Progress in Neuro-Psychopharmacology and Biological Psychiatry (PROG NEURO-PSYCHOPH)

Publications in this journal

• Article: Vascular Endothelial Growth Factor gene (VEGFA) polymorphisms may serve as a prognostic factors for recurrent depressive disorder development.

  Piotr Gałecki, Elżbieta Gałecka, Michael Maes, Agata Orzechowska, Dominika Berent, Monika Talarowska, Kinga Bobińska, Andrzej Lewiński, Małgorzata Bieńkiewicz, Janusz Szemraj
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  ABSTRACT: Recurrent depressive disorder (rDD) is a multifactorial disease. Vascular endothelial growth factor (VEGF) is one of the factors that have been suggested to play a role in the etiology and /or development of this disease. Limited information related to the role of VEGFA gene polymorphism in depressive disorder is available. The aim of the study was to analyze the association between VEGFA gene polymorphisms (+405G/C; rs2010963, +936C/T; rs 3025039), VEGFA gene expression, and its serum protein levels in rDD in the Caucasian population. In the current study, 268 patients and 200 healthy controls of the Caucasian origin were involved. Genotyping and gene expression were performed using polymerase chain reaction (PCR) - based methods. Enzyme - Linked Immunosorbent Assay (ELISA) was used for detection of circulating serum VEGF levels. The distribution of VEGFA polymorphism +405G/C differed significantly between rDD patients and healthy subjects. The results of this study indicated that the C allele and CC genotype of VEGFA are risk factors for rDD. Haplotypes CC and TG are the important factors for depression development. Further, VEGFA mRNA expression and VEGF levels were higher in rDD patients than in controls. The VEGFA gene polymorphism may serve as a prognostic factor for rDD development. Our study showed higher levels of both VEGFA mRNA in the peripheral blood cells and serum VEGF in patients diagnosed with rDD than in healthy controls. The obtained results suggest VEGF and the gene encoding the molecule play a role in the etiology of the disease and should be further investigated.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Neural Predictors and Mechanisms of Cognitive Behavioral Therapy on Threat Processing in Social Anxiety Disorder.

  Heide Klumpp, Daniel A Fitzgerald, K Luan Phan
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  ABSTRACT: Cognitive behavioral therapy (CBT) is "gold standard" psychotherapy for social anxiety disorder (SAD). Cognitive models posit that preferential processing of threat mediates excessive forms of anxiety, which is supported by exaggerated amygdala, insula, and cortical reactivity to threatening socio-emotional signals in SAD. However, little is known about neural predictors of CBT success or the mechanisms by which CBT exerts its therapeutic effects. Functional magnetic resonance imaging (fMRI) was conducted during responses to social signals of threat (fearful/angry faces) against positive signals (happy faces) in 14 patients with SAD before and after 12 weeks of CBT. For comparison, 14 healthy control (HC) participants also underwent two fMRI scans, 12 weeks apart. Whole-brain voxel-wise analyses showed therapeutic success was predicted by enhanced pre-treatment activation to threatening faces in higher-order visual (superior and middle temporal gyrus), cognitive, and emotion processing areas (dorsal anterior cingulate cortex, dorsomedial prefrontal cortex). Moreover, a group by time interaction was revealed in prefrontal regions (dorsomedial, medial gyrus) and insula. The interaction was driven by relatively greater activity during threat processing in SAD, which significantly reduced after CBT but did not significantly predict response to CBT. Therefore, pre-treatment cortical hyperactivity to social threat signals may serve as a prognostic indicator of CBT success in SAD. Collectively, CBT-related brain changes involved a reduction in activity in insula, prefrontal, and extrastriate regions. Results are consistent with cognitive models, which associate decreases in threat processing bias with recovery.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: A proposal for refining the forced swim test in Swiss mice.

