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How to determine suitable animal models of anxiety disorders and post-traumatic stress disorders (PTSD) for screening anxiolytic drugs and linking preclinical and clinical research is a crucial issue. This review paper provides background knowledge and critical determination to the animal models for discussing this issue. Moreover, this article analyzes the characteristics, properties, advantages, and disadvantages of various animal models of anxiety disorders and PTSD. It offers an overview of the pathophysiology, treatments, prevalence, and symptoms of anxiety disorders in the clinics. Furthermore, it comprehensively discusses pharmacological treatments and neural mechanisms, as well as the types and properties of the animal models of anxiety disorders in shaping and testing anxiety behaviors. In light of the previous literature discussion, we can understand the different functions of the animal models of anxiety disorders and PTSD to help us link preclinical and clinical research. Animal models are used in advanced drug discovery programs, specifically in psychiatry and neuroscience research. The challenge for the future will be to keep pace with developing the appropriate animal models of anxiolytic drugs to improve the translation of large datasets obtained to clinics. [ABSTRACT FROM AUTHOR]

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft guidelines on "prescription drug use-related software" illustrate opportunities to create drug + digital combination therapies, ultimately leading towards drug–device combination products (DTx has a status of medical devices). Digital interventions (mobile, web-based, virtual reality, and video game applications) demonstrate clinically meaningful benefits for people living with Alzheimer's disease, dementia, rheumatoid arthritis, cancer, chronic pain, epilepsy, depression, and anxiety. In the respective animal disease models, preclinical studies on environmental enrichment and other non-pharmacological modalities (physical activity, social interactions, learning, and music) as surrogates for DTx "active ingredients" also show improved outcomes. In this narrative review, we discuss how drug + digital combination therapies can impact translational research, drug discovery and development, generic drug repurposing, and gene therapies. Market-driven incentives to create drug–device combination products are illustrated by Humira® (adalimumab) facing a "patent-cliff" competition with cheaper and more effective biosimilars seamlessly integrated with DTx. In conclusion, pharma and biotech companies, patients, and healthcare professionals will benefit from accelerating integration of digital interventions with pharmacotherapies. [ABSTRACT FROM AUTHOR]

Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC50 = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions. [ABSTRACT FROM AUTHOR]

Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC50 = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions.

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts. A comprehensive summary that offers a representative overview of the primary anxiolytic drugs, their neuropharmacological mechanisms, a systematic classification of anxiolytic drug research, animal models of anxiety, and the neural circuits associated with anxiety. Color should be used in print. [Display omitted] • Novel drugs targeting the GABA and 5-HT systems exhibited high rates of failure. • Botanicals have emerged as promising anxiolytic drug candidates. • Unconditioned conflict models are the most widely used in anxiolytic drug discovery. • Eight key brain regions are related to the onset and treatment of anxiety. [ABSTRACT FROM AUTHOR]

Introduction: Our consensus statement aims to clarify the use of antidepressants and anxiolytics during breastfeeding amidst clinical uncertainty. Despite recent studies, potential harm to breastfed newborns from these medications remains a concern, leading to abrupt discontinuation of necessary treatments or exclusive formula feeding, depriving newborns of benefits from mother's milk., Methods: A panel of 16 experts, representing eight scientific societies with a keen interest in postpartum depression, was convened. Utilizing the Nominal Group Technique and following a comprehensive literature review, a consensus statement on the pharmacological treatment of breastfeeding women with depressive disorders was achieved., Results: Four key research areas were delineated: (1) The imperative to address depressive and anxiety disorders during lactation, pinpointing the risks linked to untreated maternal depression during this period. (2) The evaluation of the cumulative risk of unfavorable infant outcomes associated with exposure to antidepressants or anxiolytics. (3) The long-term impact on infants' cognitive development or behavior due to exposure to these medications during breastfeeding. (4) The assessment of pharmacological interventions for opioid abuse in lactating women diagnosed with depressive disorders., Conclusions: The ensuing recommendations were as follows: Recommendation 1: Depressive and anxiety disorders, as well as their pharmacological treatment, are not contraindications for breastfeeding. Recommendation 2: The Panel advocates for the continuation of medication that has demonstrated efficacy during pregnancy. If initiating an antidepressant during breastfeeding is necessary, drugs with a superior safety profile and substantial epidemiological data, such as SSRIs, should be favored and prescribed at the lowest effective dose. Recommendation 3: For the short-term alleviation of anxiety symptoms and sleep disturbances, the Panel determined that benzodiazepines can be administered during breastfeeding. Recommendation 4: The Panel advises against discontinuing opioid abuse treatment during breastfeeding. Recommendation 5: The Panel endorses collaboration among specialists (e.g., psychiatrists, pediatricians, toxicologists), promoting multidisciplinary care whenever feasible. Coordination with the general practitioner is also recommended.

