The International Journal of Neuropsychopharmacology - Current Issue

Volume 12 Issue 01

Sun, 01 Feb 2009 00:00:00 GMT

The International Journal of Neuropsychopharmacology, Volume 12 Issue 01

The International Journal of Neuropsychopharmacology (IJNP) serves as a major forum for the rapid publication and wide dissemination of high quality, influential research in neuropsychopharmacology, in the basic and clinical domains. The central focus of the journal is on research which advances understanding of existing and new neuropsychopharmacological agents, including their mode of action and clinical application, or which provides insights into the biological basis of neuropsychiatric disorders and thereby advances their pharmacological treatment. Such research might derive from the full spectrum of biological and psychological fields of inquiry, encompassing classical and novel techniques in neuro-psychopharmacology, as well as strategies such as neuroimaging, genetics, psycho-neuroendocrinology and neuropsychology. IJNP's rapid publication policy is facilitated by web-based submission and review, and the journal publishes the definitive versions of papers online, ahead of the printed issues. All papers are indexed in PubMed and ISI Journal Citation Reports.

PNP volume 12 issue 1 Cover and Front matter

Miscellaneous

The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp f1-f4

Abstract

PNP volume 12 issue 1 Cover and Front matter

Miscellaneous

The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp b1-b2

Abstract

Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism

Research Articles
Tetsuya Marui, Ikuko Funatogawa, Shinko Koishi, Kenji Yamamoto, Hideo Matsumoto, Ohiko Hashimoto, Eiji Nanba, Hisami Nishida, Toshiro Sugiyama, Kiyoto Kasai, Keiichiro Watanabe, Yukiko Kano, Nobumasa Kato,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 1-10

Abstract
Autism is a severe neurodevelopmental disorder of early childhood. Genetic factors play an important role in the aetiology of the disorder. In this study, we considered the NRCAM gene as a candidate gene of autism. This gene is expressed in the central nervous system and located in the 7q region, a susceptibility locus of autism. We conducted a case-control study of 18 single nucleotide polymorphisms (SNPs) within the NRCAM gene for possible association with autism in 170 autistic patients and 214 normal controls in a Japanese population. Seven SNPs in the NRCAM gene were significantly associated with autism, among which rs2300045 indicated the most prominent result (p=0.0009 uncorrected, p=0.017 corrected). In haplotype analyses, several individual haplotypes, including a common NRCAM haplotype C-T-T-C-T-T-G-C for rs3763463, rs1859767, rs1034825, rs2300045, rs2300043, rs2300039, rs722519, and rs2216259, showed a significant association after Bonferroni correction (p=0.0035 uncorrected, p=0.028 corrected). These haplotypes were located in the 5 intron-2 region of the gene. In addition, we also assessed the above mentioned SNPs and haplotypes using the transmission disequilibrium test with 148 trios of autistic families. Haplotype G-T-T-T-T-C-G-C in the same eight SNPs was also associated with autism. In summary, our findings provide evidence for a significant association of NRCAM with autism. Considering the important role of the NRCAM gene in brain development, our results therefore indicated that the NRCAM gene is one of the strong candidate genes for autism.

Reduced amygdala–prefrontal coupling in major depression: association with MAOA genotype and illness severity

Research Articles
Udo Dannlowski, Patricia Ohrmann, Carsten Konrad, Katharina Domschke, Jochen Bauer, Harald Kugel, Christa Hohoff, Sonja Schöning, Anette Kersting, Bernhard T. Baune, Lena S. Mortensen, Volker Arolt, Pienie Zwitserlood, Jürgen Deckert, Walter Heindel, Thomas Suslow,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 11-22

Abstract
The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

Onset of activity and time to response on individual CAPS-SX 17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis

Research Articles
Dan J. Stein, Ron Pedersen, Barbara O. Rothbaum, David S. Baldwin, Saeeduddin Ahmed, Jeff Musgnung, Jonathan Davidson,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 23-31