  Ana Paula Ramos Costa, Cintia Vieira, Lauren O L Bohner, Cristiane Felisbino Silva, Evelyn Cristina da Silva Santos, Thereza Christina Monteiro De Lima, Cilene Lino-de-Oliveira
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  ABSTRACT: The forced swim test (FST) is a preclinical test to the screening of antidepressants based on rats or mice behaviours, which is also sensitive to stimulants of motor activity. This work standardised and validated a method to register the active and passive behaviours of Swiss mice during the FST in order to strength the specificity of the test. Adult male Swiss mice were subjected to the FST for 6 min without any treatment or after intraperitoneal injection of saline (0.1 ml/10 g), antidepressants (imipramine, desipramine, or fluoxetine, 30 mg/kg) or stimulants (caffeine, 30 mg/kg or apomorphine, 10 mg/kg). The latency, frequency and duration of behaviours (immobility, swimming, and climbing) were scored and summarised in bins of 6, 4, 2 or 1 min. Parameters were first analysed using Principal Components Analysis generating components putatively related to antidepressant (first and second) or to stimulant effects (third). Antidepressants and stimulants affected similarly the parameters grouped into all components. Effects of stimulants on climbing were better distinguished of antidepressants when analysed during the last 4 min of the FST. Surprisingly, the effects of antidepressants on immobility were better distinguished from saline when parameters were scored in the first 2 min. The method proposed here is able to distinguish antidepressants from stimulants of motor activity using Swiss mice in the FST. This refinement should reduce the number of mice used in preclinical evaluation of antidepressants.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Homocysteine Induces Cerebral Endothelial Cell Death by Activating the Acid Sphingomyelinase-Ceramide Pathway.

  Jiunn-Tay Lee, Giia-Sheun Peng, Shao-Yuan Chen, Chang-Hung Hsu, Chun-Chieh Lin, Chun-An Cheng, Yaw-Don Hsu, Jiann-Chyun Lin
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  ABSTRACT: Homocysteine (Hcy) levels may rise after a stroke, but the mechanism of Hcy-induced cerebral endothelial cells (CECs) dysfunction has not been explored. In this study we examined the role of the acid sphingomyelinase (Asm)-ceramide pathway in the molecular mechanism of Hcy-induced CECs dysfunction. Murine CECs were prepared from fresh mouse brains. CECs were treated with 50-500 μM Hcy and 30-100 μM C2-ceramide for 48 h. Sphingomyelinase assays were performed to determine Asm activity. Quantitative assessments of cell survival and death by the MTT reduction and LDH release were conducted. Treatment of murine CECs with Hcy and ceramide caused cell death in a dose-dependent manner as determined by LDH and MTT assays. 250 μM Hcy and 50 μM C2-ceramide caused 50% cell death. Hcy induced murine CEC death also occurred in a time-dependant manner with substantial cell death noted as early as 24 h after Hcy exposure. C2-ceramide-induced murine CECs death occurred earlier than Hcy-induced cell death by about 18 hours. Homocysteine treatment increased Asm activity and intracellular ceramide accumulation. This study demonstrated that Hcy and C2-ceramide can cause murine CECs death. Hcy induces CECs death possibly by activating the Asm-ceramide pathway.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice.

  Shu Yan Yu, Minghua Zhang, Junxia Luo, Lin Zhang, Yi Shao, Gang Li
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  ABSTRACT: A number of neuroprotective effects of curcumin have been demonstrated in recent years. However, whether curcumin exerts any beneficial effects on age-related impaired cognition and memory has not been well characterized; nor was there any detailed data on the molecular pathways activated by curcumin. The present study attempts to investigate the effects of curcumin on memory decline of aged mice with a focus upon the possible contribution of the neuronal nitric oxide synthase (nNOS)/nitric oxide (NO) pathway in the memory amelioration effect of curcumin. The results showed that chronic administration of curcumin (50 mg/kg, i.p., 21 days) significantly ameliorated the memory acquisition ability of aged male mice in the novel object recognition and passive avoidance tasks. Immunoblotting revealed that chronic treatment of curcumin increased nNOS expression in the prefrontal cortex, amygdala and hippocampus, as well as the enhancement of nNOS activity and NO concentration. This enhancement was suppressed by pre-treatment with 7-nitroindazole (7-NI), a specific inhibitor of neuronal nitric oxide synthase (nNOS). Furthermore, inhibition of nNOS synthase by 7-NI also prevented the memory improvment effects of curcumin in aged mice. Taken together, the results of the present study suggest that the amelioration of memory deficits by curcumin in aged mice was mediated, at least in part, by activating the nNOS activity in specific brain regions. These findings reveal the therapeutic potential of curcumin as a preventive agent upon the deterioration of cognitive faculties.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Reduced Total Antioxidant Level and Increased Oxidative Stress in Patients with Deficit Schizophrenia: A Preliminary Study.

