Selective antagonism of GABAA receptor subtypes: an in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs

Benzodiazepines (BZs) are clinically used as anxiolytic, hypnotic, anticonvulsant, and antispasmodic drugs. Research using transgenic mouse models has suggested that the effects of BZs involve multiple subtypes of the gamma-aminobutyric acid type A (GABAA) receptor, identified by specific a subunits (alpha1, alpha2, alpha3, alpha5). This review discusses the experimental uses of b-carboline-3-carboxylate-t-butyl ester (betaCCT), a drug that binds preferentially to the GABAA alpha1 subtype but exerts no action (ie, is a pharmacologic antagonist at the GABAA alpha1 subtype receptor). betaCCT blocks the anxiolytic-like effects of BZs, although studies in primates suggests this antagonism may reflect multiple receptor populations. betaCCT antagonized the ataxic but not muscle relaxant effects of BZs, a finding that implicates the GABAA alpha1 subtype receptor in ataxia but not muscle relaxation. The potential clinical utility of betaCCT is discussed, both in terms of treatment (ie, hepatic encephalopathy) and as a diagnostic imaging agent. Altogether, these results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.     

Contributions of GABAA receptor subtype selectivity to abuse liability and dependence potential of pharmacological treatments for anxiety and sleep disorders

When benzodiazepines (BZs) supplanted barbiturates as a favored, safer treatment for anxiety and sleep disorders in the 1960s, the abuse liability and dependence potential of these drugs were little understood. Widespread recognition of the difficulty of stopping use of chronically taken BZs emerged through the popular press in the late 1970s, which resulted in reluctance to prescribe these otherwise clinically useful compounds. Evolution of the understanding of the biochemical basis for BZ effects in the 1980s and 1990s, coupled with regulatory emphasis on collection of data used in legal scheduling decisions, made possible a targeted search for drugs that would provide effective treatment for anxiety disorders in the absence of abuse liability or dependence potential. Compounds that have selective efficacy at subtypes of the gamma-aminobutyric acid type A receptor, are active in preclinical anxiolytic screens, but negative in preclinical studies of behavior relevant to evaluation of abuse liability appear to be one promising means for achieving this end.     

Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: Further evaluation

Despite its acute efficacy for the treatment of panic disorder, benzodiazepines (BZs) are associated with a withdrawal syndrome that closely mimics anxiety sensations, leading to difficulty with treatment discontinuation and often disorder relapse. An exposure-based cognitive-behavioral treatment for BZ discontinuation, Panic Control Treatment for BZ Discontinuation (CBT) targets the fear of these sensations and has demonstrated efficacy in preventing disorder relapse and facilitating successful BZ discontinuation among patients with panic disorder. In this randomized controlled trial, CBT was compared to taper alone and a taper plus a relaxation condition to control for the effect of therapist contact and support among 47 patients with panic disorder seeking taper from BZs. Based on the primary outcome of successful discontinuation of BZ use, results indicate that adjunctive CBT provided additive benefits above both taper alone and taper plus relaxation, with consistently medium and large effect sizes over time that reached significance at the six month follow-up evaluation. The efficacy of CBT relative to either of the other taper conditions reflected very large and significant effect sizes at that time. These findings suggest that CBT provides specific efficacy for the successful discontinuation from BZs, even when controlling for therapist contact and relaxation training.     

The role of glutamate in anxiety and related disorders

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the gamma-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.     

Septal co-infusions of glucose with a GABAB agonist impair memory

Septal infusions of glucose exacerbate memory deficits produced by co-infusions of drugs that increase gamma-aminobutyric acid (GABA)(A) receptor activity. To further understand the interaction between glucose and GABA, this experiment tested whether glucose would also potentiate spatial working memory deficits produced by septal infusions of the GABA(B) receptor agonist baclofen. Fifteen minutes prior to assessing spontaneous alternation (SA), male Sprague-Dawley derived rats were given septal infusions of vehicle, glucose (33 nmol), baclofen (0.1 nmol), or glucose combined with baclofen in one solution. Septal co-infusions of glucose with baclofen, at doses that individually had no effect, significantly impaired SA. Thus, the memory-impairing effects of glucose are observed with either GABA(A) or GABA(B) receptor ligands. This raises the possibility that glucose may impair memory by increasing synaptic levels of GABA and subsequent activation of these different receptor subtypes. These effects of glucose could contribute to the memory-impairing effects of hyperglycemia.     

