European Neuropsychopharmacology (v.23, #12)

Contents (OBC).

Autoimmune-induced glutamatergic receptor dysfunctions: Conceptual and psychiatric practice implications by Ayelet Rosenthal-Simons; Andrea R. Durrant; Uriel Heresco-Levy (1659-1671).
Glutamatergic neurotransmission is mediated via complex receptorial systems including N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) and metabotropic receptor subtypes and plays a critical role in the modulation of synaptic plasticity, mood, cognitive processes and motor behavior. Glutamatergic function deficits are hypothesized to contribute to the pathogenesis of neuropsychiatric disorders, including schizophrenia, mood and movement disorders. Accumulating data are rapidly leading to the characterization of specific types of autoimmune encephalitis in which the receptors and proteins critically involved in glutamatergic neurotransmission, e.g., NMDA, AMPA receptors, are antigen targets. Characteristic of these syndromes, antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble pharmacological disease models. Presently the best characterized autoimmune glutamatergic disorder is anti-NMDA receptor encephalitis. This disorder manifests with intertwined psychiatric and neurological features, defines a new syndrome, reclassifies poorly defined clinical states and extends previous hypotheses, such as hypo-NMDA receptor function in schizophrenia. The characterization of autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders including schizophrenia, affective and movement dysfunctions. Further definition of AGRD will provide additional guidelines for psychiatric diagnoses, identification of homogeneous patient subtypes within broad phenomenological classifications and will contribute to the development of personalized treatments. The body of knowledge already accumulated on anti-NMDA receptor encephalitis highlights the need for wide dissemination of these concepts among psychiatrists, and in suspected cases, for early recognition, prompt clinical and laboratory investigation and efficient interface between mental health and medical teams.
Keywords: Glutamate; NMDAR; Encephalitis; Depression; Movement disorders; Schizophrenia;

The role of inflammatory cytokines in suicidal behavior: A systematic review by Gianluca Serafini; Maurizio Pompili; Maria Elena Seretti; Henry Stefani; Mario Palermo; William Coryell; Paolo Girardi (1672-1686).
There is growing evidence that inflammatory mediators play a critical role in the pathophysiology of both major depression and suicidal behavior. Immunological differences have been reported in both major affective disorders and suicidal behavior. Specifically, increased levels of pro-inflammatory cytokines have been shown to correlate with the severity of depression and various cytokines have been identified as potentially important in understanding the pathophysiology of major affective disorders/suicidality. We aimed to conduct a systematic review of the current literature to investigate the association between inflammatory cytokines and suicidal behavior. Only articles from peer-reviewed journals were selected for inclusion in the present review. Most studies documented the association between suicidality and IL2, IL-6, IL-8, TNF-α and VEGF levels that have been found altered in suicidal behavior. The presence of major depressive disorder (MDD) with suicidal ideation/attempts was associated with differences in inflammatory cytokine profile when compared to that without suicidal ideation/attempts. Most suicide attempters or subjects with suicidal ideation showed an imbalance of the immune system but this does not imply the existence of a causal link. Also, not all studies demonstrated a positive correlation between inflammatory cytokines and suicidal behavior. Further additional studies should elucidate the molecular mechanisms of the immune activation pathways underlying suicidality.
Keywords: Inflammation; Cytokines; Inflammatory mediators; Suicidal behavior;

The endocannabinoid system and emotional processing: A pharmacological fMRI study with ∆9-tetrahydrocannabinol by Matthijs G. Bossong; Hendrika H. van Hell; Gerry Jager; René S. Kahn; Nick F. Ramsey; J. Martijn Jansma (1687-1697).
Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ∆9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative (‘fearful faces’) or a positive content (‘happy faces’) were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression.
Keywords: Endocannabinoid system; Emotional processing; Functional MRI; Δ9-tetrahydrocannabinol (THC);