  Yakup Albayrak, Cüneyt Unsal, Murat Beyazyüz, Ahmet Unal, Murat Kuloğlu
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  ABSTRACT: INTRODUCTION: Deficit schizophrenia (DS) is defined for identifying a relatively homogeneous subgroup of patients with diagnosis of schizophrenia, characterized by the presence of primary and enduring negative symptoms. There have been several studies which investigated status of oxidative stress and total antioxidant level in patients with schizophrenia. However, there is not any study which researched differences between DS and nondeficit schizophrenia (NDS) in terms of status of oxidative stress and antioxidant level. We hypothesized that patients with DS would have different status of oxidative stress and antioxidant level compared with patients with NDS. METHODS: Twenty-three patients with DS, 42 patients with NDS and 31 age, sex and smoking status matched healthy controls (HC) were included to study. Five milliliters of blood was drawn from control subjects and patients for assesing total antioxidant potential (TAOP) and total peroxide levels (TPEROX). The ratio of TPEROX to TAOP is referred as oxidative stress index (OSI). RESULTS: We noticed that serum TAOP level was significantly lower in DS group compared with NDS and HC groups. The OSI was also found to be higher in DS group compared with NDS and HC groups. Furthermore, serum TAOP level and status of OSI were similar between NDS and HC groups. CONCLUSION: Our study is the first to demostrate differences between DS and NDS in terms of status of oxidative stress and serum total antioxidant level. We suggest that our study represents novel and important results in terms of supporting provides and hypothesis which considered DS as a different disease entity respect to NDS. Further studies are needed for investigating the status of antioxidants and oxidative stress and their clinical implications in deficit schizophrenia.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: White matter deficits in first episode schizophrenia: An activation likelihood estimation meta-analysis.

  Li Yao, Su Lui, Yi Liao, Ming-Ying Du, Na Hu, Joy A Thomas, Qi-Yong Gong
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  ABSTRACT: BACKGROUND: Diffusion tensor imaging (DTI) has been widely used in psychiatric research and has provided evidence of white matter abnormalities in first episode schizophrenia (FES). The goal of the present meta-analysis was to identify white matter deficits by DTI in FES. METHODS: A systematic search was conducted to collect DTI studies with voxel-wised analysis of the fractional anisotropy (FA) in FES. The coordinates of regions with FA changes were meta-analyzed using the activation likelihood estimation (ALE) method which weighs each study on the basis of its sample size. RESULTS: A total of 8 primary studies were selected, including 271 FES patients and 297 healthy controls. Among these studies, 52 regions showed reductions in the FA in FES while 2 regions had increased FA. Consistent FA reductions in the white matter of the right deep frontal and left deep temporal lobes were identified in all FES patients relative to healthy controls. Fiber tracking showed that the main tracts involved were the cingulum bundle, the left inferior longitudinal fasciculus, the left inferior fronto-occipital fasciculus and the interhemispheric fibers running through the corpus callosum. CONCLUSIONS: The current findings provid evidence confirming the lack of connection in the fronto-limbic circuitry at the early stages of the schizophrenia. Because the coordinates reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in FES.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Intracerebroventricular administratiocn of ouabain, a Na/K-ATPase inhibitor, activates mTOR signal pathways and protein translation in the rat frontal cortex.