Implications of naturalistic use of pharmacotherapy in CBT treatment for panic disorder

This study examined naturalistic medication use and cognitive behavioral therapy (CBT) treatment outcomes in 105 patients meeting DSM-IV criteria for panic disorder (PD), assessed by structured clinical interview. The association between pre- and post-treatment use of SSRIs, benzodiazepines (BZs), and any anti-anxiety or anti-depressant (A/D) medication were investigated for three indicators of treatment outcome (PD severity, presence of agoraphobia (AG), anxiety sensitivity) at post-treatment and 6-month follow-up. Controlling for pre-treatment severity, pre-treatment SSRI use was associated with worse outcomes for AG (p=.04) and anxiety sensitivity (p=.047); post-treatment SSRI use was associated with delayed improvements in PD severity (p=.05). Pre-treatment use of A/D was associated with poorer PD severity outcomes (p=.04). Post-treatment use of A/D was associated with higher anxiety sensitivity scores across post-treatment and 6-month follow-up (p=.03). BZ use was not associated with significantly worse outcomes. However, there was a decrease in the number of patients using BZs from pre-treatment to post-treatment (p=.06) and follow-up (p=.006). In conclusion, controlling for pre-treatment severity, pre- and post-treatment use of SSRIs and A/D was associated with poorer outcomes, particularly for PD severity and anxiety sensitivity.     

The universal field hypothesis of catatonia and neuroleptic malignant syndrome

Catatonia and neuroleptic malignant syndrome (NMS) are uncommon disorders that can be life-threatening. Many researchers consider them as clinically divergent entities; however, they share similar and overlapping literature on causative agents, phenomenology, and treatment response. This hypothesis considers both disorders as a single entity that result from variable combinations of the following: 1) gamma-aminobutyric acid (GABA) hypoactivity at the GABAA receptor; 2) dopamine hypoactivity at the D2 receptor; 3) serotonin hyperactivity at the 5-HT1A receptor and hypoactivity at the 5-HT2A receptor; and 4) glutamate hypoactivity at the N-methyl-D-aspartate (NDMA) receptor. In this paper, evidence to support this hypothesis is limited to retrospective human studies of catatonia and NMS. The four components of the hypothesis are: 1) GABAA agonists have been shown to alleviate catatonia and NMS; 2) D2 antagonism is proportional to the relative likelihood of NMS and catatonia; 3) 5-HT1A agonism with 5-HT2A antagonism is implicated in catatonia and NMS; 4) NMDA receptor antagonists, such as phencyclidine and ketamine, reduce glutamate transmission. This hypothesis proposes that it is the interaction of these systems that prediposes, initiates, and maintains the twin syndromes of catatonia and NMS.     

CRHR1 antagonists as novel treatment strategies

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.     

Enhancing exposure-based therapy from a translational research perspective

Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that D-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified.     

Defense reaction elicited by microinjection of kainic acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor agonist.

Electrical stimulation of either the midbrain central gray or the medial hypothalamus induces a defense reaction in the rat, characterized mainly by increased locomotion, rearing, and leaping. However, microinjection of the excitatory amino acid glutamate was effective only in the former region. Because excitatory amino acids do not depolarize axons of passage, it was suggested that the hypothalamus is devoid of soma/dendrites of neurons commanding the defense reaction. In the present study, we show that a subtoxic dose (60 pmol) of another excitatory amino acid, kainic acid, injected into the medial hypothalamus significantly enhanced locomotion and rearing of Wistar rats systematically observed in an open field. Similar behavioral changes have been reported following microinjection of drugs impairing GABAergic neurotransmission. Local pretreatment with the GABAA receptor agonist THIP (2 nmol) blocked the effect of kainic acid. Therefore, the medial hypothalamus of the rat seems to contain a population of neuronal cell bodies commanding the defense reaction, which is activated by excitatory amino acids and tonically inhibited by GABAergic fibers.     

