European Neuropsychopharmacology - Articles in Press

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers - Corrected Proof

2010-07-26

Abstract: The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

Mapping of CBV changes in 5-HT1A terminal fields by functional MRI in the mouse brain - Corrected Proof

2010-07-26

Abstract: Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT1A receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT1A receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT1A receptor antagonist WAY-100635, or in 5-HT1A knock-out mice, suggests that 5-HT1A receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT1A receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT1A receptor or the serotonergic system, including depression and anxiety.

Brain responses to chronic social defeat stress: Effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats - Corrected Proof

2010-07-26

Abstract: Chronic social defeat stress, a depression model in rats, reduced struggling in the forced swimming test dependent on a hedonic trait-stressed rats with high sucrose intake struggled less. Social defeat reduced brain regional energy metabolism, and this effect was also more pronounced in rats with high sucrose intake. A number of changes in gene expression were identified after social defeat stress, most notably the down-regulation of Gsk3b and Map1b. The majority of differences were between stress-susceptible and resilient rats. Conclusively, correlates of inter-individual differences in stress resilience can be identified both at gene expression and oxidative metabolism levels.

Periadolescent exposure to cannabinoids alters the striatal and hippocampal dopaminergic system in the adult rat brain - Corrected Proof

2010-07-26

Abstract: In a previous work, we have shown that chronic administration of the cannabinoid agonist CP 55,940 (CP) during periadolescence increases cocaine self-administration in adult female rats, while it produces no such effect in males (Higuera-Matas et al., 2008). To extend these findings, we have analysed here the brains of the rats used as subjects in this previous work to evaluate the impact of the interaction between CP exposure and cocaine self-administration on dopaminergic parameters. We evaluated the levels of the dopamine transporter (DAT), and the D1- (D1R) and D2-type (D2R) dopaminergic receptors, as well as tyrosine hydroxylase (TH) mRNA in dopaminergic areas of the adult, cocaine self-administered, rat brain that had been chronically exposed to CP or vehicle (VH) during periadolescence. Control groups with CP/VH exposure and no self-administration experience were also included. In adult females, CP administration induced an up-regulation of DAT in the caudate-putamen that was maintained after cocaine self-administration. In males, CP induced an increase in the D1Rs content in the nucleus accumbens shell, which was not evident after cocaine self-administration. CP also reduced the expression of D2Rs in CA1 irrespective of sex. Finally, an increase in D1Rs was observed in the substantia nigra following cocaine self-administration. These findings suggest that a dopaminergic component modulated by cannabinoids may underlie the enhanced cocaine self-administration previously observed in adult female rats.

Chronic all-trans retinoic acid administration induced hyperactivity of HPA axis and behavioral changes in young rats - Corrected Proof

Li Cai, Xue-Bo Yan, Xiao-Ning Chen, Qing-Yuan Meng, Jiang-Ning Zhou — 2010-07-26

Abstract: Although clinical reports suggest a possible relationship between excess retinoids and the development of depression, the effect of retinoids on mood-related behavior remains controversial. Hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis plays a key role in the development of affective disorders. The present study aimed to elucidate the effect of retinoid on the activity of HPA axis in rat and whether this goes together with behavioral changes. All-trans retinoic acid (ATRA) was administered to juvenile male rats by daily intraperitoneal injection for 6weeks. ATRA treatment increased basal serum corticosterone concentration as well as the thickness of adrenal cortex in young rat. Furthermore, the mRNA expression of corticotropin release factor (CRF) and retinoic acid receptor-α (RAR-α) in the hypothalamus was both markedly increased in ATRA-treated rats compared with vehicle. Some behavioral alterations were also observed. ATRA-treated rats showed anxiety-like behavior in elevated-plus maze and decreased spontaneous exploratory activities in novel open field. However, in the sucrose preference test chronic ATRA treatment did not modify behavior in the juvenile animals. Chronic administration of ATRA did not impair physical motor ability in either the prehensile traction or the beam balance/walk test. In conclusion, long-term ATRA administration resulted in hyperactivated HPA axis which was accompanied by several behavioral changes in young rat.