  Se Hyun Kim, Hyun-Sook Yu, Hong Geun Park, Kyooseob Ha, Yong Sik Kim, Soon Young Shin, Yong Min Ahn
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  ABSTRACT: Intracerebroventricular (ICV) injection of ouabain, a specific Na/K-ATPase inhibitor, induces behavioral changes in rats in a putative animal model of mania. The binding of ouabain to Na/K-ATPase affects signaling molecules in vitro, including ERK1/2 and Akt, which promote protein translation. We have also reported that ERK1/2 and Akt in the brain are involved in the ouabain-induced hyperactivity of rats. In this study, rats were given an ICV injection of ouabain, and then their frontal cortices were examined to determine the effects of ouabain on the mTOR/p70S6K/S6 signaling pathway and protein translation, which are important in modifications of neural circuits and behavior. Rats showed ouabain-induced hyperactivity up to 8 h following injection, and increased phosphorylation levels of mTOR, p70S6K, S6, eIF4B, and 4E-BP at 1, 2, 4, and 8 h following ouabain injection. Immunohistochemical analyses revealed that increased p-S6 immunoreactivity in the cytoplasm of neurons by ouabain was evident in the prefrontal, cingulate, and orbital cortex. These findings suggested increased translation initiation in response to ouabain. The rate of protein synthesis was measured as the amount of [(3)H]-leucine incorporation in the cell-free extracts of frontal cortical tissues, and showed a significant increase at 8 h after ouabain injection. These results suggest that ICV injection of ouabain induced activation of the protein translation initiation pathway regulated by ERK1/2 and Akt, and prolonged hyperactivity in rats. In conclusion, protein translation pathway could play an important role in ouabain-induced hyperactivity in a rodent model of mania.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2013;
• Article: Meta-Analysis: Aerobic Exercise for the Treatment of Anxiety Disorders.

  Christine A Bartley, Madeleine Hay, Michael H Bloch
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  ABSTRACT: BACKGROUND: This meta-analysis investigates the efficacy of exercise as a treatment for DSM-IV diagnosed anxiety disorders. METHODS: We searched PubMED and PsycINFO for randomized, controlled trials comparing the anxiolytic effects of aerobic exercise to other treatment conditions for DSM-IV defined anxiety disorders. Seven trials were included in the final analysis, totaling 407 subjects. The control conditions included non-aerobic exericise, waitlist/placebo, cognitive-behavioral therapy, psychoeducation and meditation. A fixed-effects model was used to calculate the standardized mean difference of change in anxiety rating scale scores of aerobic exercise compared to control conditions. Subgroup analyses were performed to examine the effects of (1) comparison condition; (2) whether comparison condition controlled for time spent exercising and (3) diagnostic indication. RESULTS: Aerobic exercise demonstrated no significant effect for the treatment of anxiety disorders (SMD=0.02 (95%CI: -0.20-0.24), z=0.2, p=0.85). There was significant heterogeneity between trials (χ2 test for heterogeneity=22.7, df=6, p=0.001). The reported effect size of aerobic exercise was highly influenced by type of control condition. Trials utilizing waitlist/placebo controls and trials that did not control for exercise time reported large effects of aerobic exercise while other trials report no effect of aerobic exercise. CONCLUSIONS: Current evidence does not support the use of aerobic exercise as an effective treatment for anxiety disorders as compared to the control conditions. This remains true when controlling for length of exercise sessions and type of anxiety disorder. Future studies evaluating the efficacy of aerobic exercise should employ larger sample sizes and utilize comparison interventions that control for exercise time.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain.

  Juan M Lima-Ojeda, Miriam A Vogt, Natascha Pfeiffer, Christof Dormann, Georg Köhr, Rolf Sprengel, Peter Gass, Dragos Inta
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  ABSTRACT: NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioural and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801-triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population.

