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Rationale: Early Life Stress (ELS) increases risk for both adult traumatization and posttraumatic stress disorder (PTSD). Adult PTSD may also reflect a continuation of a response to an earlier exposure to adversity. Given similarities between neuroendocrine aspects of PTSD and ELS, such as in reduced cortisol signaling and glucocorticoid receptor (GR) responsiveness, some aspects of the biology of PTSD may reflect biological correlates of risk., Objectives: This paper will examine how empirical findings regarding the biological basis of ELS can inform our understanding of the neuroendocrinology of PTSD. This paper will also propose a hypothetical model to guide future research that integrates genetic, epigenetic, neuroendocrine, and psychological observations to understand the contribution of ELS neurobiology to PTSD., Results: Recent genetic findings demonstrate heritable aspects of at least some of these cortisol-related disturbances. Furthermore, ELS may produce at least some of the PTSD-associated changes in glucocorticoid responsiveness through epigenetic mechanisms such as developmental programming. These, then, may contribute to enduring changes in stress responsiveness as well as enhanced risk for adult exposure and PTSD., Conclusion: Molecular mechanisms associated with gene x environment interactions or GR programming are essential in explaining current observations in the neuroendocrinology of PTSD that have been difficult to understand through the lens of contemporary stress theory.

Recent evidence suggests that the GABA transporter 1 (GAT-1; SLC6A1) plays a role in the pathophysiology and treatment of anxiety disorders. In order to understand the impact of genetic variation within SLC6A1 on pathological anxiety, we performed a case-control association study with anxiety disorder patients with and without syndromal panic attacks. Using the method of sequential addition of cases, we found that polymorphisms in the 5' flanking region of SLC6A1 are highly associated with anxiety disorders when considering the severity of syndromal panic attacks as phenotype covariate. Analysing the effect size of the association, we observed a constant increase in the odds ratio for disease susceptibility with an increase in panic severity (OR approximately 2.5 in severely affected patients). Nominally significant association effects were observed considering the entire patient sample. These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety and highlight GAT-1 as a promising target for treatment of anxiety disorders with panic symptoms.

Introduction: Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition., Objective: To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression., Materials and Methods: The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology., Results and Discussion: Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice., Conclusion: Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

Rationale: Regional-specific corticotropin-releasing factor receptor 1 (CRF-R1) knockout mice have been generated recently as a tool to dissociate CNS functions modulated by this receptor. In these mice, CRF-R1 function is postnatally inactivated in the anterior forebrain including limbic brain structures but not in the pituitary leading to normal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis under basal conditions and reduced anxiety-related behavior in the light-dark box and the elevated plus maze (EPM) as compared to wild-type (WT) mice (Müller et al., Nat Neurosci 6:1100-1107, 2003)., Objective: To identify neurobiological correlates underlying this reduced anxiety-like behavior, the expression of c-Fos, an established marker for neuronal activation, which was examined in response to a mild anxiogenic challenge., Materials and Methods: Mice were placed for 10 min on the open arm (OA) of the EPM, and regional c-Fos expression was investigated by immunohistochemistry., Results: OA exposure enhanced c-Fos expression in both conditional CRF-R1 knockout and WT mice in a number of brain areas (39 of 55 quantified), including cortical, limbic, thalamic, hypothalamic, and hindbrain regions. The c-Fos response in conditional CRF-R1 knockout animals was reduced in a restricted subset of activated neurons (4 out of 39 regions) located in the medial amygdala, ventral lateral septum, prelimbic cortex, and dorsomedial hypothalamus., Conclusions: These results underline the importance of limbic CRF-R1 in modulating anxiety-related behavior and suggest that reduced neuronal activation in the identified limbic and hypothalamic key structures of the anxiety circuitry may mediate or contribute to the anxiolytic-like phenotype observed in mice with region-specific deletion of forebrain CRF-R1.

Rationale: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets., Objective: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model., Results: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775., Conclusion: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.

Background: Symptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated., Methods: 238 RLS patients were assessed with a standardized diagnostic interview (Munich-Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18-65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types., Results: RLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1-10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7-7.1), and major depression (OR=2.6; 95% CI=1.5-4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls., Conclusions: The results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.

About 25 years ago the observation that neuropeptides serve as signalling molecules in the nervous system generated great expectations for drug industry. In this article the progress made since then in exploiting neuropeptide systems pharmacologically in psychiatry is highlighted. In affective disorders a number of neuropeptides seem to be causally involved in development and course of illness, especially corticotropin releasing hormone (CRH), vasopressin (AVP) and substance P, whose receptors are now targeted with small molecules designed to reduce depressive and anxiety symptoms. Although not exactly neuropeptides, also neurotrophins, may have a distinct role in antidepressant action and possibly also in causation of depression. Schizophrenia-like symptoms are caused by neurotensin (NT), supporting the notion that drugs interfering with NT systems are potential antipsychotics. Finally, sleep disorders, currently treated with hypnotics, that have serious adverse effects can be targeted with neuropeptides. According to the work by Axel Steiger several neuropeptides even if peripherally administered produce improvements of quality of sleep. All these observations call for intensified application of novel research tools necessary to exploit the potential of neuropeptide systems as psychopharmaceutical targets.

