Anti-Inflammatory Therapy as a Promising Target in Neuropsychiatric Disorders.

This chapter analyzes the therapeutic potential of current anti-inflammatory drugs in treating psychiatric diseases from a neuro-immunological perspective. Based on the bidirectional brain-immune system relationship, the rationale is that a dysregulated inflammation contributes to the pathogenesis of psychiatric and neurological disorders, while the immunology function is associated with psychological variables like stress, affective disorders, and psychosis. Under certain social, psychological, and environmental conditions and biological factors, a healthy inflammatory response and the associated "sickness behavior," which are aimed to resolve a physical injury and microbial threat, become harmful to the central nervous system. The features and mechanisms of the inflammatory response are described across the main mental illnesses with a special emphasis on the profile of cytokines and the function of the HPA axis. Next, it is reviewed the potential clinical utility of immunotherapy (cytokine agonists and antagonists), glucocorticoids, unconventional anti-inflammatory agents (statins, minocycline, statins, and polyunsaturated fatty acids (PUFAs)), the nonsteroidal anti-inflammatory drugs (NSAIDs), and particularly celecoxib, a selective cyclooxygenase-2 (Cox-2) inhibitor, as adjuvants of conventional psychiatric medications. The implementation of anti-inflammatory therapies holds great promise in psychiatry. Because the inflammatory background may account for the etiology and/or progression of psychiatric disorders only in a subset of patients, there is a need to elucidate the immune underpinnings of the mental illness progression, relapse, and remission. The identification of immune-related bio-signatures will ideally assist in the stratification of the psychiatric patient to predict the risk of mental disease, the prognosis, and the response to anti-inflammatory therapy.

Does endogenous cholecystokinin modulate alcohol intake?

Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.

Neurogenesis and Neuroplasticity in Major Depression: Its Therapeutic Implication.

The neurochemical model of depression, based on monoaminergic theories, does not allow on its own to understand the mechanism of action of antidepressants. This approach does not explain the gap between the immediate biochemical modulations induced by antidepressants and the time required for their clinical action. Several hypotheses have been developed to try to explain more precisely the action of these molecules, each of them involving mechanisms of receptor regulation. At the same time, data on the neuroanatomy of depression converge toward the existence of specific lesions of this pathology. This chapter aims to provide an overview of recent advances in understanding the mechanisms of neural plasticity involved in pathophysiology depression and in its treatment.

Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A "Dimmer-Switch" Hypothesis.

Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.

Experimental Anxiety Model for Anxiety Disorders: Relevance to Drug Discovery.

This chapter describes the various animal models that seem relevant to the development of anxiolytic drugs, as well as the human models of induced anxiety, or more precisely the panic inducers including cholecystokinin. It is also mentioned the theoretical model of Deakin and Graeff which seems to keep all its relevance. The knock animals are evoked as relevant tools as well as a new optogenetic technique that needs to be used in this field.

Blockade of the cholecystokinin CCK-2 receptor prevents the normalization of anxiety levels in the rat.

Cholecystokinin (CCK), through the CCK-2 receptor, exerts complex effects on anxiety. While CCK agonists are panicogenic, CCK-2 antagonists fail to alleviate human anxiety. Preclinical studies with CCK-2 antagonists are also inconsistent because their anxiolytic effects largely depend on the behavioral paradigm and antecedent stress. The controversy might be accounted by the neuromodulatory role for CCK in anxiety which is ill-defined. If this is its actual role, blocking CCK-2 will have carry-over effects on the anxiety baseline over time. To test this hypothesis, the consequences of acute administration of the CCK-2 antagonist Ly225.910 (0.1 mg Kg-1) was evaluated in the temporal expression of aversion toward exploration-conflicting tasks. Ly225.910 effects were evaluated in rats exposed to the elevated plus-maze (EPM) twice, an approach-avoidance anxiety-like test. While LY225.910-treated rats had less anxiety than vehicle-treated rats, the difference was reversed during the EPM retest 24 h later without drug. Moreover, Ly225.910 effects in stress-induced cognitive impairment was measured giving the novel-object discrimination (NOD) test to rats not habituated to the exploration apparatus to elicit neophobia. After a first encounter with objects ("old"), Ly225.910-treated rats did not recognize the "novel" object introduced 6 h later. Ly225.910-exposed rats did not discriminate the new location of the "novel object" when it was repositioned in the arena 24 h later. Ly225.910-treated rats also failed to explore objects. In line with its neuromodulatory role, aversive carry-over effects of Ly225.910 suggest that CCK-2 activation by endogenous CCK, rather than triggering anxiety, may return the anxiety state to its normal level.