  Asem Surindro Singh, Rashmi Chandra, Subhrangshu Guhathakurta, Swagata Sinha, Anindita Chatterjee, Shabina Ahmed, Saurabh Ghosh, Usha Rajamma
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  ABSTRACT: BACKGROUND: Serotoninergic dysfunction leads to neurodevelopmental abnormalities and behavioral impairments. Platelet hyperserotoninemia is reported as the best identified endophenotype for autism spectrum disorders. Therefore, in the present study we investigate association of TPH2, the rate limiting enzyme in 5-HT biosynthesis and ITGB3, a serotonin quantitative trait locus with ASD in the Indian population. METHODS: Population and family-based genetic association and gene-gene interaction analyses were performed to evaluate the role of ITGB3 and TPH2 markers in ASD etiology. RESULTS: Association tests using ITGB3 markers revealed significant paternal overtransmission of T allele of rs5918 to male probands. Interestingly for TPH2, we observed significant overrepresentation of A-A (rs11179000-rs4290270), G-A (rs4570625-rs4290270), G-G-A (rs4570625-rs11179001-rs4290270) and A-G-A (rs11179000-rs11179001-rs4290270) haplotypes in the controls and maternal preferential transmission of A-A (rs11179001-rs7305115), T-A-A (rs4570625-rs11179001-rs7305115) and T-A-A (rs11179000-rs11179001-rs7305115) and nontransmission of G-G-A (rs4570625-rs11179001-rs7305115) haplotypes to the affected offspring. Moreover, interaction of ITGB3 marker, rs15908 with TPH2 markers was found to be significant and influenced by the sex of the probands. Predicted individual risk, which varied from very mild to moderate, supports combined effect of these markers in ASD. CONCLUSION: Overall results of the present study indicate likely involvement of ITGB3 and TPH2 in the pathophysiology of ASD in the Indian population.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Decreased Gray Matter Volume of the Medial Orbitofrontal Cortex in Panic Disorder with Agoraphobia: A Preliminary Study.

  Kyoung-Sae Na, Byung-Joo Ham, Min-Soo Lee, Leen Kim, Yong-Ku Kim, Heon-Jeong Lee, Ho-Kyoung Yoon
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  ABSTRACT: BACKGROUND: Patients with panic disorder with agoraphobia (PDA) has clinical symptoms such as the fear of being outside or of open spaces from which escape would be difficult. Although recent neurobiological studies have suggested that fear conditioning and extinction are associated with PDA, no study has examined the possible structural abnormalities in patients with PDA. METHODS: This preliminary study compares the gray matter volume among patients with PDA, those with panic disorder without agoraphobia (PDW), and healthy controls (HC) using high-resolution 3.0 Tesla magnetic resonance imaging (MRI) with voxel-based morphometry (VBM). RESULTS: Compared with HC, patients with PDA showed decreased gray matter volume in their left medial orbitofrontal gyrus. However, differences were not found in the gray matter volumes of patients with PDW and whole panic disorder compared with HC. CONCLUSIONS: These findings suggest that the phobic avoidance found in patients with PDA arise from abnormalities in the medial orbitofrontal cortex, which plays an important role in fear extinction. Future studies should investigate the neuroanatomical substrates of PDA and distinguish them from those of PDW.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: The influence of ionotropic and metabotropic glutamate receptors ligands on anxiety-like effect of amphetamine withdrawal in rats.

  D Koltunowska, E Gibula-Bruzda, J H Kotlinska
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  ABSTRACT: Chronic amphetamine use results in anxiety-like states after drug cessation. The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptors ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats. In our study memantine (8 and 12 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist did not reduce amphetamine withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate 5 receptor (mGluR5) antagonist) at the dose 200 and 400 mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and a number of open arms entries. mGluR5 selective antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride) and mGluR2/3 agonist, LY354740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), caused effects similar to acamprosate at doses 1.25 - 5 mg/kg and 2.5 - 5 mg/kg, respectively. None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group. Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking, our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder.