A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence - Corrected Proof

Jon E. Grant, Brian L. Odlaug, Suck Won Kim — 2010-07-23

Abstract: Reducing both glutamatergic and dopaminergic drive in the nucleus accumbens may offer complementary mechanisms by which to reduce drug cravings. This 8-week study sought to examine the efficacy of a combination of a glutamate modulator, N-acetyl cysteine (NAC), plus the opioid antagonist, naltrexone, compared to placebo in the treatment of methamphetamine dependence. Thirty-one subjects with methamphetamine dependence (mean age 36.8±7.12years; 29% female) were randomly assigned in a 1:1 fashion to NAC plus naltrexone or placebo and returned for one post-baseline visit. The Penn Craving Scale was the primary outcome measure. Self-report methamphetamine use frequency and urine toxicology were secondary measures. NAC plus naltrexone failed to demonstrate statistically significant differences from placebo on primary and secondary outcomes. The current study failed to demonstrate greater efficacy for NAC plus naltrexone compared to placebo. Given the small sample size, the statistical power to detect significant effects of active treatment versus placebo was limited. The question of whether a larger, well-powered sample would have detected differences between NAC plus naltrexone and placebo deserves further examination.

Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice - Corrected Proof

Philipp Singer, Detlev Boison, Hanns Möhler, Joram Feldon, Benjamin K. Yee — 2010-07-21

Abstract: Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.

The HTR1A and HTR1B receptor genes influence stress-related information processing - Corrected Proof

2010-07-20

Abstract: The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. We investigated the possible association between depression and anxiety scores and SNPs within the HTR1A and HTR1B genes in a population sample (n=1387). There was no direct SNP-phenotype association, but in interaction with recent stressful life events rs6295 G, rs878567 T alleles and rs6296 C alleles were associated with significantly higher symptom scores. A subset of control subjects (n=101) took part in a computerised face emotion processing task. Healthy rs6295 GG carriers did not show an affective bias to perceive more negative emotions but reacted more quickly to fearful faces. Thus we conclude that the serotonin-1A receptor conveys vulnerability to these psychiatric disorders by modulating threat-related information processing. Our results extend previous findings of an interaction between stressful life events and the serotonin transporter gene to two other genes in the serotonergic pathway and emphasise the possible role of increased threat-related information processing as an intermediate phenotype.

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia - Corrected Proof

2010-07-14

Abstract: Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987.Methods: Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mg/kg; s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance.Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01–0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10mg/kg (P<0.01) and 20mg/kg (P<0.001), and in novel object recognition at 10mg/kg on day 1 (P<0.01) and on day 15 (P<0.001).Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

The economic impact of depression: Resistance or severity? - Corrected Proof

L. Fostick, A. Silberman, M. Beckman, B. Spivak, D. Amital — 2010-07-12

Abstract: Treatment-Resistant Depression (TRD) affects 60 to 70% of patients with Major Depressive Disorder (MDD). The economic impact of depression in general, and of TRD specifically, was found to be relatively high. As the course of depression can be defined both by the severity of the disease and by the resistance to treatment, the question of the unique contribution of MDD severity vs. resistance to the economic burden of depression is being raised. One hundred and seven unipolar MDD patients, all treated for at least 4weeks, were enrolled in the study. Patients were assessed for their current MDD severity using the Hamilton Depression Rating Scale (HDRS) and past treatments, and for medical-related costs (number of blood and imaging tests, visits paid to physicians, psychiatric hospitalizations) and incapacity-related costs (number of working days lost) during the last episode. TRD and non-TRD patients were, respectively, 39.3% and 60.7% of the patients recruited for the study. TRD patients had more severe depression, and higher costs for imaging tests, physician visits, psychiatric hospitalizations, and number of working days lost. In addition, higher MDD severity was found to be associated with higher costs. Finally, when controlling for the shared variance of TRD and MDD severity, by using residual scores, TRD was associated with higher costs, but MDD severity was no longer related to costs. While both resistance and severity are associated with higher direct and indirect costs, our findings suggest that TRD may be the main factor in determining the economic burden of depression.

Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity - Corrected Proof

2010-07-12

Abstract: Using the rodent activity-based anorexia (ABA) model that mimics clinical features of anorexia nervosa that include food restriction-induced hyperlocomotion, we found that plasma ghrelin levels are highly associated with food anticipatory behaviour, measured by running wheel activity in rats. Furthermore, we showed that ghrelin receptor (GHS-R1A) knockout mice do not anticipate food when exposed to the ABA model, unlike their wild type littermate controls. Likewise, food anticipatory activity in the ABA model was suppressed by a GHS-R1A antagonist administered either by acute central (ICV) injection to rats or by chronic peripheral treatment to mice. Interestingly, the GHS-R1A antagonist did not alter food intake in any of these models. Therefore, we hypothesize that suppression of the central ghrelin signaling system via GHS-R1A provides an interesting therapeutic target to treat hyperactivity in patients suffering from anorexia nervosa.