The estrogen receptor alpha has been shown to be activated both in a ligand-dependent and in a ligand independent fashion. We investigated whether antidepressants may directly activate the estrogen receptor alpha or enhance ligand-dependent or ligand-independent activation of the estrogen receptor alpha. Whereas both ligand-dependent and ligand-independent activation of the estrogen receptor alpha could be demonstrated in transient transfection studies, antidepressants neither directly activated the estrogen receptor alpha nor did they enhance ligand-dependent or ligand-independent activation. Thus, there are differences between the glucocorticoid receptor and the estrogen receptor alpha with regard to ligand-independent activation and action of antidepressants.

Although the exact etiology of multiple sclerosis (MS) remains unresolved, immune reactions are believed to be the central pathogenic mechanisms. Endogenous and therapeutic steroid hormones affect the immune system, and inflammatory diseases are associated with activation of the hypothalamic-pituitary-adrenal axis, providing evidence of an immune-endocrine interplay. Function tests in MS have revealed dysregulation of the hypothalamic-pituitary-adrenal system in a substantial proportion of patients. We characterized glucocorticoid receptor (GR) binding in peripheral blood lymphocytes from 39 MS patients and 14 age- and sex-matched controls with respect to dissociation constant and binding capacity, using a whole-cell binding assay with [3H]dexamethasone as the ligand. GR binding parameters did not differ significantly between patients (Kd 8.98 +/- 1.07 nM, Bmax 183 +/- 29.8 fmol/mg) and controls (Kd 9.36 +/- 1.17 nM, Bmax 158 +/- 16 fmol/mg). No effect of age, sex, course, duration or severity of disease, or prior steroid treatments was detected. GR binding parameters were analyzed in relation to the results of the combined dexamethasone-CRH test, which reflects corticosteroid receptor function at the hypothalamus, in 30 patients and 9 controls. While controls showed a moderate correlation between binding affinity of the GR in lymphocytes and regulatory function at the hypothalamic level, the patients did not. These data suggest that the physiological relationship between binding and function of the glucocorticoid receptor is disturbed in MS.

Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABA(A) receptor functioning. To assess the involvement of GABA(A) receptors, we investigated the sleep responses to one dose of the GABA(A) antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (< or = 8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABA(A) receptors play an important role in the sleep effects of progesterone.

The sigma (sigma) receptor has been proposed as a target of neuroleptic drugs. Preclinical data suggest that panamesine (EMD 57445), a novel sigma ligand, has antipsychotic effects and is free of side effects related to the extrapyramidal motoric system (EPMS). Here we report the results of an exploratory study aimed at determining the appropriate dose range and the safety of panamesine in patients with an acute episode of schizophrenia. The first trial with four patients revealed insufficient clinical efficacy of a protocol where the daily dosage was increased stepwise from 7.5 mg during week 1, up to 30 mg during weeks 3 and 4. In a second set of trials, 12 patients received 15 mg at the beginning, this being increased up to 60 mg/day within 3 days and then maintained at this level for 4 weeks. As assessed by a decrease in the Brief Psychiatric Rating Scale score by at least 50%, five patients were judged as responders, whereas six patients showed only a slight improvement, and one deteriorated. Moreover, intent-to-treat analysis showed significant improvement in psychometric variables. In all patients prolactin levels increased during treatment, probably due to an active metabolite with weak dopamine-2-receptor antagonistic effects. No major side effects occurred, and in particular, no EPMS symptoms were seen.

Anxiolytic effects of ethanol have been proposed to be important factors in the initiation of ethanol consumption. To examine this hypothesis, drug-naive Wistar rats were tested in the elevated plus-maze to determine their initial level of anxiety. Based on their response, we separated the animals into anxious and non-anxious groups. After that, animals went through an oral ethanol self-administration procedure. Rats that were initially classified as anxious showed a significantly (P < 0.01) higher intake and preference for ethanol during the initiation phase of the voluntary drinking procedure than non-anxious animals. In another experiment, intraperitoneal (IP) injections of ethanol (0.5-1.5 g/kg) produced dose-dependent anxiolytic effects in rats when tested in the elevated plus-maze procedure. Blood ethanol levels following IP injections during the plus-maze test were similar to those reached during the oral ethanol self-administration procedure, which shows that the rats indeed drank sufficient amounts of ethanol to experience its anxiolytic effects. These findings indicate that the basal level of anxiety plays an important role in vulnerability to alcohol drinking.

Preclinical data suggest that the imidazodiazepinone derivative bretazenil (Ro 16-6028) has anxiolytic and anticonvulsant properties with only weak sedative effects. We examined the influence of oral administration of 1 mg bretazenil on the sleep EEG and the concomitant nocturnal secretion of cortisol, growth hormone and prolactin in ten healthy young men. After bretazenil we found a significant increase in stage 2 sleep and a significant reduction in stage 3 sleep. REM latency was prolonged. Spectral analysis of sleep-EEG power revealed a decrease in delta and in theta power and an increase in sigma power. We found no significant influence on sleep onset latency or on intermittent wakefulness. Bretazenil prompted a significant decrease in cortisol secretion and a significant increase in prolactin release. It had no major influence on growth hormone secretion.