Cocaine users with comorbid Cluster B personality disorders show dysfunctional brain activation and connectivity in the emotional regulation networks during negative emotion maintenance and reappraisal by Natalia Albein-Urios; Juan Verdejo-Román; Carles Soriano-Mas; Samuel Asensio; José Miguel Martínez-González; Antonio Verdejo-García (1698-1707).
Cocaine dependence often co-occurs with Cluster B personality disorders. Since both disorders are characterized by emotion regulation deficits, we predicted that cocaine comorbid patients would exhibit dysfunctional patterns of brain activation and connectivity during reappraisal of negative emotions. We recruited 18 cocaine users with comorbid Cluster B personality disorders, 17 cocaine users without comorbidities and 21 controls to be scanned using functional magnetic resonance imaging (fMRI) during performance on a reappraisal task in which they had to maintain or suppress the emotions induced by negative affective stimuli. We followed region of interest (ROI) and whole-brain approaches to investigate brain activations and connectivity associated with negative emotion experience and reappraisal. Results showed that cocaine users with comorbid personality disorders had reduced activation of the subgenual anterior cingulate cortex during negative emotion maintenance and increased activation of the lateral orbitofrontal cortex and the amygdala during reappraisal. Amygdala activation correlated with impulsivity and antisocial beliefs in the comorbid group. Connectivity analyses showed that in the cocaine comorbid group the subgenual cingulate was less efficiently connected with the amygdala and the fusiform gyri and more efficiently connected with the anterior insula during maintenance, whereas during reappraisal the left orbitofrontal cortex was more efficiently connected with the amygdala and the right orbitofrontal cortex was less efficiently connected with the dorsal striatum. We conclude that cocaine users with comorbid Cluster B personality disorders have distinctive patterns of brain activation and connectivity during maintenance and reappraisal of negative emotions, which correlate with impulsivity and dysfunctional beliefs.
Keywords: Cocaine; Borderline personality disorder; Histrionic personality disorder; Antisocial personality disorder; Negative emotion; Reappraisal; Anterior cingulate cortex; Lateral orbitofrontal cortex; Amygdala;

Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations by Nora Preuss; Jan Willem van der Veen; Paul J. Carlson; Jun Shen; Gregor Hasler (1708-1713).
The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0 mg, 150 mg and 300 mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300 mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system.
Keywords: Gamma-aminobutyric acid; Gabapentin; Magnetic resonance spectroscopy; Epilepsy; Anxiety; Mood disorders;

Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence by Cleo L. Crunelle; Wim van den Brink; Dick J. Veltman; Katelijne van Emmerik-van Oortmerssen; Geert Dom; Robert A. Schoevers; Jan Booij (1714-1723).
Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [123I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients.
Keywords: Attention deficit hyperactivity disorder; Cocaine addiction; Dopamine transporter; Methylphenidate; SPECT; Substance use disorder;

Oxytocin administration alters HPA reactivity in the context of parent–infant interaction by Omri Weisman; Orna Zagoory-Sharon; Ruth Feldman (1724-1731).
The neuropeptide oxytocin (OT) and the steroid cortisol (CT) have each been implicated in complex social behavior, including parenting, and one mechanism by which OT is thought to exert its pro-social effects is by attenuating hypothalamic–pituitary–adrenal (HPA) response to stress. Yet, no study to date has tested whether OT functions to reduce CT production in the context of the parent–infant attachment. In the current study, we examined the effects of intranasal OT administered to the parent on parent’s and infant’s CT levels following parent–child interaction that included a social stressor. Utilizing a double-blind, placebo-controlled, within-subject design, 35 fathers and their 5-month-old infants were observed in a face-to-face-still-face paradigm twice, one week apart. Interactions were micro-coded for social synchrony, and salivary CT were repeatedly assessed from parent and child. Results showed that OT increased fathers’ overall CT response to the stress paradigm. Furthermore, OT altered infants’ physiological and behavioral response as a function of parent–infant synchrony. Among infants experiencing high parent–infant synchrony, OT elevated infant HPA reactivity and increased infant social gaze to the father while father maintained a still-face. On the other hand, among infants experiencing low social synchrony, parental OT reduced the infant’s stress response and diminished social gaze toward the unavailable father. Results are consistent with the “social salience” hypothesis and highlight that OT effects on human social functioning are not uniform and depend on the individual’s attachment history and social skills. Our findings call to further investigate the effects of OT administration within developmental contexts, particularly the parent–infant relationship.
Keywords: Oxytocin; Cortisol; Stress; Parent–infant synchrony; Gaze; Still-face;