The EU paediatric regulation: Effects on paediatric psychopharmacology in Europe - Corrected Proof

2010-07-12

Abstract: Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology.The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations.The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge.The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.

Deep brain stimulation of the subthalamic or entopeduncular nucleus attenuates vacuous chewing movements in a rodent model of tardive dyskinesia - Corrected Proof

Meaghan Creed, Clement Hamani, José N. Nobrega — 2010-07-12

Abstract: Deep brain stimulation (DBS) has recently emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists as yet regarding optimal stimulation parameters or neuroanatomical target for DBS in TD. Here we report the use of DBS in an animal model of TD. We applied DBS (100μA) acutely to the entopeduncular nucleus (EPN) or subthalamic nucleus (STN) in rats with well established vacuous chewing movements (VCMs) induced by 12weeks of haloperidol (HAL) treatment. Stimulation of the STN or EPN resulted in significant reductions in VCM counts at frequencies of 30, 60 or 130Hz. In the STN DBS groups, effects were significantly more pronounced at 130Hz than at lower frequencies, whereas at the EPN the three frequencies were equipotent. Unilateral stimulation at 130Hz was also effective when applied to either nucleus. These results suggest that stimulation of either the EPN or STN significantly alleviates oral dyskinesias induced by chronic HAL. The chronic HAL VCM model preparation may be useful to explore mechanisms underlying DBS effects in drug-induced dyskinesias.

Searching for functional SNPs or rare variants in exonic regions of DRD3 in risperidone-treated patients - Corrected Proof

2010-07-09

Abstract: Previously one intronic DRD3 SNP, rs167771, was associated with risperidone-induced extrapyramidal side-effects (EPS). The aim of the present study was to search hitherto unidentified common functional variants or rare variants, in DRD3 associated with risperidone-induced EPS. 126 subjects treated with risperidone participated in this study. We sequenced the seven exons of DRD3. After sequencing we localized five dbSNPs and four new rare variants. None of the dSNPs or rare variants seems to be functional after bioinformatics analysis. Our results suggest that, rather than exonic regions, regulatory regions and introns could be related to the associations reported for DRD3 and the incidence of locomotor side-effects.

First episode drug-naïve major depressive disorder with panic disorder: Gray matter deficits in limbic and default network structures - Corrected Proof

Chien-Han Lai, Yuan-Yu Hsu, Yu-Te Wu — 2010-07-05

Abstract: This study was designed to investigate the structural differences in the brains of first episode, drug-naïve patients with major depressive disorder and panic disorder versus healthy control subjects. High-resolution brain magnetic resonance images were performed on patients and health control subjects (age, sex and handedness matched). Structural magnetic resonance images of brain were estimated by optimized voxel-based morphometry of FSL (FMRIB Software Library). Patients had deficits of gray matter volumes over right anterior cingulate cortex, right medial frontal gyrus, left posterior cingulate cortex, right parahippocampal gyrus, limbic areas, occipital lingual gyrus and bilateral cerebellums when compared to controls. These results suggested that this group of patients has possible deficits of gray matter volumes over the default-mode network, fronto-cingulate and limbic structures. The decline of gray matter volumes might have started since the first episode.

Activity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: Deregulation in schizophrenia - Corrected Proof

Efrat Dresner, Galila Agam, Illana Gozes — 2010-07-05

Abstract: Activity-dependent neuroprotective protein (ADNP) and the homologous protein ADNP2 provide cell protection. ADNP is essential for brain formation, proper brain development and neuronal plasticity, all reported to be impaired in the schizophrenia patient brains. Furthermore, reduction in ADNP expression affects social interactions, a major hallmark of schizophrenia. To evaluate a possible involvement of ADNP and ADNP2 in the pathophysiology of schizophrenia in humans, we measured relative brain mRNA transcripts of both proteins compared with control subjects. Quantitative real time polymerase chain reaction in postmortem hippocampal specimens from normal control subjects exhibited a significant ADNP to ADNP2 transcript level correlation (r=0.931, p<0.001), also apparent in a neuroglial model system. In contrast, in the hippocampus of matched schizophrenia patients, this correlation (r=0.637, p=0.014) was drastically decreased in a statistically significant manner (p=0.03), mirroring disease-associated increased ADNP2 transcripts. In the prefrontal cortex of schizophrenia patients the correlation between ADNP and ADNP2 mRNA levels was apparently higher than in the hippocampus (r=0.854, p<0.001), but did not reach a significant difference (p=0.25). Thus, imbalance in ADNP/ADNP2 expression in the brain may impact disease progression in schizophrenia.