Animal Research in Psychiatry.

Animal research in psychiatry suffers from a poor translational value. It is the same for all other disciplines. Our purpose in this chapter is therefore to highlight all the parameters that can lead to a non-reproducibility of interlaboratory experiments as well as intralaboratory. This is to point out the experimental parameters that are likely to lead to bias. Parameters are essentially: breeding conditions, animal strains, housing, handling, illumination, weather conditions, age, and the actual experimental conditions. Controlling these parameters is not enough if there is no consensus of the scientific community to implement them in a standardized way. However, it is possible to improve the translational concept by taking stock of what has been operational without forgetting to standardize as much as possible the essential parameters of behavioral research. Now there are calls to take a different approach to animal experimentation, by asking not what was controlled in an experiment, but what was ignored. This new school of thinking has been termed "therioepistemology"; the study of how knowledge is gained from animal research. The focus is on what's been ignored in an animal data set, why it's been ignored, and how it affects the model or experiment.

An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action.

Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When choosing between treatment options, anxiety needs to be understood in the situational, psychiatric, and biological context in which it arises. Etifoxine, a non-benzodiazepine anxiolytic drug belonging to the benzoxazine class, is an effective treatment for anxiety in response to a stressful situation. In the present review, we focused on several aspects of the cerebral and somatic biological mechanisms involved in anxiety and investigated the extent to which etifoxine's mode of action can explain its anxiolytic activity. Its two mechanisms of action are the modulation of GABAergic neurotransmission and neurosteroid synthesis. Recent data suggest that the molecule possesses neuroprotective, neuroplastic, and anti-inflammatory properties. Etifoxine was first shown to be an effective anxiolytic in patients in clinical studies comparing it with clobazam, sulpiride, and placebo. Randomized controlled studies have demonstrated its anxiolytic efficacy in patients with adjustment disorders (ADs) with anxiety, showing it to be superior to buspirone and comparable to lorazepam and phenazepam, with a greater number of markedly improved responders and a better therapeutic index. Etifoxine's noninferiority to alprazolam has also been demonstrated in a comparative trial. Significantly less rebound anxiety was observed after abrupt cessation of etifoxine compared with lorazepam or alprazolam. Consistent with this finding, etifoxine appears to have a very low dependence potential. Unlike lorazepam, it has no effect on psychomotor performance, vigilance, or free recall. Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Taken together, its dual mechanisms of action in anxiety and the positive data yielded by clinical trials support the use of etifoxine for treating the anxiety signs and symptoms of individuals with ADs.

The test retest model of anxiety: An appraisal of findings to explain benzodiazepine tolerance.

A test retest protocol in animal model of anxiety induces an increase of anxious behavior and a loss of benzodiazepine-induced effect. This effect, known as the "one trial tolerance", is mainly observed in the elevated plus maze, an ethological model of anxiety in mice, but also in the four plate test, a model based on punishment. A review of some hypotheses based on behavioral, pharmacological and neurochemical approaches are proposed here to explain this benzodiazepines tolerance phenomenon.

Anxiety Disorders: Sex Differences in Serotonin and Tryptophan Metabolism.

INTRODUCTION: Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. METHODS: A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. RESULTS: This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sexrelated differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men, and therefore, females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. CONCLUSION: The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through the production of anxiogenic TRYCATs.

Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition.

OBJECTIVE: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). METHODS: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. RESULTS: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. CONCLUSIONS: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial.

BACKGROUND: Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. AIMS: To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. METHOD: Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). RESULTS: No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. CONCLUSIONS: Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

Potential serotonergic agents for the treatment of schizophrenia.

INTRODUCTION: For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia. AREAS COVERED: In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed. EXPERT OPINION: Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia.

Animal models for screening anxiolytic-like drugs: a perspective.