Pharmacological treatment and demographic characteristics of pediatric patients with Attention Deficit Hyperactivity Disorder, Sweden by Shahram Bahmanyar; Anders Sundström; Magnus Kaijser; Anne-Liis von Knorring; Helle Kieler (1732-1738).
The aim of this study was to describe the pediatric population with ADHD and their pharmacological treatment. Using the Swedish National Patient Register and the Prescribed Drug Register we identified individuals below 19 years of age who were diagnosed or medically treated for ADHD for the first time 2006–2007. The unique patient identifiers were used to link information from the two registers to describe demographic characteristics, hospital care and drug treatments. Logistic regression model estimated the association between age, sex, frequency of hospitalization, diagnosis or treatment for other mental disorders and risk of gap in the treatment. Totally the study included 7931 patients of whom 74% were males. The mean age at first diagnosis was 12 years. Some 84% were medically treated for ADHD and approximately 90% received methylphenidate as the first substance. Combination therapy was rare and the most common combination was methylphenidate and atomoxetine. More than 55% of the patients, which could be followed up for two years after start of treatment, had at least one treatment gap of six months. Older age at diagnosis, lower number of hospitalizations and comorbidity with other mental disorders increased risks of gaps in medication. Approximately one fifth of the patients recorded in the National Patient Register as diagnosed with ADHD did not receive pharmacological treatment. Medication adherence seems to be low, when measured as gaps in treatment.
Keywords: Attention Deficit Disorder with Hyperactivity; Methylphenidate; Atomoxetine; Amphetamine; Dextroamphetamine; Pediatrics; Cohort study;

In major depression, when a first antidepressant does not cause remission of symptoms (60%–75%), there are several options for continuing treatment in the next step. This study is a cost-utility analysis (CUA) of different second-line approaches. In a simulated trial outpatients with MDD were treated with citalopram for 13 weeks (level 1), then based on two alternative algorithms implemented from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Algorithm A: citalopram was continued until study endpoint (week 26). Algorithm B: patients who remitted during level 1 continued citalopram. Those who did not remit could opt for switching to another antidepressant (venlafaxine; sertraline) (b1) or adding bupropion to citalopram treatment (augmentation; b2). Algorithm B increased remission rate by 10.6% over Algorithm A (number needed to treat: 9.9; sensitivity range: 9.1–12.5). As a comparison, differences between active antidepressants and placebo are associated with NNT values of 6 to 8. In CUA Algorithm B was dominant with an ICER of $11,813 (sensitivity range=$1783 – $21,784), which is <1 GDP per capita cost-effectiveness threshold (USA=$47,193). Among Algorithm B options, switching (b1) dominated Algorithm A with a smaller number of responders than augmentation approach (b2) (NNT 11 vs. 7.7), whereas ICER values were similar (b1: $14,738; b2: $15,458). However we cannot exclude a bias in selecting second treatment. This cost-utility analysis shows (in line with current guidelines) a benefit in modifying antidepressant treatment if response to first-line agent does not occur within 3 months, but not a clear-cut evidence in terms of NNT.
Keywords: Depression; Antidepressants; Pharmacoeconomics; Cost-benefit; Switching;

The flush that develops during whole-body heat stress depends partly on prostaglandins production in the skin. Variations in the strength of this local mechanism may contribute to individual differences in susceptibility to blushing and associated anxiety. To investigate this in the present study, the anti-inflammatory agent ibuprofen (which blocks prostaglandins formation) was applied topically to a small area of the cheek in 16 participants with a fear of blushing and in another 14 without this fear. Changes in skin blood flow were monitored at the ibuprofen-treated site and at a mirror image control site while participants sang (to induce embarrassment and blushing) and during aerobic exercise (to induce flushing). The topical ibuprofen treatment inhibited increases in cheek blood flow in both groups during both of these tasks. However, increases in cheek blood flow were greater in participants with high than low fear of blushing immediately after exercise. These findings suggest that prostaglandins contribute to dilatation of facial blood vessels both during emotional arousal (embarrassment) and aerobic exercise. Furthermore, fear of blushing may be associated with mechanisms that delay the resumption of normal vascular tone after a period of vasodilatation. Whether topical ibuprofen gel is suitable for intermittent or long-term use as an aid for blushing control requires further investigation.
Keywords: Blushing; Flushing; Embarrassment; Exercise; Skin blood flow; Prostaglandins;