Estrogen deficiency increases the incidence of female anxiety disorders; however, whether estrogen deficiency alters responses to anxiolytic drugs is unknown. We studied whether long-term estrogen deprivation (ovariectomy, OVX) changes the behavior of mice to anxiolytic drugs (buspirone, diazepam, and venlafaxine), using the elevated plus maze (EPM) test. The percentages of EPM open-arm time and EPM open-arm entries of the OVX mice decreased significantly compared to control, and sham mice 2 months after OVX. The response to buspirone increased in the OVX mice at 1 week, while OVX decreased the response to diazepam at 2 months. Moreover, we found the efficacy of diazepam was significantly decreased, compared to buspirone and venlafaxine, at 2 months. These results suggest that OVX may change responses to different anxiolytic drugs. Not all anti-anxiety drugs appear to be suitable for anxiety caused by estrogen deficiency. [ABSTRACT FROM AUTHOR]

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Accumulating data highlight the contribution of brain mitochondria and bioenergetics to psychiatric disorders and stress-related pathologies. Although anxiety has not received much attention in this booming literature, a bidirectional interplay between anxiety and brain mitochondria and metabolism has recently started to emerge. Substantial observations indicate alterations in mitochondria and metabolism in highly anxious individuals and, conversely, anxiety symptoms in humans suffering from mitochondrial disorders. Genetic and pharmacological efforts have made substantial progress at advancing the causal involvement of specific mitochondrial and metabolic factors in anxiety. In this review, we discuss this converging evidence and highlight the relevance of developing a research focused on targeting mitochondria as an approach to alleviate anxiety. Despite the established link between mitochondrial dysfunction and various psychiatric disorders, the contribution of mitochondria in anxiety disorders has not been extensively addressed. Mitochondria are emerging as modulators of anxiety-related behavior, as evidenced both by animal and human studies. There is a bidirectional link between mitochondria and anxiety. Mitochondrial, energy metabolism, and oxidative stress alterations are observed in high anxiety; conversely, changes in mitochondrial function can lead to heightened anxiety. Pharmacological manipulation of mitochondria may be a potential therapeutic approach to relieve high anxiety symptoms. [ABSTRACT FROM AUTHOR]