Contemporary biological psychiatry uses experimental animal models to increase our understanding of affective disorder pathogenesis. Modern anxiolytic drug discovery mainly targets specific pathways and molecular determinants within a single phenotypic domain. However, greater understanding of the mechanisms of action is possible through animal models. Primarily developed with rats, animal models in anxiety have been adapted with mixed success for mice, easy-to-use mammals with better genetic possibilities than rats. In this review, we focus on the three most common animal models of anxiety in mice used in the screening of anxiolytics. Both conditioned and unconditioned models are described, in order to represent all types of animal models of anxiety. Behavioral studies require careful attention to variable parameters linked to environment, handling, or paradigms; this is also discussed. Finally, we focus on the consequences of re-exposure to the apparatus. Test-retest procedures can provide new answers, but should be intensively studied in order to revalidate the entire paradigm as an animal model of anxiety.

La psiquiatría biológica actual emplea modelos animales experimentales para aumentar la comprensión acerca de la patogénesis del trastorno afectivo. El descubrimiento de los fármacos ansiolíticos modernos apunta principalmente a vías especificas y determinantes moleculares dentro de un dominio fenotípico único. Sin embargo, es posible una mayor comprensión de los mecanismos de acción a través de los modelos animales. Los modelos animales de ansiedad, inicialmente desarrollados en ratas, han sido adaptados con relativo éxito en ratones, un mamífero fácil de emplear y con mejores posibilidades genéticas que las ratas. Esta revisión se focaliza en los tres modelos animales de ansiedad empleados más comúnmente en ratones, que se utilizan para la evaluación de ansiolíticos. Se describen tanto los modelos condicíonados como los incondicionados con el fin de representar todos los tipos de modelos animales de ansiedad. También se analiza el gran cuidado que se debe poner en los parámetros variables relacionados con el ambiente, la manipulación o el paradigma que tienen los estudios de comportamiento. Por último se centra la atención en las consecuentias de la re-exposición al aparato. Los procedimientos de test-retest pueden proportionar nuevas respuestas, pero deben ser ampliamente estudiados para revalidar todo el paradigma como un modelo animal de ansiedad.

La psychiatrie biologique actuelle utilise les modèles animaux expérimentaux pour mieux comprendre la pathogenèse des troubles affectifs. La recherche moderne sur les anxiolytiques cible principalement les voies spécifiques et les déterminants moléculaires dans un phénotype unique. Les modèles animaux permettent néanmoins de mieux comprendre les mécanismes d'action. D'abord développés chez le rat, les modèles animaux de l'anxiété ont été adaptés avec un succès variable chez la souris, un mammifère facile à utiliser dont les possibilités génétiques sont meilleures que celles du rat. Dans cet article, nous nous intéressons aux trois modèles d'anxiété les plus courants chez la souris, utilisés pour la sélection d'anxiolytiques. Nous décrivons à la fois les modèles conditionnés et non conditionnés afin de représenter tous les types de modèles animaux d'anxiété. Les études de comportement nécessitant une observation soigneuse des paramètres variables liés à l'environnement, aux façons de réagir ou aux modèles, sont aussi analysées. Enfin nous nous intéressons aux conséquences de la ré-exposition au dispositif. Les techniques de fiabilité test-retest peuvent fournir de nouvelles réponses mais doivent être étudiées en profondeur afin de revalider le modèle entier comme modèle animal de l'anxiété.

Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study.

Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ≥20, and score ≥4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add-on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.

How assess drugs in the treatment of acute bipolar mania?