The effect of acute citalopram on face emotion processing in remitted depression: A pharmacoMRI study - Corrected Proof

2010-07-05

Abstract: Both reduced serotonergic (5-HT) function and negative emotional biases have been associated with vulnerability to depression. In order to investigate whether these might be related we examined 5-HT modulation of affective processing in 14 remitted depressed subjects compared with 12 never depressed controls matched for age and sex. Participants underwent function magnetic resonance imaging (fMRI) during a covert face emotion task with and without intravenous citalopram (7.5mg) pretreatment. Compared with viewing neutral faces, and irrespective of group, citalopram enhanced left anterior cingulate blood oxygen level dependent (BOLD) response to happy faces, right posterior insula and right lateral orbitofrontal responses to sad faces, and reduced amygdala responses bilaterally to fearful faces. In controls, relative to remitted depressed subjects, citalopram increased bilateral hippocampal responses to happy faces and increased right anterior insula response to sad faces. These findings were not accounted for by changes in BOLD responses to viewing neutral faces. These results are consistent with previous findings showing 5-HT modulation of affective processing; differences found in previously depressed participants compared with controls may contribute to emotional processing biases underlying vulnerability to depressive relapse.

Seasonality and winter-type seasonal depression are associated with the rs731779 polymorphism of the serotonin-2A receptor gene - Corrected Proof

2010-06-28

Abstract: Seasonal Affective Disorder (SAD), seasonality and increased sensitivity to the fluctuation of seasons in biological and psychological parameters can manifest to varying degrees across a normal population. The serotonin-2A (5-HT2A) receptor gene has long been suggested as a candidate for the genetic basis of this phenomenon. We hypothesized that functional sequence variation in this gene could contribute to seasonality and the development of winter- and/or summer-type seasonal depression. Seasonality was measured by the self-rating Global Seasonality Score (GSS) of the Seasonal Pattern Assessment Questionnaire, and SAD by the Seasonal Health Questionnaire (SHQ). We analysed associations between GSS or SAD scores and 5-HTR2A receptor gene polymorphisms rs731779, rs985934 and rs6311, in 609 individuals. People carrying the GG genotype of rs731779 were six times more likely to manifest winter or summer SAD compared to GT or TT genotypes (OR = 6.47), and the chance of having winter-type SAD was almost nine-fold (OR = 8.7) with the GG genotype. GG subjects of rs731779 also scored significantly higher on the GSS scale compared to carriers of the T allele. In the haplotype analysis subjects carrying the G allele of rs731779 scored higher on the GSS scale, while the presence of the T allele leads to lower scores. These results suggest that variations in the 5-HTR2A gene play a significant role in the development of seasonality and especially in winter-type SAD. The fact that the above polymorphism showed association not only with clinical SAD but also seasonality symptoms in a general population provides evidence for the spectrum nature of this connection.

GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus - Corrected Proof

2010-06-07

Abstract: The activity of dentate gyrus granule neurons is under a strong GABAergic tonic inhibitory control which contributes to the sparse activation pattern of these neurons after environmental stimuli. Previously, we reported that in sparse dentate gyrus neurons such stimuli evoke Ser-10 (S10) phosphorylation and Lys-14 (K14) acetylation in the nucleosomal protein histone H3 (H3S10p-K14ac) resulting in the induction of c-Fos. We hypothesized that GABA is an important modulator of novelty stress-evoked epigenomic mechanisms in rat dentate neurons. As reported previously, exposure to novelty (30min in new cage) evoked a significant increase in H3S10p-K14ac-and c-Fos-positive neuron numbers in the dentate gyrus. Pre-treatment of rats with the benzo Lorazepam, an indirect GABA-A receptor agonist, had no effects on baseline levels of H3S10p-K14ac and c-Fos but dose-dependently inhibited the novelty-induced epigenomic effects. At the applied doses (0.1–0.3mg/kg), Lorazepam's effects on behavior were mainly anxiolytic-like. To examine the effects of attenuated GABAergic inhibition on dentate granule neurons we applied the partial inverse GABA-A agonist FG-7142. This drug profoundly enhanced baseline levels as well as novelty-induced increases in the number of H3S10p-K14ac- and c-Fos-positive dentate neurons. Furthermore, FG-7142 evoked behavior in the novel cage congruous with increased anxiety and hyper-vigilance. Interestingly, the FG-7142-evoked enhancements in epigenomic changes were completely blocked by the NMDA receptor antagonist MK-801. We conclude that GABA tonically controls epigenomic responses to psychologically salient events in dentate gyrus granule neurons. Furthermore, GABA appears to exert its controller activity through modulation of NMDA receptor function. These findings may be of significance for the elucidation of anxiety disorders especially PTSD.

Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam - Corrected Proof

2010-06-07

Abstract: Dopamine D3 receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D3−/−) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D3−/− mice treated with diazepam (0.1 or 0.5mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D3−/− mice, but not in WT, 1mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10mg/kg) in combination with diazepam, in WT animals. D3−/− mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [3H]flunitrazepam autoradiographic analysis revealed no significant changes in D3−/− mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABAA changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D3−/− mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects.

Acute quetiapine dose-dependently exacerbates anhedonia induced by withdrawal from escalating doses of d-amphetamine - Corrected Proof

Simon Zhornitsky, Stéphane Potvin, Emmanuel Stip, Pierre-Paul Rompré — 2010-06-04

Abstract: Recent clinical studies show that the atypical antipsychotic medication, quetiapine, may be beneficial in the treatment of substance abuse by alleviating the withdrawal-negative affect stage of addiction. Since the effect of quetiapine on central reward function is largely unknown we studied its effects on brain stimulation reward in animals under withdrawal from escalating doses of d-amphetamine. Male Sprague–Dawley rats were trained to produce an operant response to receive a short train of electrical stimulation to the lateral hypothalamus. Measures of reward threshold were determined with the curve-shift method in different groups of rats before, and during four days after treatment with escalating doses (1 to 10mg/kg, i.p.) of d-amphetamine or its vehicle. At 24h of withdrawal, the effects of two doses of quetiapine (2 and 10mg/kg i.p.) were tested. Animals treated with d-amphetamine showed a 25% reward deficit at 24h of withdrawal, an effect that decreased progressively over the next three days. Quetiapine attenuated reward in the vehicle-control animals, and amplified the anhedonia at the moderate, but not the low, dose in the animals under withdrawal. These results show that acute treatment with clinically relevant doses of quetiapine for the treatment of schizophrenia may exacerbate anhedonia induced by amphetamine withdrawal. Further research should investigate whether repeated treatment with quetiapine has the ability to reverse amphetamine withdrawal-induced anhedonia.

Association study of the GSK-3B gene with tardive dyskinesia in European Caucasians - Corrected Proof

2010-06-04

Abstract: There is solid evidence of a genetic predisposition to tardive dyskinesia (TD) although the pathophysiological mechanisms of TD are still unclear. Nevertheless, the dopamine overactivity hypothesis of the TD etiology receives support from both pharmacological and physiological evidence. Dopaminergic signaling modulates the glycogen synthase kinase 3B (GSK-3B), a kinase that may play a critical role in the pathogenesis of neurodegenerative diseases. GSK-3B is an essential element of the apoptotic signaling cascade induced by oxidative stress, which may be involved in TD pathogenesis. We investigated whether GSK-3B polymorphisms (rs11919783, rs6805251, rs7624540, rs6438552, rs4072520, rs9878473, rs6779828 and rs3755557) selected using tagging method were associated with TD manifestation and abnormal involuntary movement severity. We evaluated 215 schizophrenia subjects from whom 169 were European Caucasians. All eight evaluated variants had their minor allele carriers consistently showing lower risk to TD and lower Abnormal Involuntary Movement Scale. The rs6805251, rs6438552 and rs9878473 variants showed a trend for association with TD in European Caucasian subjects (permuted p=0.07). Furthermore, all tested markers showed p≤0.0007 after we incorporated age as covariate in the analysis of the abnormal involuntary movement severity. Our results suggest that GSK-3B polymorphism may play a role in the genetic vulnerability to TD manifestation in schizophrenia subjects with European Caucasian background further implicating polymorphisms in the dopamine D2-like receptor signaling in this context. These findings should be read with caution particularly before independent replication.