We exposed male and female rats of SHR (Spontaneously Hypertensive Rats) and SLA16 (SHR.LEW-Anxrr16) strains, in a non-drugged state, for five consecutive days to the Triple Test (experiment 1); or after repeated treatment with midazolam (MDZ), for four consecutive days. The fifth day was performed without treatment (experiment 2). The first experiment showed that males did not avoid and females increased the exploration of the open arms over the days. In experiment 2, SLA16 from both sexes approached more the open arms than SHR rats. The MDZ anxiolytic-like effect was sustained in both strains and sexes over the days. On the fifth day, SLA16 still approached more the open arms than SHR rats. Data suggest an absence of repeated-trial tolerance to MDZ anxiolytic-like effects. Testing the SHR and SLA16 strains, especially females, could be necessary for the future search for the genes and molecular pathways underlying anxiety/emotionality. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to examine the potential benefit to take into account duration and intensity of drug exposure using the recently published method based on individual drug trajectories. This approach was used to define profiles of exposure to anxiolytics/hypnotics during pregnancy and to evaluate the potential effect on newborn health. Methods The study was performed in EFEMERIS database (54 918 mother-children pairs). An estimation of adaptation to extrauterine life was assessed using several criteria especially cardio-respiratory symptoms. A proxy variable called 'neonatal pathology' was created. The occurrence of this event was studied using two approaches: The Standard Method comparing exposed and unexposed newborns,, The Trajectory Method comparing the different profiles of exposure., Results Around 5% of newborns ( n = 2768) were identified to be exposed to anxiolytics or hypnotics during pregnancy. Using the Standard Method, 6.2% of exposed newborns developed a 'neonatal pathology' against 4.8% of unexposed newborns (odds ratios [OR] = 0.9[0.8-1.2], p = 0.7). With the Trajectory Method taking into account evolution of exposure during pregnancy and treatment intensity, four profiles of pregnant women were identified. A significant difference in the rates of 'neonatal pathologies' was observed between profiles ( p = 0.0002). Newborns of the two profiles exposed in utero to high constant level of anxiolytics or hypnotics were more at risk of developing 'neonatal pathology' than unexposed newborns (OR1 = 2.0 [1.0-3.9] and OR2 = 7.6 [2.8-20.5]). Conclusions The present study demonstrates the interest of this method based on individual drug trajectories for the evaluation of outcomes in pharmaco-epidemiological studies and more specifically during pregnancy. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: The initiative of a consensus on the topic of antidepressant and anxiolytic drug use in pregnancy is developing in an area of clinical uncertainty. Although many studies have been published in recent years, there is still a paucity of authoritative evidence-based indications useful for guiding the prescription of these drugs during pregnancy, and the data from the literature are complex and require expert judgment to draw clear conclusions., Methods: For the elaboration of the consensus, we have involved the scientific societies of the sector, namely, the Italian Society of Toxicology, the Italian Society of Neuropsychopharmacology, the Italian Society of Psychiatry, the Italian Society of Obstetrics and Gynecology, the Italian Society of Drug Addiction and the Italian Society of Addiction Pathology. An interdisciplinary team of experts from different medical specialties (toxicologists, pharmacologists, psychiatrists, gynecologists, neonatologists) was first established to identify the needs underlying the consensus. The team, in its definitive structure, includes all the representatives of the aforementioned scientific societies; the task of the team was the evaluation of the most accredited international literature as well as using the methodology of the "Nominal Group Technique" with the help of a systematic review of the literature and with various discussion meetings, to arrive at the drafting and final approval of the document., Results: The following five areas of investigation were identified: (1) The importance of management of anxiety and depressive disorders in pregnancy, identifying the risks associated with untreated maternal depression in pregnancy. (2) The assessment of the overall risk of malformations with the antidepressant and anxiolytic drugs used in pregnancy. (3) The evaluation of neonatal adaptation disorders in the offspring of pregnant antidepressant/anxiolytic-treated women. (4) The long-term outcome of infants' cognitive development or behavior after in utero exposure to antidepressant/anxiolytic medicines. (5) The evaluation of pharmacological treatment of opioid-abusing pregnant women with depressive disorders., Conclusions: Considering the state of the art, it is therefore necessary in the first instance to frame the issue of pharmacological choices in pregnant women who need treatment with antidepressant and anxiolytic drugs on the basis of data currently available in the literature. Particular attention must be paid to the evaluation of the risk/benefit ratio, understood both in terms of therapeutic benefit with respect to the potential risks of the treatment on the pregnancy and on the fetal outcome, and of the comparative risk between the treatment and the absence of treatment; in the choice prescription, the specialist needs to be aware of both the potential risks of pharmacological treatment and the equally important risks of an untreated or undertreated disorder.