Neuropeptide S: a novel modulator of stress and arousal

Neuropeptide S (NPS) is a recently identified bioactive peptide that modulates stress and arousal. NPS is expressed in a few discrete nuclei in the brainstem, such as the pericoerulear (locus coeruleus (LC)) area and the parabrachial nucleus. NPS activates its cognate G protein-coupled receptor at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP, therefore acting as an excitatory transmitter. The NPS receptor is widely expressed in the brain, including regions known to regulate stress responses such as hypothalamus, thalamus, amygdala and limbic cortex. We have recently reported that the NPS system can modulate stress responses and induce wakefulness based on a battery of behavioral tests. Activation of NPS receptors induces arousal and reduces all sleep stages. At the same time, NPS produces anxiolytic-like effects in rodents. These studies indicate that the NPS system has a unique pharmacological profile to promote both anxiolytic and arousal effects. NPS might interact with other hypothalamic neuropeptide systems that are known to be involved in stress and appetite control and thus might be a valuable target for development of a new class of drugs to treat anxiety disorders.     

Functional and pharmacological characterization of the first specific agonist and antagonist for the V1b receptor in mammals

By activating three distinct vasopressin receptor isoforms called V1a-R, V1b-R (V3-R) and V2-R, vasopressin (VP) mediates a wide number of biological effects in mammals and may be involved in several pathological states. Up to now only specific V1a and V2 receptor agonists and antagonists have been successfully designed. The role of the V1b-R still remains partially unknown, due to the lack of selective V1b-R ligands and orally-active molecules, which are crucial tools for investigating the central and peripheral functions or pathological disorders associated with this receptor. In this review, we report the biological and pharmacological properties of the first two specific V1b-R ligands: d[Cha4] AVP, a high affinity V1b-R agonist and SSR149415, a potent orally-active V1b-R antagonist with good selectivity with respect to other VP/OT receptor isoforms and able to control ACTH secretion in vitro and in vivo. Indeed, these molecules constitute invaluable tools for exploring the central and peripheral roles of VP mediated via V1b receptors. Interestingly, SSR149415 displays potent anxiolytic and antidepressant-like activities, indicating that this new class of drugs has a promising therapeutical potential in the treatment of stress-related disorders, anxiety and depression.     

Associations between adults' recalled childhood bullying victimization,current social anxiety,coping, and self-blame: evidence for moderation and indirect effects

Abstract

Prior studies have shown that bullying victimization is common during childhood and may have negative effects over the short term. Evidence is also emerging that childhood bullying victimization in the form of teasing may precipitate social anxiety in adulthood. The present study extended the field by testing for associations between adults' recall of four common subtypes of childhood bullying victimization and their current social anxiety. It also provided the first test of whether coping moderated those associations, if they were indirect effects through self-blame, and if sex differences existed. Data were collected from 582 students aged 23+ years at two universities in the UK. Collectively, and for social exclusion and relational victimization uniquely, the subtypes of bullying victimization did predict social anxiety. Evidence for hypothesized moderation and indirect effects was obtained but these varied by subtype of victimization (but not sex). The theoretical and practical implications of these results were discussed.     

Substance P antagonists: meet the new drugs,same as the old drugs? Insights from transgenic animal models

Antidepressants that primarily target the reuptake of monoamines have been highly successful treatments. However, therapies with these drugs still have several drawbacks, namely severe side effects, delays in the onset of action, and a significant percentage of non-responders. Recently, non-peptidic antagonists of the neurokinin 1 receptor, or substance P antagonists, have emerged as a novel class of drugs with antidepressant efficacy that is comparable to current drugs, but a potentially reduced side effect profile. This review summarizes the pre-clinical evidence derived from pharmacological and transgenic animal studies that suggests an important role for the substance P/neurokinin 1 system in anxiety and depression. Also, potential mechanisms by which substance P antagonists may produce their therapeutic effects are discussed.     

Short- and long-term effects of juvenile stressor exposure on the expression of GABAA receptor subunits in rats