Abstract
This pooled analysis of data from two randomized, placebo-controlled trials of venlafaxine extended release (ER) assessed onset of activity and time to response on the 17 symptoms of post-traumatic stress disorder (PTSD) listed in DSM-IV and measured by the 17-item Clinician-Administered PTSD Scale (CAPS-SX17). The intent-to-treat (ITT) population comprised 687 patients (placebo, n=347; venlafaxine ER, n=340). Significant (p 0.05) separation between venlafaxine ER and placebo was observed on most CAPS-SX17 items, with earliest onset of activity and response (week 2) on items 5 (physiological reactivity on exposure to cues) and 14 (irritability or anger outbursts), and (week 4) items 1 (intrusive recollections) and 4 (psychological distress at exposure to cues). Onset of activity and response occurred later (generally, weeks 6 8) on items 9 (diminished interest/participation in activities), 10 (detachment or estrangement), 11 (restricted range of affect), 12 (sense of foreshortened future), all associated with numbing, 15 (difficulty concentrating), 16 (hypervigilance), 17 (exaggerated startle response), associated with hyperarousal, and 6 (avoidance of thoughts/feelings or conversations). Significant differences between venlafaxine ER and placebo were largely absent throughout the treatment period and at the primary week-12 end-point for items 2 (distressing dreams), 7 (avoidance of activities, places or people), 8 (inability to recall important aspect of trauma) and 13 (difficulty falling/staying asleep). These results indicate that symptoms of physiological reactivity and psychological distress in response to cues, and irritability/anger outbursts show early and robust improvement with venlafaxine ER treatment, while symptoms of numbing and hyperarousal take longer. The early and persistent effect of venlafaxine ER over placebo on anger/irritability is noteworthy in view of the clinical significance of these symptoms in PTSD.

Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder

Research Articles
Akiko Hayashi, Takaoki Kasahara, Mizue Kametani, Tomoko Toyota, Takeo Yoshikawa, Tadafumi Kato,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 33-43

Abstract
Impaired endoplasmic reticulum (ER) stress response has been suggested as a possible pathophysiological mechanism of bipolar disorder (BD). The expression of ER stress-related genes, spliced form or unspliced form of XBP1, GRP78 (HSPA5), GRP94 (HSP90B1), CHOP (DDIT3), and calreticulin (CALR), were examined in lymphoblastoid cells derived from 59 patients with BD and 59 age- and sex-matched control subjects. Basal mRNA levels and induction by 4 h or 12 h of treatment with two ER stressors, thapsigargin or tunicamycin, were examined using real-time quantitative reverse transcription polymerase chain reaction. Induction of the spliced form of XBP1 as well as total XBP1 by thapsigargin was significantly attenuated in patients with BD. Induction of GRP94 by thapsigargin was also decreased in the BD group. A haplotype of GRP94, protective against BD, exhibited significantly higher GRP94 expression upon ER stress. This report confirms and extends earlier observations of impaired ER stress response in larger samples of lymphoblastoid cell lines derived from BD patients. Altered ER stress response may play a role in the pathophysiology of BD by altering neural development and plasticity.

Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N -methyl- d -aspartic acid receptor up-regulation

Research Articles
Laura Gray, Maarten van den Buuse, Elizabeth Scarr, Brian Dean, Anthony J. Hannan,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 45-60

Abstract
Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.

Role of serotonin 5-HT 1A receptors in the antidepressant-like effect and the antinociceptive effect of venlafaxine in mice

Research Articles
Esther Berrocoso, Juan A. Mico,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 61-71

Abstract
The present study was undertaken to evaluate the potential role of 5-HT1A receptors in the antidepressant-like effect and antinociceptive effect of venlafaxine. With this aim, the effect of either a selective 5-HT1A receptor antagonist (WAY-100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT; 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) was investigated in mice in combination with venlafaxine by means of the forced swimming test, a paradigm aimed at screening potential antidepressants, and the hot-plate test, a phasic pain model. Surprisingly, the results showed that WAY-100635 produced a large decrease in the antidepressant-like effect of venlafaxine, while 8-OH-DPAT rendered effective a non-effective dose of this antidepressant. However, in the hot-plate test WAY-100635 significantly enhanced the antinociceptive effect of venlafaxine, whereas 8-OH-DPAT counteracted its antinociceptive effect. These findings show that 5-HT1A receptors play differing roles in modulating the antidepressant-like and antinociceptive effects of venlafaxine in the models investigated. The results imply that blockade of the 5-HT1A receptors in the forebrain will counteract the favourable (antidepressant-like) effect at raphe nuclei level, and consequently, the overall effect evidenced is an antagonism. This suggests a predominant role of 5-HT1A receptors located in the forebrain area for the antidepressant-like effect. In contrast, the antinociceptive effect of venlafaxine is probably potentiated due to the blockade of somatodendritic 5-HT1A receptors in the same raphe nuclei, facilitating the descending monoaminergic pain control system.