  Zhi-Kun Qiu, Li-Ming Zhang, Nan Zhao, Hong-Xia Chen, You-Zhi Zhang, Yan-Qin Liu, Tian-Yue Mi, Wen-Wen Zhou, Yang Li, Ri-Fang Yang, Jiang-Ping Xu, Yun-Feng Li
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  ABSTRACT: Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a serious traumatic event. It is a psychiatric condition that can afflict anyone who has experienced a life-threatening or violent event. Previous studies have shown that changes in 18 kDa translocator protein (TSPO) expression (or function), a promising target for treating neurological disorders without benzodiazepine-like side effects, may correlate with PTSD. However, few studies have investigated the anti-PTSD effects of TSPO ligands. AC-5216, a ligand for TSPO, induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether AC-5216 ameliorates PTSD behavior in mice. Following the training session consisting of exposure to inescapable electric foot shocks, animals were administered AC-5216 daily during the behavioral assessments, i.e., situational reminders (SRs), the open field (OF) test, the elevated plus-maze (EPM) test, and the staircase test (ST). The results indicated that exposure to foot shocks induced long-term behavioral deficiencies in the mice, including freezing and anxiety-like behavioral, which were significantly ameliorated by repeated treatment with AC-5216 but without any effect on spontaneous locomotor activity or body weight. In summary, this study demonstrated the anti-PTSD effects of AC-5216 treatment, suggesting that TSPO may represent a therapeutic target for anti-PTSD drug discovery and that TSPO ligands may be a promising new class of drugs for the future treatment of PTSD.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Lack of association between dendritic cell nuclear protein-1 gene and major depressive disorder in the Han Chinese population.

  Hui Li, Yong-Jun Wang, Lin Hua, Yu-Tao Yang, Min Zhang, Dabao Zhang, Chuanyue Wang, Zhi-Qing David Xu
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  ABSTRACT: OBJECTIVES: Dendritic cell nuclear protein-1(DCNP1) has been associated with major depressive disorder (MDD) based on analysis of a population of patients in the United Kingdom. In the present study we have investigated a possible role of DCNP in MDD in the Han Chinese population, including a meta-analysis of different ethnic populations. METHODS: Eight single nucleotide polymorphisms (SNPs) spanning the entire DCNP1 were carefully selected, genotyped and used for the SNP and haplotype analyses in 574 patients with MDD and 642 healthy controls. Considering the potential genetic association difference across different ethnic populations, we further conducted a meta-analysis for Chinese and European populations. RESULTS: rs10061623 showed initial association with MDD in females in the allele analysis (p-value: 0.043). However, this association did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected p-value: 0.344). Other single-marker and haplotype analyses did not reveal any significant differences between patients and controls. The SNP (rs12520799), positive in the original UK study, gave negative results in all our analyses. The meta-analysis results of rs12520799 also suggested possible negative association between this SNP and MDD in the Han Chinese population. CONCLUSIONS: In the Han Chinese population, common DCNP1 polymorphisms are unlikely to be important in the genetic susceptibility to MDD.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Monoamine neurocircuitry in depression and strategies for new treatments.