The benzodiazepines´ electrochemical reduction process, a tool, capable to be used in electroanalytic investigation, was anaylzed by mechanistic and mathematical means. The correspondent model was analyzed by means of linear stability theory and bifurcation analysis, and by its mean it was possible to get the requisite for the best process efficiency, the pH-dependence of its function, like also of oscillatory and monotonic instability. An effort is made fot the systematic mechanistic analysis of the work of benzodiazepine electrochemical sensors. [ABSTRACT FROM AUTHOR]

This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

A procedure based on ultra-high-pressure liquid chromatography tandem mass spectrometry has been developed for the determination of 22 antidepressant and anxiolytic drugs ad metabolites in the three consecutive maternal hair segments representing the pregnancy trimesters and paired neonatal meconium samples. After hair washing with methyl alcohol and diethyl ether and subsequent addition of internal standards, hair samples were treated with 500 μl VMA-T M3 reagent for 1 h at 100 °C. After cooling, 100 μl M3 extract were diluted with 400 μl water and a volume of 10 μl was injected into chromatographic system. Meconium samples were firstly treated with 1 ml methyl alcohol and the organic layer back-extracted twice with 1.5 ml of a mixture of ethylacetate:hexane (80:20, v/v). Chromatographic separation was achieved at ambient temperature using a reverse-phase column and a linear gradient elution with two solvents: 0.3% formic acid in acetonitrile and 5 mM ammonium formate pH 3. The mass spectrometer was operated in positive ion mode, using multiple reaction monitoring via positive electrospray ionization. The method was linear from the limit of quantification (0.05–1 ng/mg hair and 5–25 ng/g meconium depending on analyte under investigation;) to 10 ng/mg hair and 1000 ng/g meconium, with an intra- and inter-assay imprecision and inaccuracy always less than 20% and an analytical recovery between 66.6% and 95.3%, depending on the considered analyte and biological matrix. Using the validated method, 7 mothers were found positive to one or more hair segments and 5 meconium samples were found positive to one or more antidepressant and anxiolytic drugs, assessing prenatal exposure to these drugs following maternal consumption in one or more pregnancy trimesters. [ABSTRACT FROM AUTHOR]

Experimental drugs and/or plant extracts are often dissolved in solvents, including propylene glycol. Nevertheless, there is evidence for psychoactive properties of this alcohol. In this study we found that in the hole-board test 10% propylene glycol did not modify the head-dipping behavior. However, 30% propylene glycol induced an increase in the number of head-dips (46.92 ± 2.37 compared to 33.83 ± 4.39, P