The α2 adrenergic receptor antagonist idazoxan, but not the serotonin-2A receptor antagonist M100907, partially attenuated reward deficits associated with nicotine, but not amphetamine, withdrawal in rats - Corrected Proof

Svetlana Semenova, Athina Markou — 2010-06-04

Abstract: Based on phenomenological similarities between anhedonia (reward deficits) associated with drug withdrawal and the negative symptoms of schizophrenia, we showed previously that the atypical antipsychotic clozapine attenuated reward deficits associated with psychostimulant withdrawal. Antagonism of α2 adrenergic and 5-HT2A receptors may contribute to these effects of clozapine. We investigated here whether blockade of α2 or 5-HT2A receptors by idazoxan and M100907, respectively, would reverse anhedonic aspects of psychostimulant withdrawal. Idazoxan treatment facilitated recovery from spontaneous nicotine, but not amphetamine, withdrawal by attenuating reward deficits and increase the number of somatic signs. Thus, α2 adrenoceptor blockade may have beneficial effects against nicotine withdrawal and may be involved in the effects of clozapine previously observed. M100907 worsened the anhedonia associated with nicotine and amphetamine withdrawal, suggesting that monotherapy with M100907 may exacerbate the expression of the negative symptoms of schizophrenia or nicotine withdrawal symptoms in people, including schizophrenia patients, attempting to quit smoking.

The β3 adrenoceptor agonist, amibegron (SR58611A) counteracts stress-induced behavioral and neurochemical changes - Corrected Proof

Alessandra Tamburella, Vincenzo Micale, Gian Marco Leggio, Filippo Drago — 2010-05-31

Abstract: These experiments were made to study the mechanisms underlying the antidepressant-like effects of the β3 adrenoceptor agonist amibegron (SR58611A). To this purpose, the expression levels of the hippocampal cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl-2) and Bax proteins were assessed, by using western blot analysis, in rats tested in the forced swim test (FST). Under basal conditions (no previous exposure to stressors), different groups of male Wistar rats received acutely or repeatedly (once/day for 7days) intraperitoneal (i.p.) injections of amibegron (1, 5 and 10mg/kg), the tricyclic antidepressant (TCA) clomipramine (50mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (15mg/kg) or their vehicles. The influence of stress-related conditions was studied in rats subjected to acute (4h) or repeated (4h/day for 7days) restraint stress, applied prior to the FST procedure. Compared to the control groups, both stressor procedures increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression, which were counteracted by amibegron (5 and 10mg/kg) treatment. Opposite effects were found in the CREB expression, since it was lower after acute and higher after repeated stress procedure, respectively. Again, these effects were reversed by amibegron treatment. Different results were obtained in animals treated with clomipramine or citalopram. Hence, it is likely that the observed behavioral effects of amibegron could be due, at least in part, to its action on hippocampal expression of neurotrophic and/or anti-apoptotic factors, supporting the hypothesis that β3 adrenoceptors may be a therapeutic target for the treatment of stress-related disorders.

Levodopa and 3-OMD levels in Parkinson patients treated with Duodopa - Corrected Proof

A. Antonini, G. Bondiolotti, F. Natuzzi, S.R. Bareggi — 2010-05-31

Abstract: We studied 19 patients (14 men, 5 women, Hoehn and Yahr (H&Y)≥3) with advanced Parkinson's disease (PD) attending the Parkinson Institute, Milan, whose motor fluctuations and dyskinesia were not controlled by oral medications. After all oral PD medications had been withdrawn, they received a duodenal levodopa infusions (Duodopa, Solvay Pharmaceuticals) for 14h/day through a transabdominal port; levodopa boluses were administered in the morning and during “off” periods. The patients were evaluated by means of the UPDRS in the morning (“off”) and 60–120min after the infusion (“on”) at baseline and for a mean follow-up of 13.5±12.5months (up to 36months in 10 patients:). Levodopa (l-DOPA) and its metabolites were determined by HPLC with electrochemical detection. l-DOPA concentrations tended to higher in the afternoon (2008±345 vs 1713±274ng/mL) and correlated with the daily dose. O-methyldopa (OMD) levels correlated with l-DOPA levels, and the OMD/l-DOPA ratios were stable over the day. There was a relationship between decreasing UPDRS III scores and decreasing OMD/l-DOPA ratios. Dyskinesia (UPDRS IV, items 32–34) showed a clear improvement over time but there was no clear relationship with l-DOPA and OMD levels, or the OMD/l-DOPA ratio. The l-DOPA/dose ratio was stable over time, whereas OMD levels and the OMD/l-DOPA ratio decreased. It is conceivable that continuous infusion decreases metabolism possibly due to a reduction in methyl donor availability, as demonstrated by the increase in total homocysteine levels. Our results do not support the development of tolerance even after several months of continuous infusion, and indicate that pharmacodynamic factors play a role in afternoon off periods.