Bipolar affective disorder is a serious mental disease associated with significant morbidity and mortality. Good-quality research available to guide treatment strategies remains insufficient, particularly with regard to manic or hypomanic episodes. A critical review of the various stages of mania might be helpful for pharmaceutical companies and investigators as a prerequisite for the clinical evaluation of potential antimanic properties of medications. The main difficulty is with a comparison between anticonvulsants, antipsychotics, and mood stabilizers such as lithium (with equal efficacy in the acute phase and the prevention of recurrent manic episodes). No consensus has been reached with regard to the treatment of bouts of acute mania in various parts of the world. Controlled clinical trials have, at last, provided irrefutable evidence of the activity of lithium, which has long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine. The new antipsychotic agents have more recently established their efficacy, especially aripiprazole, asenapine, quetiapine; olanzapine, risperidone, and ziprasidone (not sure where the paradox is). In Europe, haloperidol is still the reference substance used in clinical trials despite the fact that it is not officially indicated in the treatment of mania. In the USA, lithium, divalproate, or antipsychotics can be prescribed as first-line treatment. In Europe, lithium remains the first-line medication, whereas divalproate and atypical antipsychotic agents are used only as second-line therapy. Although both types of medication (antipsychotics, normothymic agents, and/or anticonvulsants) have proved to be clinically effective in the management of mania by reducing the mania scores overall, the same does not apply, however, to all symptoms of mania. Factorial approaches to mania have all shown that since there are several clinical forms of mania, several clusters of manic symptoms can be identified. Antipsychotic and normothymic agents and/or anticonvulsants do not appear to have the same effects on each of these identifiable clusters of symptoms, mainly psychotic features. We believe that it is vitally important for future clinical trials of mania treatment to focus on the treatment effect by adopting a factorial approach to characterization of the episode using an appropriate methodological structure. These questions highlight the uncertainty shrouding the very structure of manic episodes, namely that these are predominantly of a thymic or psychotic nature. The Europeans undoubtedly consider mania to be more of a thymic episode and prefer lithium as the first-line treatment, whereas the Americans believe that psychotic symptoms dominate and widely prescribe antipsychotic agents. However, from the standpoint of clinical trials currently available, even though antipsychotic agents are certainly effective in reducing the scores on the mania scales, it is not clear whether they can be considered purely as antimania treatments.

Potential role of cortical 5-HT(2A) receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal.

The antipsychotic cyamemazine is a potent serotonin 5-HT(2A) receptor (5-HT(2AR)) antagonist. A positron emission tomography (PET) study in human patients showed that therapeutic doses of cyamemazine produced near saturation of 5-HT(2AR) occupancy in the frontal cortex, whereas dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics. Recently, numerous studies have revealed the involvement of 5-HT(2AR) in the pathophysiology of anxiety and a double-blind, randomized clinical trial showed similar efficacy of cyamemazine and bromazepam in reducing the anxiety associated with benzodiazepine withdrawal. Therefore, we reviewed the above articles about 5-HT(2AR) and anxiety in order to understand better the anxiolytic mechanisms of cyamemazine in benzodiazepine withdrawal. The 5-HT(2AR) is the most abundant serotonin receptor subtype in the cortex. Non-pharmacological studies with antisense oligodeoxynucleotides and genetically modified mice clearly showed that cortical 5-HT(2AR) signaling positively modulates anxiety-like behavior. With a few exceptions, most other studies reviewed here further support this view. Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT(2AR) antagonistic activity at the cortical level.

Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice.

UNLABELLED: Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepine and neurosteroids but potentiating GABA(A) receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Etifoxine has been shown to possess some anxiolytic-like effects in rodents. METHODS: Using the four-plate test (FPT) model of anxiety in mice the potential anxiolytic-like effect of etifoxine was first to re-evaluate. In a second part, in order to better understand the mechanism of action of etifoxine, interaction studies with 5-HT(2) ligands were performed in the FPT as mixed serotonergic and GABAergic mechanisms are highly implicated in the anxiolytic-like effect observed in the FPT. RESULTS: A dose response effect was observed for etifoxine from the dose of 40-100 mg/kg. Doses above to 60 mg/kg induced a sedative effect as was determined in the actimeter test. The 5-HT(2A) receptor antagonist SR 46349B blocked the anti-punishment activity of etifoxine (40 and 50 mg/kg), while the 5-HT(2B/2C) receptor antagonist, SB 206553 and the 5-HT(2C) receptor antagonist, RS 10-2221 did not alter its effects. In a same way, only the 5-HT(2A) agonist DOI induced anti-punishment effect when co-administered with subthreshold doses of etifoxine. CONCLUSION: The present results demonstrated that etifoxine effect was modulated by 5-HT(2A) ligands co-administration. The large literature concerning GABA and 5-HT suggests that they could be co-released and could act as co-transmitters in some regions of the CNS and cross-communication between the two neurotransmitters might be an important modulator process of neuronal activity.