Introduction: Sexual dysfunction is a potential side eff ect of mood stabilizers and anxiolytic drugs: this article presents a critical review of the current literature. Although many studies have been published on sexual side eff ects of psychopharmacological treatment, only a minority relate to mood stabilizers and anxiolytic drugs. Most of these studies are not methodologically robust, few are RCTs and most did not use a validated rating scale to evaluate sexual functioning. In addition, many of the studies on sexual dysfunction associated with mood stabilizers and anxiolytic drugs are limited by other methodological flaws. While there is evidence to suggest that mood stabilizers, with some exceptions, negatively affect sexual functioning, there is still insufficient evidence to draw any clear conclusions about the eff ects of anxiolytic drugs on sexual function. There is some weak evidence to indicate that switching from enzyme-inducing to non-enzyme-inducing anticonvulsant drugs, could be clinically useful. Some researchers recommend that sexual dysfunction in patients taking antiepileptic drugs should in general be treated according to standard guidelines for the management of sexual dysfunction, since reliable data on special populations is not available. However, specific approaches may be useful, but cannot yet be recommended until further validating research has been conducted. We did not find evidence supporting the use of any specific treatment strategy for sexual dysfunction associated with anxiolytic treatment. Methods: This study was conducted in 2013 using the paper and electronic resources of the library of the Azienda Provinciale per i Servizi Sanitari (APSS) in Trento, Italy (http://atoz.ebsco. com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/ Titles/2793, or at the APSS web site (http://www. apss.tn.it). In completing this review, a literature search was conducted using the key words "anxiolytic drugs", "mood stabilizers", "benzodiazepines", "psychotrophic drugs", "sexual dysfunction", "sexual side eff ects", "treatment-emergent sexual dysfunction". All resulting listed articles were reviewed. Discussion: This review includes studies that investigated the relationship between mood stabilizer and anxiolytic drug treatment and sexual dysfunction. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The free exploratory paradigm is regarded as a reliable test for trait anxiety in mice but it may also be useful in rats. Previously, we showed that rat strains differ in their free exploration of novel areas, i.e. the surroundings of their familiar home cage when the lid was removed. Aim: Therefore, the purpose of the present study was to further examine strain, sex, and age differences in animals from different breeders in combination with pharmacological treatment designed to modify anxiety. Methods: In the present study free exploratory behaviour test was evaluated in Sprague Dawley and Wistar rats from different breeders. We assessed seasonal variation, habituation to the test, and the impact of gender and age on exploration. Furthermore, we monitored exploration following intraperitoneal diazepam, 8-OH-DPAT and caffeine administration. Parameters measured were latency to start exploring the outside of the cage, the percentage of rats that explored the outside, as well as the number of visits. Results: There was no seasonal variability in free exploratory behaviour. However, strains and sexes differed in the test results, though age-related differences had less impact. Diazepam (2mg/kg) and 8-OH-DPAT (30, 100 and 300μg/kg) decreased neophobia while caffeine (50mg/kg) increased the latency to explore the outside the next day. Discussion: The free exploratory behaviour test can be used as a simple and complementary test to study trait anxiety-related behaviour in rats. [Copyright &y& Elsevier]

Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. (2012) Neuropharmacology 62:155-160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the Ih blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem-evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Cocaine is used worldwide and considered a public health problem. Relapse from addiction is one of the difficulties faced by cocaine users, and in most cases according to the period of abstinence, users may present symptoms such as anxiety or depression. To evaluate the anxiety-like behavior induced by different periods, rats were treated for 7 days with cocaine 20mg/kg, i.p., and 24h, 7 and 21 days after drug withdrawal were submitted to the elevated plus maze (EPM) and the open field (OF) tests. In different protocol, propranolol (10mg/kg, i.p.), ondansetron (4mg/kg, i.p.) and buspirone (5mg/kg, i.p.) were administered once after 24h and 7 days of abstinence from cocaine to evaluate possible reversal or attenuation of the symptoms caused by cocaine withdrawal. EPM results showed a reduction in all parameters after 24h and 7 days of the last exposure to cocaine, indicating anxiety-like behavior. In the OF test, 24h and 7 days of abstinence showed increased locomotor activity, while in the withdrawal 21 days the animals not alter the locomotor activity. The administration of propranolol, ondansetron or buspirone after a 24h abstinence period reduced the animalś anxiety in the EPM, and in the OF all drugs were able to reduce locomotor activity. After abstinence 7d, the drugs reduced locomotor activity in the OF, in the EMP propranolol and ondansetron reversed the anxiogenic effect induced by cocaine. These results suggest that the treatment of anxyogenic effects of abstinence from cocaine is dependent on the period of the withdrawal. [Copyright &y& Elsevier]