Childhood methylphenidate treatment of ADHD and response to affective stimuli - Corrected Proof

2010-05-31

Abstract: Neural correlates of emotional dysregulation in attention-deficit/hyperactivity disorder (ADHD) and persisting influence of Methylphenidate (MPH) still remain insufficiently understood. Decreased activation in the subgenual cingulate and the ventral striatum were found during the perception of positive and negative affective pictures in drug-naïve males with ADHD during childhood (n=10). Males with ADHD during childhood treated with MPH (n=10) did not show any significant differences compared to healthy controls (n=10). Further prospective studies need to clarify direct and indirect mechanisms of MPH treatment that may contribute to emotional processing, which is dysfunctional in males without pharmacological treatment in childhood.

Involvement of dorsal raphe nucleus and dorsal periaqueductal gray 5-HT receptors in the modulation of mouse defensive behaviors - Corrected Proof

Roger L.H. Pobbe, Helio Zangrossi, D. Caroline Blanchard, Robert J. Blanchard — 2010-05-31

Abstract: Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqueductal gray (dPAG) serotonergic receptors in the mediation of defensive responses that are associated with specific subtypes of anxiety disorders. These studies have mostly been conducted with rats tested in the elevated T-maze, an experimental model of anxiety that was developed to allow the measurement, in the same animal, of two behaviors mentioned: inhibitory avoidance and one-way escape. Such behavioral responses have been respectively related to generalized anxiety disorder (GAD) and panic disorder (PD). In order to assess the generality of these findings, in the current study we investigated the effects of the injection of 5-HT-related drugs into the DRN and dPAG of another rodent species, mouse, on the mouse defense test battery (MDTB), a test of a range of defensive behaviors to an unconditioned threat, a predator. Male CD-1 mice were tested in the MDTB after intra-DRN administration of the 5-HT1A receptor antagonist WAY-100635 or after intra-dPAG injection of two serotonergic agonists, the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT2A/2C receptor agonist DOI. Intra-DRN injection of WAY-100635 did not change behavioral responses of mice confronted with a rat in the MDTB. In the dPAG, both 8-OH-DPAT and DOI consistently impaired mouse escape behavior assessed in the MDTB. Intra-dPAG infusion of 8-OH-DPAT also decreased measures of mouse risk assessment in the rat exposure test. In conclusion, the current findings are in partial agreement with previous results obtained with rats tested in the elevated T-maze. Although there is a high level of similarity between the behavioral effects obtained in rats (elevated T-maze) and mice (MDTB and RET) with the infusion of 5-HT agonists into the dPAG, the same is not true regarding the effects of blockade of DRN 5-HT1A receptors in these rodent species. These data suggest that there may be differences between mice and rats regarding the involvement of the DRN in the mediation of defensive behaviors.

The effect of chronic methylphenidate administration on presynaptic dopaminergic parameters in a rat model for ADHD - Corrected Proof

Y. Simchon, A. Weizman, M. Rehavi — 2010-05-24

Abstract: Dysregulations in monoaminergic systems have been implicated in attention deficit/hyperactivity disorder. The spontaneous hypertensive rats (SHR) are used as an animal model for ADHD. Juvenile SHR rats exhibited low dopamine transporter (DAT) density, low vesicular monoamine transporter 2 (VMAT2) density and lower unstimulated dopamine (DA) release in comparison to their corresponding WKY controls. Chronic methylphenidate treatment of the young SHR rats was associated with lower DAT density and lower unstimulated basal dopamine release but with enhanced potassium- and amphetamine-induced dopamine release. These neurochemical alterations might be relevant to the pathophysiology and to the beneficial effect of methylphenidate in ADHD.