The effects of flumazenil, a benzodiazepine antagonist, on the sleep electroencephalogram (EEG) and neuroendocrine secretion in early morning recovery sleep (0500-0800 hours) following sleep deprivation (SD; 2300-0500 hours) were studied in seven healthy men. SD induced an increase in slow wave sleep (SWS), a decrease in sleep onset latency (SOL), an enhancement of EEG delta and theta power in non-rapid-eye-movement sleep, an increase in plasma human growth hormone (GH) concentration, and a decrease in plasma cortisol levels in recovery sleep (0500-0800 hours). Plasma GH, but neither plasma cortisol nor adrenocorticotrophic hormone (ACTH) concentration was attenuated during SD as compared to sleep (2300-0445 hours). The administration of flumazenil (3 x 1 mg intravenously) during recovery sleep resulted in an inhibition in SWS, an increase in stage 2 sleep, a selective reduction in delta and theta power, and a tendency to prolongation of SOL. Plasma GH concentration was decreased but plasma cortisol and ACTH remained unaffected. Since the SD-induced changes in sleep EEG and plasma GH secretion were antagonized by flumazenil, it is suggested that electrophysiological and hormonal effects of SD are mediated at least in part through GABAergic mechanisms.

The physiological function of benzodiazepine (BDZ) receptors includes regulation of sleep and neuroendocrine activity. Most of the pharmacological effects of BDZ are blocked by flumazenil. However, recent neurological and behavioral studies suggest that flumazenil has its own central intrinsic activity. This issue was addressed in a study of the sleep EEG and the nocturnal secretion of growth hormone and cortisol in ten normal male controls, who were given flumazenil either alone or in combination with the BDZ agonist midazolam, placebo and midazolam alone. Flumazenil prompted an increase in sleep onset latency, a decrease in slow wave sleep and an increase in wakefulness. Plasma cortisol concentrations after flumazenil administration were lower than after midazolam. Both flumazenil and midazolam decreased nocturnal growth hormone secretion. After simultaneous application of both BDZ receptor ligands the growth hormone blunting was amplified. Our study demonstrates that at the level of the sleep EEG and neuroendocrine activity flumazenil is capable of exerting both agonistic and inverse agonistic or antagonistic effects.

The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and subscores demonstrated a moderate improvement of mainly positive schizophrenic symptoms. In contrast to animal test results, savoxepine in a broad dose range produced typical untoward extrapyramidal symptoms in the majority of patients. Our results indicate that savoxepine may not possess the expected "atypical" neuroleptic response pattern, and that the predictive validity of the animal models in question used to separate antipsychotic effects from extrapyramidal reactions may be ill-founded.

The effects of brofaremine (CGP 11 305A), a short-acting, reversible and selective inhibitor of MAO-A, on sleep, nocturnal penile tumescence (NPT) and hormonal secretion during the night were studied during a long-term trial. Three healthy males underwent sleep-EEG and NPT recordings during consecutive nights (1) under placebo, (2) under stepwise increasing dosages of brofaremine and (3) under placebo after withdrawal. Hormone profiles were sampled during selected nights to analyze the plasma concentration of cortisol, HGH, prolactin, testosterone, LH and FSH. REM sleep was suppressed markedly under 150 mg brofaremine, while stages 1 and 2 increased. In comparison to the effect of irreversible MAOIs the REM suppression was shorter and did not persist after withdrawal. A decrease of the plasma concentration of the drug coincided with a return of sleep variables to baseline values. A REM rebound occurred after withdrawal of brofaremine. REM sleep and NPT showed a dissociation; NPT variables did not follow the decrease of REM sleep. The effects of REM parameters are correlated with the dosage and the plasma concentration of the substance. Intraindividually, a decrease in secretion of HGH was observed throughout the trial. No marked changes were found in the other endocrinological variables.

Plasma ACTH levels after oral ingestion of 2 g metyrapone at 24.00 hours in six healthy subjects were higher after pretreatment with zimelidine (300 mg) in comparison to placebo. Since zimelidine is a relatively selective serotonin reuptake inhibitor its action on hypothalamic-pituitary-adrenal (HPA) activity suggests that serotonin is a potent stimulator of ACTH release. The ratio of cortisol to 11-deoxycortisol was taken as a measure of 11-hydroxylase activity, which indicates biological activity of secreted ACTH. These cortisol/11-deoxycortisol ratios were significantly increased after zimelidine treatment, when compared to placebo. Both the ACTH response and the cortisol/11-deoxycortisol ratios substantiate evidence derived from animal experiments, indicating a stimulatory influence of serotonin on HPA activity. No firm conclusion, however, may be drawn on by which mechanism zimelidine exerts its action on the HPA-axis. Moreover these findings provide no information on whether serotonin has a stimulatory role on ACTH production under physiological condition.