  Michel Hamon, Pierre Blier
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  ABSTRACT: Extensive studies showed that monoaminergic neurotransmission that involves serotonin (5-HT), norepinephrine (NE) and dopamine (DA) exerts major influence on brain circuits concerned by the regulation of mood, reactivity to psychological stress, self-control, motivation, drive, and cognitive performance. Antidepressants targeting monoamines directly affect the functional tone of these circuits, notably in limbic and frontocortical areas, and evidence has been provided that this action plays a key role in their therapeutic efficacy. Indeed, at least some of functional changes detected by fMRI in emotion- and cognitive-related circuits such as the one involving limbic-cortical-striatal-pallidal-thalamic connections in depressed patients can be reversed by monoamine-targeted antidepressants. However, antidepressants acting selectively on only one monoamine, such as selective inhibitors of 5-HT or NE reuptake, alleviate depression symptoms in a limited percentage of patients, and are poorly effective to prevent recurrence. Thorough investigations for the last 30 years allowed the demonstration of the existence of functional interactions between 5-HT, NE and DA systems, and the identification of the specific receptors involved. In particular, 5-HT systems were shown to exert negative influence on NE and DA systems through 5-HT2A and 5-HT2C receptor- mediated mechanisms, respectively. On the other hand, complex positive and negative influences of NE system on 5-HT neurotransmission are mediated through 1- and 2-adrenergic receptors, respectively. These data provided a rationale for the design of new, multimodal, therapeutic strategies involving drugs acting not only at the "historical" targets such as the 5-HT and/or the NE transporter, but also at other molecular targets to improve their efficacy and their tolerability.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as "bath salts"

  Raúl López-Arnau, José Martínez-Clemente, Marcel Li Carbó, David Pubill, Elena Escubedo, Jorge Camarasa
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  ABSTRACT: INTRODUCTION: Methylone (3,4-methylenedioxymethcathinone) is a new psychoactive substance and an active ingredient of "legal highs" or "bath salts". We studied the pharmacokinetics and locomotor activity of methylone in rats at doses equivalent to those used in humans. MATERIAL AND METHODS: Methylone was administered to male Sprague-Dawley rats intravenously (10mg/kg) and orally (15 and 30mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240min. RESULTS: Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α=1.95h(-1) and β=0.72h(-1). For oral administration, peak methylone concentrations were achieved between 0.5- 1h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42±0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate. DISCUSSION: Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Neuronal injury, but not microglia activation, is associated with ketamine-induced experimental schizophrenic model in mice.

  Yue Hou, Hongli Zhang, Guanbo Xie, Xinyue Cao, Yanan Zhao, Yang Liu, Zhihao Mao, Jingyu Yang, Chunfu Wu
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  ABSTRACT: Schizophrenia is a chronic debilitating psychiatric disorder affecting as many as 1% of the population worldwide. Unfortunately, its etiology and pathophysiology are poorly defined. Previous studies have shown that neuronal injury and microglia activation were observed in the schizophrenic patients. The present study aims to evaluate the role of neurons and microglia in ketamine-induced experimental schizophrenic model to further understand its pathophysiology. Firstly, ketamine was used to simulate the behavior abnormalities associated with schizophrenia. The effects of ketamine on mice locomotor activity, Y-maze task, novel object recognition, and forced swimming test were studied. The results showed that ketamine (25, 50, and 100 mg/kg i.p.) administered acutely or repeatedly (for 7 days) can increase the locomotor number significantly. In Y-maze task, ketamine (25, 50, and 100 mg/kg) impaired spontaneous alternation after both acute and repeated treatments. In novel object recognition test, acute or chronic ketamine treatment showed no significant effect on mouse exploratory preference behaviour. In forced swimming test, repeated treatment of ketamine (100 mg/kg) enhanced the immobility duration. Secondly, immunohistochemical method was used to study the changes of neurons and microglia. The results showed that acute treatment of ketamine (100 mg/kg) had no effect on neurons in the prefrontal cortex or hippocampus (1, 3, 5, and 7 d after the treatment). In contrast, repeated treatment of ketamine caused neuronal impairment in mouse hippocampus (3(rd) day, 5(th) day and 7(th) day after the final administration). The results of immunohistochemistry demonstrated that microglia in prefrontal cortex and hippocampus were not affected after acute or repeated administration of ketamine. Finally, the neuronal impairment caused by repeated administration of ketamine was further investigated from the oxidative stress aspects. The results showed that repeated administration of ketamine increased nitric oxide (NO) and nitric oxide synthase (NOS) in prefrontal cortex, hippocampus and serum, while decreased SOD in hippocampus and serum. In summary, chronic ketamine treatment to mice successfully mimics the core behavioural deficits in schizophrenia. It is demonstrated for the first time that neuronal injury was associated with the chronic ketamine-induced experimental schizophrenic model, while microglial cells may play little role in this model. Oxidative stress may contribute to the significant neuronal injury in mouse brain induced by chronic ketamine treatment.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Neural correlate of impulsivity in subjects at ultra-high risk for psychosis.