Reduced platelet G protein-coupled receptor kinase 2 in major depressive disorder: Antidepressant treatment-induced upregulation of GRK2 protein discriminates between responder and non-responder patients - Corrected Proof

2010-05-24

Abstract: The homologous regulation of neurotransmitter receptors by G protein-coupled receptor kinases (GRKs) is important in the pathogenesis and treatment of major depressive disorder (MDD). Previous studies have reported that the basal status of GRK2 is different in brains (upregulation) and platelets (downregulation) of subjects with MDD. The principal aim of this study was to re-examine the status of platelet membrane GRK2 protein in patients with MDD, along with GRK3 (a close kinase homolog) and GRK5 (a kinase with different properties), before and after treatment with serotonin-selective reuptake inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) antidepressants. The main findings indicated that platelet GRK2 and p-Ser670 GRK2 were reduced (36–41%) in unmedicated MDD subjects, and that GRK2 content correlated inversely with the severity of depression (r=−0.51). Effective antidepressant treatments normalized platelet GRK2, and, notably, GRK2 upregulation discriminated between responder and non-responder patients. Other findings revealed a modest reduction of platelet GRK3 (23%) and no alteration of platelet GRK5 content. In untreated subjects with MDD, lymphocyte GRK2 and GRK5 mRNAs were unaltered but antidepressant treatment-induced upregulation of GRK2 mRNA expression. The reduced content of platelet GRK2 protein is a relevant target in MDD. Although this peripheral GRK2 defect does not mirror the canonical regulation of brain GRK2 in depressed suicides, it could well represent a disease state marker as well as a surrogate of response to effective antidepressant treatment.

F15599, a preferential post-synaptic 5-HT1A receptor agonist: Activity in models of cognition in comparison with reference 5-HT1A receptor agonists - Corrected Proof

2010-05-20

Abstract: We assessed the activity of F15599, a selective and high efficacy 5-HT1A agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04–2.5) was less disruptive than F13714 (0.005–0.16) or 8-OH-DPAT (0.01–0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT1A receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression.

S41744, a dual neurokinin (NK)1 receptor antagonist and serotonin (5-HT) reuptake inhibitor with potential antidepressant properties: A comparison to aprepitant (MK869) and paroxetine - Corrected Proof

2010-05-19

Abstract: Though neurokinin1 (NK1) receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks NK1 receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK1 receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pKB, 7.7). Further, it dose-dependently (0.63–40.0mg/kg, i.p.) displaced ex vivo [3H]-[Sar9,Met(O2)11]-Substance P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the NK1 agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pKB, 7.9), and dose-dependently (0.63–10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 “neutral”, reflecting balanced NK1 antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative NK1 antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders.

Activity-based anorexia in C57/BL6 mice: Effects of the phytocannabinoid, △9-tetrahydrocannabinol (THC) and the anandamide analogue, OMDM-2 - Corrected Proof

David Y. Lewis, Ros R. Brett — 2010-05-17

Abstract: The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nervosa. We present here the translation of this approach to C57/BL6 mice, a common background for genetically modified mice, and investigate the effects of the cannabinoid agonist, Δ9-tetrahydrocannabinol (THC) and the endocannabinoid uptake inhibitor, OMDM-2 in this model. The ABA paradigm was optimised so that food-restricted wheel-running mice displayed anorexia, reduced body weight and disrupted activity and circadian cycles. These conditions produced a murine ABA model with a defined stage and stability to allow for pharmacological intervention. Daily Δ9-THC (0.5mg/kg) decreased survival in the ABA animals but increased feeding in the survivors, OMDM-2 (3mg/kg) increased food intake, but not sufficiently to reverse weight loss. The effects of this model on endocannabinoid tone in the brain remain to be determined. Since the endocannabinoid system may be implicated in anorexia nervosa and in view of the positive modulation by cannabinoids of some aspects of ABA in this study, further investigation of the effects of cannabinoids in ABA is warranted.

Blood–brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein - Corrected Proof

2010-05-13

Abstract: According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10mg/kg bw) was intraperitoneally injected to knockout (−/−) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2–3, 2–6 and 3–12 times higher in abcb1ab (−/−) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

Mixture regression analysis on age at onset in Bipolar Disorder patients: Investigation of the role of serotonergic genes - Corrected Proof

2010-05-11

Abstract: Bipolar Disorder (BPD) is a complex psychiatric disease with a relevant underlying genetic basis. HTR2A T102C, HTR2C Cys23Ser, SLC6A4 5-HTTLPR and rs25531 polymorphisms were genotyped in 230 BPD patients and inserted as covariates in a mixture regression model of age at onset (AAO). 5-HTTLPR polymorphism associated with early onset component under recessive and additive model. HTR2A T102C, HTR2C Cys23Ser and 5-HTTLPR interaction terms associated with early onset component under dominant, recessive and additive model. These findings suggest a role of genes codifying for elements of the serotonergic system in influencing the AAO in BPD.