CPs (59.2% females). Perceptions on benefits of benzodiazepines (and Z-drugs) between GPs and CPs were not different for 3 (and 2) of 5 items. Concerning side effects of benzodiazepines, there were no statistically significant differences for 3 of 5 comparisons. CPs perceived that 4 of 5 studied side effects of Z-drugs occur significantly more often than GPs (p=0.003 or less). For instance, whereas 45.2% of CPs answered that withdrawal effects on stopping happen often or very often/always on Z-drugs, these were only 28.3% of the GPs. Conclusions: Although it is difficult to draw unambiguous conclusions from these findings, pharmacists might have a somewhat more critical view on Z-drugs, especially concerning side effects.

Deep sedation and atrioventricular nodal reentry tachycardia ablation.

Cardiac ablation is an invasive procedure requiring conscious and deep sedation for immobility and analgesia. AVNRT ablation generates acute pain during the radiofrequency application. Although the success rate is high, the procedure is uncomfortable for patients who must remain motionless. Sedation in EP lab is needed for several purposes such as providing anaesthesia and airway management for cardio version during EP study and induction of atrial fibrillation, pain management, and haemodynamic monitoring. The best anaesthetic agent should not alter Electrophysiological properties including SA node, AV node functions, conduction velocities, and refractoriness. Most anaesthetic agents have not been studied in the context of EPS and most of our data were based on animal and laboratory experiments. A few investigators reported that anesthetic agents have no significant clinical effects on conduction system (1, 2). There are some reports concerning non-inducibility of AVNRT after intravenous sedation in pediatrics (3). Fazelifar et al. investigated inducibility of AVNRT and electrophysiological properties after deep sedation (4). Anesthesia with benzodiazepines and opiates used in a repeated bolus fashion can easily be provided without influencing accurate EP testing and/or arrhythmia induction. There are no known specific side-effects of benzodiazepines on cardiac conduction (1). Propofol and benzodiazepine may change heart rate via baroreflex regulatory mechanisms (5, 6). The authors demonstrated that AVNRT induction is not related to anesthetic agents and it could be performed safely in all patients who undergo slow pathway induction. Induction and ablation of reentrant arrhythmias such as AVNRT can be performed safely after deep sedation. Ablation after sedation in other supra-ventricular tachy-arrhythmias requires another well-designed randomized trial.

Five-Year Trajectories of Long-Term Benzodiazepine Use by Adolescents: Patient, Provider, and Medication Factors

Five-Year Trajectories of Long-Term Benzodiazepine Use by Adolescents: Patient, Provider, and Medication Factors

The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3–30mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3–30mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments.

Benzodiazepines: uses, mode of action and prescribing issues

The use of benzodiazepines, such as diazepam, chlordiazepoxide, lorazepam and temazepam, are commonly used for insomnia and anxiety. They act on the GABAA receptors in the central nervous system, thus having central effects. This article discusses the acute and long-term side effects of benzodiazepines, as well as their prescribing issues amid fears of tolerance, dependence and withdrawal effects.

Ethyl 8-Fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as Novel, Highly Potent, and Safe Antianxiety Agent

Ethyl 8-fluoro-6-(4-nitrophenyl)- and ethyl 8-fluoro-6-(3-nitrophenyl)-4 H-imidazo[1,5-a][1,4]benzodiazepine 3-carboxylate 6 and 7 were synthesized as central benzodiazepine receptor (CBR) ligands and tested for their ability to displace [(3)H]flumazenil from bovine and human cortical brain membranes. Both compounds showed high affinity for bovine and human CBR. In particular, compound 7 emerged as the most interesting compound, having a partial agonist profile in vitro while possessing useful activity in various animal models of anxiety. In accordance with its partial agonist profile, compound 7 was devoid of typical benzodiazepine side effects. The homology model of the GABA A receptor developed by Cromer et al. was used to assess the binding modes of ligands 6 and 7. From our docking results, the partial agonist activity elicited by compound 7 is likely to be due to the 3'-nitro substituent, which is in the appropriate position to interact with Thr193 of the gamma 2-subunit by means of a hydrogen bond.

Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates.

Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain alpha1-, alpha2-, alpha3-, and alpha5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABAA receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABAA receptors containing alpha1-subunits (alpha1GABAA receptors); L-838,417, which shows functional selectivity for alpha2GABAA, alpha3GABAA, and alpha5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha2GABAA, alpha3GABAA, and/or alpha5GABAA subtypes. Our results also suggest that the alpha1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.

Significance of GABAA receptors for the pathophysiology and therapy of panic disorders

Gamma aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system. Its action is exerted in the brain through GABA(A) receptors which belong to the family of ligand-gated ion channels. These GABA(A) receptors consist of various subunits and are targets for benzodiazepines, barbiturates, neuroactive steroids, and distinct anticonvulsive agents. Meanwhile, there is considerable evidence that a dysfunction of GABA(A) receptors plays an important role in the pathophysiology of panic disorder. The anxiolytic effects of benzodiazepines are widely used in the treatment of panic disorder. Nevertheless, side effects of benzodiazepines, e.g., dependency and withdrawal symptoms, limit their use as a long-term treatment. In the meantime, antidepressants, especially selective serotonin reuptake inhibitors, comprise first-line treatment in the pharmacotherapy of panic disorder. They interfere with the synthesis of endogenous neuroactive steroids that allosterically modulate GABA(A) receptor function. With regard to experimentally evoked panic attacks in patients with panic disorder and healthy controls, recent investigations demonstrated that enhancing endogenous GABA through the blockade of the GABA transaminase by vigabatrin or inhibition of GABA transporters by tiagabine may exert anxiolytic effects. This novel strategy targeting the GABA binding site of the GABA(A)/benzodiazepine receptor complex and specific agonists for the benzodiazepine binding site present interesting perspectives for the future pharmacotherapy of panic disorder.