During the juvenile period rodents are particularly sensitive to stressors. Aversive events encountered during this period may have enduring effects that are not evident among animals initially stressed as adults. Interestingly, experiencing stressor during juvenile period was found to elicit a biphasic behavioral pattern over the course of development. During the juvenile period, the expression of several GABAA receptor subunits is subject to elevated plasticity, rendering the GABAergic system sensitive to stressors. In the present investigation, animals were exposed to a juvenile variable stressor regimen (JUV-S) at 27-29 postnatal days (PND): 27 PND-acute swim stress (10 min), 28 PND-elevated platform stress (3 sessions×30 min each), and 29 PND-restraint (2 h). One hour following the last exposure to stressor or in adulthood (60 PND), anxiety-related behaviors were assessed in a 5-min elevated plus maze test. The western blotting technique was used to evaluate whether the juvenile stress induced behavioral pattern will be accompanied by respective changes in GABAA α1, α2, and α3 protein expression in male rats. Our findings further established that juvenile stressor elicits hyper-reactivity when rats were tested as juveniles, whereas rats exhibited reduced activity and increased anxiety when tested as adults. Additionally, the effects of juvenile stressor on α1, α2, and α3 were more pronounced among juvenile stressed rats that were challenged as adults compared with rats that were only challenged as juveniles. Interestingly, the stress-induced modulation of the subunits was particularly evident in the amygdala, a brain region closely associated with anxiety. Thus, age- and region-specific alterations of the α subunits may contribute to the age-specific behavioral alterations observed following juvenile stress exposure.     

小学儿童数学焦虑的潜在类别转变及其父母教育卷入效应：3年纵向考察

研究采用潜在转变分析考察小学儿童数学焦虑的类别转变以及父母教育卷入在小学儿童数学焦虑类别转变中的作用。以1720名三、四年级儿童为被试, 对其数学焦虑和感知到的父母教育卷入进行3次追踪, 每次间隔1年。结果表明：(1)小学儿童数学焦虑存在低数学焦虑组、高数学评估焦虑组和高数学获得焦虑组3种不同类别; (2)随时间的推移, 高数学评估焦虑组倾向于向低数学焦虑组转变, 高数学获得焦虑组倾向于向高数学评估焦虑组转变, 而低数学焦虑组稳定性较强; (3)父亲/母亲教育卷入对儿童数学焦虑类别转变的预测作用, 因不同的数学焦虑类别而异。上述发现为深入理解数学焦虑的形成机制以及干预措施的制定提供了重要参考。     

Pharmacotherapeutic options in the treatment of comorbid depression and anxiety

Although anxiety and mood disorders are listed as separate disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, they frequently coexist. They may be expressed phenotypically as comorbidities or as the provisional entity mixed anxiety-depressive disorder. Patients with both anxiety and depression are more symptomatic, use more health care resources, and have a worse prognosis than those with a single disorder. Recognizing and treating these patients are challenges for physicians because the symptoms of the two disorders often overlap. Administration of effective treatment, comprising both anxiolytic and antidepressant effects, can reduce patient distress and disability, as well as inappropriate utilization of medical services. Medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors, nefazodone, venlafaxine XR (extended release) and mirtazapine, are highly effective in treating comorbid depression and anxiety. These newer agents now represent the pharmacotherapeutic treatments of choice for the comorbid conditions.     

Prenatal anxiety effects: A review

This review is based on literature on prenatal anxiety effects that was found on Pubmed and PsycINFO for the years 2010–2016. Prenatal anxiety is thought to have distinct features, although it has been measured both by specific prenatal anxiety symptoms as well as by standardized anxiety scales. Its prevalence has ranged from 21 to 25% and it has been predicted by a number of pregnancy – related variables such as unintended pregnancy, demographic variables such as low acculturation and income and psychosocial factors including pessimism and partner tension. Prenatal anxiety effects on pregnancy include increased cortisol levels, pro-inflammatory cytokines, obstetric problems and cesarean section. Effects on the neonate include lower gestational age, prematurity, less insulin-like growth factor in cord blood, less exclusive breast-feeding and less self-regulation during the heelstick procedure. Prenatal anxiety effects continue into infancy and childhood both on physiological development and emotional/mental development. Among the physiological effects are lower vagal activity across the first two years, and lower immunity, more illnesses and reduced gray matter in childhood. Prenatal anxiety effects on emotional/mental development include greater negative emotionality and in infants, lower mental development scores and internalizing problems. Anxiety disorders occur during childhood and elevated cortisol and internalizing behaviors occur during adolescence. Interventions for prenatal anxiety are virtually nonexistent, although stroking (massaging) the infant has moderated the pregnancy – specific anxiety effects on internalizing behaviors in the offspring. The limitations of this literature include the homogeneity of samples, the frequent use of anxiety measures that are not specific to pregnancy, and the reliance on self-report. Nonetheless, the literature highlights the negative, long-term effects of prenatal anxiety and the need for screening and early interventions.