  Tae Young Lee, Sung Nyun Kim, Joon Hwan Jang, Geumsook Shim, Wi Hoon Jung, Na Young Shin, Jun Soo Kwon
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  ABSTRACT: OBJECTIVE: Impulsivity is one of the most commonly reported behavioral characteristics of patients with schizophrenia. Although there is accumulating evidence regarding behavioral problems in individuals at ultra-high risk (UHR) for psychosis, as yet, no study has reported on impulsivity in this population. The aim of the present study was to assess impulsivity in UHR subjects and to investigate the associated grey matter correlates. METHOD: This study included 32 UHR subjects and 32 age- and gender-matched healthy controls (HC). The Barratt Impulsiveness Scale Version-11 (BIS-11) was employed to assess impulsivity. Differences between the groups in grey matter volume in the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and orbitofrontal cortex (OFC) were assessed. Then, a correlational analysis between the BIS-11 scores and significant clusters of grey matter volume was conducted in UHR subjects. RESULTS: UHR subjects were more impulsive than HC subjects in terms of attention (t = 3.5187, p < 0.01), motor (t = 3.1751, p < 0.01), and non-planning (t = 4.4154, p < 0.01) scores. The grey matter volume of the ACC was negatively correlated with the motor (r = -0.472, p < 0.01) and non-planning (r = -0.354, p = 0.04) scores of the BIS-11 in UHR subjects. CONCLUSION: These results suggest that impulsivity in UHR subjects may reflect altered integrated conflict processing, which likely stems from abnormalities in the ACC, rather than altered reward/punishment processing or executive control.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;
• Article: Brain Structural Abnormalities in Doberman Pinschers with Canine Compulsive Disorder.

  Niwako Ogata, Timothy E Gillis, Xiaoxu Liu, Suzanne M Cunningham, Steven B Lowen, Bonnie L Adams, James Sutherland-Smith, Dionyssios Mintzopoulos, Amy C Janes, Nicholas H Dodman, Marc J Kaufman
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  ABSTRACT: Obsessive compulsive disorder (OCD) is a debilitating condition, the etiology of which is poorly understood, in part because it often remains undiagnosed/untreated for a decade or more. Characterizing the etiology of compulsive disorders in animal models may facilitate earlier diagnosis and intervention. Doberman pinschers have a high prevalence of an analogous behavioral disorder termed canine compulsive disorder (CCD), which in many cases responds to treatments used for OCD. Thus, studies of CCD may help elucidate the etiology of compulsive disorders. We compared brain structure in Dobermans with CCD (N=8) and unaffected controls (N=8) to determine whether CCD is associated with structural abnormalities comparable to those reported in humans with OCD. We obtained 3 Tesla magnetic resonance structural and diffusion images from anesthetized Dobermans and subjected images to segmentation, voxel based morphometry, and diffusion tensor analyses. CCD dogs exhibited higher total brain and gray matter volumes and lower dorsal anterior cingulate cortex and right anterior insula gray matter densities. CCD dogs also had higher fractional anisotropy in the splenium of the corpus callosum, the degree of which correlated with the severity of the behavioral phenotype. Together, these findings suggest that CCD is associated with structural abnormalities paralleling those identified in humans with OCD. Accordingly, the CCD model, which has a number of advantages over other animal models of OCD, may assist in establishing the neuroanatomical basis for and etiology of compulsive disorders, which could lead to earlier diagnosis of and new treatments for humans and animals with these disorders.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013;