Abstract: Hippocampal theta rhythms have been associated with a number of behavioural processes, including learning, memory and arousal. Recently it has been argued that the suppression of hippocampal theta is a valid indicator of anxiolytic drug action. Like all such models, however, it has relied almost exclusively on the experimental effects of well-known, clinically proven anxiolytic compounds for validation. The actual predictive validity of putative models of anxiolytic drug action, however, cannot be rigorously tested with this approach alone. The present study provides a stringent test of the predictive validity of the theta suppression model, using the drug phenytoin (50 mg/kg and 10 mg/kg), and a positive comparison compound, diazepam (2 mg/kg). Phenytoin has two important properties that are advantageous for assessing the validity of the theta suppression model: 1) it is a standard antiepileptic drug with no known anxiolytic effects, and 2) its primary mechanism of action is through suppression of the persistent sodium current, an effect that should also suppress hippocampal theta. Because of the latter property, we also directly compared the effects of phenytoin in the theta suppression model with its effects in the most widely tested behavioural model of anxiolytic drug action, the elevated plus-maze. While an anxiolytic-like effect of phenytoin in the theta suppression model might be expected simply due to its suppressive effects on sodium channel currents, anxiolytic effects in both tests would provide strong support for the predictive validity of the theta suppression model. Surprisingly, phenytoin produced clear anxiolytic-like effects in both neurophysiological and behavioural models, thus providing strong evidence of the predictive validity of the theta suppression model. This article is part of a Special Issue entitled ‘Anxiety and Depression’. [Copyright &y& Elsevier]

Abstract: Zebrafish (Danio rerio) are becoming increasingly popular in neurobehavioral research. Here, we summarize recent data on behavioral responses of adult zebrafish to a wide spectrum of putative anxiolytic and anxiogenic agents. Using the novel tank test as a sensitive and efficient behavioral assay, zebrafish anxiety-like behavior can be bi-directionally modulated by drugs affecting the gamma-aminobutyric acid, monoaminergic, cholinergic, glutamatergic and opioidergic systems. Complementing human and rodent data, zebrafish drug-evoked phenotypes obtained in this test support this species as a useful model for neurobehavioral and psychopharmacological research. [Copyright &y& Elsevier]

Abstract: The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium®. The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for “minor forms” (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex. [Copyright &y& Elsevier]

Many case reports and results of a few controlled studies have documented the sexual side effects of all classes of psychotropic medications-neuroleptics, benzodiazepines, mood stabilizers and antidepressants. Sexual side effects are clinically important because they contribute to noncompliance with treatment regimens and may impair the user's quality of life . For this reason, clinicians must be aware of these side effects, and are advised to ask patients about their sexual functions during their psychiatric treatments. [ABSTRACT FROM AUTHOR]

Application of anxiolytic drug Selank to hippocampal slices increased the amplitude and discharge rate of spontaneous inhibitory postsynaptic currents in rat hippocampal pyramidal CA1 neurons. In some neurons, Selank-induced up-regulation of spontaneous inhibitory postsynaptic currents was preceded by a transient decrease in this activity. In the examined concentration range (1-8 μM), Selank demonstrated no significant dose-dependence. [ABSTRACT FROM AUTHOR]

Abstract: Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT1A receptor agonist) anxiolytic drug with some D2 dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic). [Copyright &y& Elsevier]

Abstract: The hypothesis that kainate receptor blockade would be associated with anxiolytic-like effects was tested with a selective ligand, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). LY382884 selectively binds the GLUK5 kainate receptor subunit (K b =0.6μM) and has 30μM or greater affinity for cloned human AMPA receptor subtypes. The anxiolytic potential of LY382884 was tested in rats responding under a Vogel conflict procedure, a pharmacologically validated model for the prediction of antianxiety efficacy in humans. Both the benzodiazepine anxiolytic chlordiazepoxide and LY382884 increased suppressed licking without affecting rates of non-suppressed licking. In contrast, an AMPA receptor selective antagonist, 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI) (GYKI53655), did not increase suppressed responding. The finding that a selective GLUK5 receptor antagonist produced anxiolytic-like effects in an animal model predictive of efficacy in humans combined with data in the literature on glutamatergic modulation of anxiety suggests that kainate receptor sensitivity to glutamate might be an important mediating event in the pathophysiological expression of anxiety states. The selective targeting of kainate receptors with an antagonist could therefore be a novel pharmacological mechanism to treat anxiety disorders. [Copyright &y& Elsevier]