Single immobilization stress differentially alters the expression profile of transcripts of the brain-derived neurotrophic factor ( BDNF ) gene and histone acetylation at its promoters in the rat hippocampus

Research Articles
Manabu Fuchikami, Shigeru Morinobu, Akiko Kurata, Shigeto Yamamoto, Shigeto Yamawaki,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 73-82

Abstract
Decreased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus are implicated in the pathophysiology of major depression, although the mechanism has yet to be characterized. Epigenetic studies revealed that DNA methylation and histone modifications at the promoter of exons of the BDNF gene are the pivotal factors in the regulation of BDNF transcription. Histone acetylation regulates gene transcription through chromatin remodelling. We examined the influence of a single immobilization stress (SIS) at 2 h and 24 h afterwards on the levels of total BDNF mRNA with each exon mRNA by quantitative real-time PCR, acetylated histone at the promoters of the BDNF gene by chromatin immunoprecipitation followed by real-time PCR, and BDNF protein by ELISA in the rat hippocampus. SIS significantly decreased the levels of total BDNF mRNA with significantly reduced levels of exons I and IV mRNA followed by a significant reduction in BDNF protein 4 h after SIS. Significant decreases in the levels of acetylated histone H3, but not H4, were found at the promoters of exons I, IV, and VI. In contrast, no marked changes in the levels of either acetylated histone or BDNF mRNA and protein were found 24 h after SIS. This study demonstrated the involvement of histone acetylation in the regulation of BDNF transcription by SIS, and the plastic change in histone acetylation after SIS. These findings suggest that stress affects BDNF gene transcription via epigenetic regulation, and glucocorticoid may be involved in this regulation.

We are in the dark here: induction of depression- and anxiety-like behaviours in the diurnal fat sand rat, by short daylight or melatonin injections

Research Articles
Tal Ashkenazy, Haim Einat, Noga Kronfeld-Schor,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 83-93

Abstract
Circadian rhythms are considered an important factor in the aetiology, expression and treatment of major affective disorders, including seasonal affective disorder (SAD). However, data on the effects of daylight length manipulation or melatonin administration are complex. It has been suggested that since diurnal and nocturnal mammals differ significantly in their physiological and behavioural responses to daylight, diurnal rodents offer a preferable model of disorders related to circadian rhythms in the diurnal human. We previously found that diurnal fat sand rats maintained under short daylight (SD), show depression-like behaviour in the forced swim test (FST). The present study was designed to test additional behaviours related to affective disorders and study the involvement of melatonin in these behaviours. Sand rats were divided into short-daylight (SD, 5 h light:19 h dark) and long-daylight (LD, 12 h light:12 h dark) groups, and received 100 g melatonin or vehicle administration for 3 wk (5 h and 8.5 h after light onset in the LD room). Animals were then tested for reward-seeking behaviour (saccharin consumption), anxiety (elevated plus-maze), aggression (resident-intruder test), and depression-like behaviour (FST). SD or melatonin administration resulted in a depressed/anxious-like behavioural phenotype including reduced reward seeking, increased anxiety, decreased aggression and decreased activity in the FST, supporting the notion that in a diurnal animal, reduced light results in a variety of behavioural changes that may model depression and anxiety; and that melatonin may be a significant factor in these changes. We suggest that the sand rat may offer an excellent model species to explore the interactions between daylight, affective behaviour and the related underlying mechanisms.

Chronic cold stress increases excitatory effects of norepinephrine on spontaneous and evoked activity of basolateral amygdala neurons

Research Articles
Deanne M. Buffalari, Anthony A. Grace,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 95-107

Abstract
Neurons of the amygdala respond to a variety of stressors. The basolateral amygdala (BLA) receives dense norepinephrine (NE) innervation from the locus coeruleus, and stressful and conditioned stimuli cause increases in NE levels within the BLA. Furthermore, chronic stress exposure leads to sensitization of the stress response. The actions of NE in different structures involved in the stress circuit have been shown to play a role in this sensitization response. Here, we examine how chronic cold stress alters NE modulation of spontaneous and evoked activity in the BLA. In controls, NE inhibited spontaneous firing in the majority of BLA neurons, with some neurons showing excitation at lower doses and inhibition at higher doses of NE. NE also decreased the responsiveness of these neurons to electrical stimulation of the entorhinal and sensory association cortices. After chronic cold exposure, NE caused increases in spontaneous activity in a larger proportion of BLA neurons than in controls, and now produced a facilitation of responses evoked by stimulation of entorhinal and sensory association cortical inputs. These studies show that chronic cold exposure leads to an increase in the excitatory effects of NE on BLA neuronal activity, and suggest a mechanism by which organisms may display an enhancement of hormonal, autonomic, and behavioural responses to acute stressful stimuli after chronic stress exposure.