Abstract: Selected derivatives of 1,4-benzodiazepine: lorazepam, lormetazepam, oxazepam and temazepam, used as active substances in anxiolytic drugs, have been studied by 35Cl NQR method in order to find the correlation between electronic structure and biological activity. The 35Cl NQR resonance frequencies (ν Q ) measured at 77K have been correlated with the following parameters characterising their biological activity: biological half-life period (t 0.5), affinity to benzodiazepine receptor (IC50) and mean dose equivalent. The results of experimental study of some benzodiazepine derivatives by nuclear quadrupole resonance of 35Cl nuclei are compared with theoretical results based on DFT calculations which were carried out by means of Gaussian’98 W software. [Copyright &y& Elsevier]

Rationale: Although convergent evidence exists for a role of glutamate in the regulation of anxiety, the involvement of specific glutamate receptor subtypes has yet to be defined. Objective: To evaluate the potential for blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors to produce anxioltyic-like effects with the AMPA/GLUK5 (kainate) antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5yl)ethyl]decahydroisoquinoline-3carboxylic acid (LY293558). Materials and methods: Punished responding of rats was used to determine the efficacy of LY293558. Other in vivo and in vitro studies further characterized the specificity of LY293558 for AMPA/kainate receptors. Results: LY293558 had a rank order of potency of GLUK5 = GLUK5/6 ≥ GLUA2i ≈ GLUK2/5 ≈ GLUA1i ≈ GLUA2o ≈ GLUA3i ≈ GLUA1o ≥ GLUA3o ≥ GLUA4i ≈ GLUA4o and >100 µM affinity for rat cortical GABAA receptors. Comparison of the blockade of AMPAvs N-methyl-D-aspartate (NMDA)-induced inward currents demonstrated that LY293558 was fivefold more potent as an antagonist at AMPAvs NMDA receptors in vitro. In keeping with the low affinity of LY293558 for NMDA receptors, LY293558 was not effective in preventing NMDA-induced seizures in mice. LY293558 increased punished responding, a preclinical predictor of anxiolytic efficacy, at a dose that decreased unpunished responding (10 mg/kg, i.p.). Chlordiazepoxide produced comparable increases in both punished and unpunished responding. The NMDA antagonist dizocilpine [(+)-MK-801] also increased both punished and unpunished responding. Conclusions: These data along with those in the literature suggest that AMPA and/or kainate receptor blockade may be an important component to producing anxiolytic-like effects and may therefore be a target for compounds with efficacy in the therapeutic treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

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Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray''s theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder. [Copyright &y& Elsevier]

Rationale. Effects of compounds on punished responding have been predictive of anxiolytic efficacy in humans. The use of mice in these tests has been limited, but the utility of this species in drug discovery and for neurobiological inquiry would benefit from a rapid, reliable method. Objectives. The present experiments were designed to validate a new procedure in mice. Methods. Male, NIH Swiss mice were food deprived and placed in an experimental chamber with two nose-poke holes. Every nose poke (FR1) produced a 20 mg food pellet. On the following day, a drug vehicle was administered and the mice were again exposed to the FR1 schedule. On day 3, a compound was given and the mice were run under a mixed FR1 (food), FR1 (food+shock) schedule in alternating, unsignalled periods of 4 and 10 min for three cycles. In the 10-min periods, nose-pokes produced both food plus brief electrification of the grid floor (0.5 mA for 100 ms). Effects of compounds on food intake were also evaluated in separate groups of mice. Results. The introduction of shock substantially decreased responding during the 10-min punishment periods without significantly affecting responding during the non-punishment periods. The clinically effective anxiolytic agents chlordiazepoxide, pentobarbital, and bretazenil, but not buspirone, produced dose-dependent increases in suppressed responding, whereas d-amphetamine, chlorpromazine, and morphine were not effective. Chlordiazepoxide and bretazenil increased food consumption. Conclusions. The present method enables rapid and reliable evaluation of potential anxiolytic agents in mice with minimal training. Increases in food intake are not necessary for anxiolytic-like effects under these conditions. [ABSTRACT FROM AUTHOR]