Dysregulation of cell death machinery in the prefrontal cortex of human alcoholics

Brief Report
Sofia Johansson, Tomas J. Ekström, Zoya Marinova, Anna Ökvist, Donna Sheedy, Therese Garrick, Clive Harper, Alexander Kuzmin, Tatjana Yakovleva, Georgy Bakalkin,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 109-115

Abstract
In human alcoholics, the cell density is decreased in the prefrontal cortex (PFC) and other brain areas. This may be due to persistent activation of cell death pathways. To address this hypothesis, we examined the status of cell death machinery in the dorsolateral PFC in alcoholics. Protein and mRNA expression levels of several key pro- and anti-apoptotic genes were compared in post-mortem samples of 14 male human alcoholics and 14 male controls. The findings do not support the hypothesis. On the contrary, they show that several components of intrinsic apoptotic pathway are decreased in alcoholics. No differences were evident in the motor cortex, which is less damaged in alcoholics and was analysed for comparison. Thus, cell death mechanisms may be dysregulated by inhibition of intrinsic apoptotic pathway in the PFC in human alcoholics. This inhibition may reflect molecular adaptations that counteract alcohol neurotoxicity in cells that survive after many years of alcohol exposure and withdrawal.

Low doses of antipsychotic drugs for hospitalized schizophrenia patients in East Asia: 2004 vs. 2001

Brief Report
Kang Sim, Hsin Chuan Su, Senta Fujii, Shu-yu Yang, Mian-Yoon Chong, Tianmei Si, Yan Ling He, Eun Kee Chung, Yiong Huak Chan, Naotaka Shinfuku, Chay Hoon Tan, Gabor Ungvari, Ross J. Baldessarini,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 117-123

Abstract
We test the hypothesis of increasing prevalence of low-dose antipsychotic use (300 mg/d chlorpromazine-equivalent) in East Asia and examine clinical correlates of conservative dosing. Rates of low-dose antipsychotic prescription were determined for 4535 patients with DSM-IV diagnosis of schizophrenia in six East Asian countries and territories, with comparisons analysed for 2004 vs. 2001. Between 2001 (n=2399 subjects) and 2004 (n=2136 subjects), prescription rates for low doses of antipsychotic drugs (APDs) increased from 24.8% to 44.0% (p 0.001). Low doses were more likely among older patients (p=0.005), during first-lifetime hospitalizations (p 0.001), and among patients with less prominent delusions, hallucinations or disorganized speech (all p 0.05). Multivariate modelling indicated that low doses were strongly associated with older age, first admission, sampling year (2004 2001), less use of antipsychotic polytherapy (all p 0.001) and depot antipsychotics (p=0.009). Conservative dosing of APDs was increasingly prevalent in East Asia. Our findings suggest characteristics of patients who may be particularly likely to require low antipsychotic doses.

Central auditory dysfunction in schizophrenia as revealed by the mismatch negativity (MMN) and its magnetic equivalent MMNm: a review

Review Articles
Risto Näätänen, Seppo Kähkönen,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 125-135

Abstract
Since the early 1990s, the auditory change-detection response, mismatch negativity (MMN) and its magnetoencephalographic (MEG) equivalent MMNm have been applied in a large number of studies on schizophrenia. These studies have enhanced our understanding of the central auditory dysfunction underlying schizophrenia. The attenuation of the MMN amplitude is a systematic and robust neurophysiological finding in these patients. The gradual attenuation of the MMN amplitude resulting from frequency change reflects the progress of the disease, particularly the impairment occurring as a function of illness duration, whereas the MMN deficiency for duration change may be more closely linked to the genetic aspect of the illness. Electroencephalographic (EEG) and magnetoencephalographic (MEG) studies, together, suggest that both the temporal and frontal cortices contributing to MMN generation are affected in schizophrenia patients. Furthermore, abnormalities in auditory perception and discrimination revealed by a deficient temporal MMN generator process might be associated with patients' positive symptoms, whereas the dampened frontal attention-switching function, suggested by the attenuated responses of the frontal MMN generator, might contribute to the negative symptoms such as social withdrawal. In addition, gradual MMN amplitude reduction, in particular that for frequency change, reflects cognitive and functional impairment occurring as a function of illness duration. Finally, as MMN can be detected even in animals such as the mouse, it might provide a useful biomarker for assessing the effects of the drugs developed to fight the cognitive and functional impairments in schizophrenia patients.

Accelerated age-related decrease in brain-derived neurotrophic factor levels in bipolar disorder

Letter
Lakshmi N. Yatham, Flavio Kapczinski, Ana C. Andreazza, L. Trevor Young, Raymond W. Lam, Marcia Kauer-Sant'Anna,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 137-139

Abstract

Zopiclone and sleepwalking

Letter
Panagiotis Ferentinos, Thomas Paparrigopoulos,
The International Journal of Neuropsychopharmacology, Volume 12 Issue 01 , pp 141-142

Abstract