Drug attitude and other predictors of medication adherence in schizophrenia: 12 months of electronic monitoring (MEMS®) in the Swedish COAST-study by Cecilia Brain; Katarina Allerby; Birgitta Sameby; Patrick Quinlan; Erik Joas; Ulla Karilampi; Eva Lindström; Jonas Eberhard; Tom Burns; Margda Waern (1754-1762).
The aim was to investigate clinical predictors of adherence to antipsychotics. Medication use was electronically monitored with a Medication Event Monitoring System (MEMS®) for 12 months in 112 outpatients with schizophrenia and schizophrenia-like psychosis according to DSM-IV. Symptom burden, insight, psychosocial function (PSP) and side effects were rated at baseline. A comprehensive neuropsychological test battery was administered and a global composite score was calculated. The Drug Attitude Inventory (DAI-10) was filled in. A slightly modified DAI-10 version for informants was distributed as a postal questionnaire. Non-adherence (MEMS® adherence ≤0.80) was observed in 27%. In univariate regression models low scores on DAI-10 and DAI-10 informant, higher positive symptom burden, poor function, psychiatric side effects and lack of insight predicted non-adherence. No association was observed with global cognitive function. In multivariate regression models, low patient-rated DAI-10 and PSP scores emerged as predictors of non-adherence. A ROC analysis showed that DAI-10 had a moderate ability to correctly identify non-adherent patients (AUC=0.73, p<0.001). At the most “optimal” cut-off of 4, one-third of the adherent would falsely be identified as non-adherent. A somewhat larger AUC (0.78, p<0.001) was observed when the ROC procedure was applied to the final regression model including DAI-10 and PSP. For the subgroup with informant data, the AUC for the DAI-10 informant version was 0.68 (p=0.021). Non-adherence cannot be properly predicted in the clinical setting on the basis of these instruments alone. The DAI-10 informant questionnaire needs further testing.
Keywords: Adherence; Predictors; Schizophrenia; Antipsychotics; Medication Event Monitoring System; Drug Attitude Inventory;

Prospective analysis of the association between estrogen receptor gene variants and the risk of cognitive decline in elderly women by Joanne Ryan; Isabelle Carrière; Helene Amieva; Olivier Rouaud; Claudine Berr; Karen Ritchie; Pierre-Yves Scarabin; Marie-Laure Ancelin (1763-1768).
A plethora of data suggests a role for estrogen in cognitive function and genetic variants in the estrogen receptors ESR1 and ESR2 have been implicated in a range of hormone-sensitive diseases. It remains unknown however, whether ESR polymorphisms are associated with the risk of decline in specific domains of cognitive function. Data came from 3799 non-demented, community-dwelling elderly women recruited in France to the 3C Study. A short cognitive test battery was administered at baseline and 2, 4 and 7 years follow-up to assess global function, verbal fluency, visual memory, psychomotor speed and executive function. Detailed socio-demographic, behavioral, physical and mental health information was also gathered and genotyping of five common ESR1 and ESR2 polymorphisms was also performed. In multivariable-adjusted Cox analysis, ESR1 rs2234693 and rs9340799 were not significantly associated with the risk of decline on any of the cognitive tasks. However, significant associations with ESR2 polymorphisms were identified. The A allele of rs1256049 was associated with an increased risk of substantial decline in visual memory (HR:1.64, 95% CI: 1.23–2.18, p=0.0007), psychomotor speed (HR:1.43, 95% CI: 1.12–1.83, p=0.004), and on the incidence of Mild Cognitive Impairment (HR:1.31, 95% CI: 1.05–1.64, p=0.02). There was also a weaker association between the A allele of rs4986938 and a decreased risk of decline in psychomotor speed. Our large multicentre prospective study provides preliminary evidence that ESR2 genetic variants may be associated with specific cognitive domains and suggests that further examination of the role of this gene in cognitive function is warranted.
Keywords: Cognition; Cognitive decline; Estrogen receptor; Estrogen receptor polymorphisms; Women;

Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide by Vitor S. Pereira; Plinio C. Casarotto; Vinícius A. Hiroaki-Sato; Ariandra G. Sartim; Francisco S. Guimarães; Sâmia R.L. Joca (1769-1778).
Activation of purinergic receptors by ATP (P2R) modulates glutamate release and the activation of post-synaptic P2R is speculated to induce nitric oxide (NO) synthesis. Increased glutamatergic and nitrergic signaling have been involved in the neurobiology of stress-related psychiatric disorders such as anxiety and depression. Therefore, the aim of this study was to test the effects of two P2R antagonists (PPADS and iso-PPADS) in animals submitted to models predictive of antidepressant-, anxiolytic- and anticompulsive-like effects. Swiss mice receiving PPADS at 12.5 mg/kg showed reduced immobility time in the forced swimming test (FST) similarly to the prototype antidepressant imipramine (30 mg/kg). This dose was also able to decrease the number of buried marbles in the marble-burying test (MBT), an anticompulsive-like effect. However, no effect was observed in animals submitted to the elevated plus maze (EPM) and to the open field test. The systemic administration of iso-PPADS, a preferential P2XR antagonist, also reduced the immobility time in FST, which was associated to a decrease in NO x levels in the prefrontal cortex. In addition, P2X7 receptor was found co-immunoprecipitated with neuronal nitric oxide synthase (NOS1) in the prefrontal cortex. These results suggest that P2X7, possibly coupled to NOS1, could modulate behavioral responses associated to stress-related disorders and it could be a new target for the development of more effective treatments for affective disorders.
Keywords: P2 receptor; PPADS; Forced swimming test; Marble burying; Purinergic system;

β-endorphin degradation and the individual reactivity to traumatic stress by Alexandra Kavushansky; Milli Kritman; Mouna Maroun; Ehud Klein; Gal Richter-Levin; Koon-Sea Hui; Dorit Ben-Shachar (1779-1788).
Reactivity to traumatic stress varies between individuals and only a minority of those exposed to trauma develops stress-induced psychopathologies. Currently extensive effort is made to unravel the specific mechanisms predisposing to vulnerability vs. resilience to stress. We investigated in rats the role of β-endorphin metabolism in vulnerability to acute traumatic stress. Responders (showing extreme anxiety; n=7) and resilient non-responders (not differing from the non-stressed individuals; n=8) to traumatic foot-shock stress were compared for their blood levels of stress hormones as well as brain levels and activity of two opioid-degrading enzymes. β-endorphin is a substrate to insulin degrading enzyme, which also degrades insulin. Therefore, the effects of insulin application on behavioral and hormonal responses and on β-endorphin degradation were tested. Pre- and post-stress levels of serum corticosterone, and post-stress plasma β-endorphin concentration differentiated between the responders and the non-responders. In brain, responders showed enhanced degradation rates of β-endorphin, assessed by Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS), in hippocampal and amygdalar slices as compared to non-responders. Application of insulin to the amygdala, prior to exposure to traumatic stress, reduced post-stress anxiety and serum corticosterone levels only in the responders. In parallel, amygdalar β-endorphin degradation rate was also reduced by insulin. These results suggest that slowing down β-endorphin degradation rate may constitute an integral part of the normal stress-response, upon a failure of which an extreme anxiety develops. Modulation of opioid degradation may thus present a potential novel target for interference with extreme anxiety.
Keywords: β-endorphin; Acute traumatic stress; Insulin; LC-MS/MS; Opioid degrading enzymes; Anxiety; Rat;

Electroconvulsive therapy remains the most effective treatment for depression including a fast onset of action. However, this therapeutic approach suffers from some potential drawbacks. In the acute phase this includes amnesia. Electroconvulsive stimulation (ECS) has previously been shown to reverse a depression-like state in the chronic mild stress model of depression (CMS), but the effect of ECS on cognition has not previously been investigated. In this study the CMS model was used to induce a depressive-like condition in rats. The study was designed to investigate the acute effect of ECS treatment on working memory and the chronic effect of repeated ECS treatments on depression-like behavior and working memory. The results indicated that, in the acute phase, ECS treatment induced a working memory deficit in healthy controls unexposed to stress, while repeated treatments reversed stress-induced decline in working memory, as well as recovering rats submitted to the CMS paradigm from the anhedonic-like state. Like in the clinical setting, a single ECS exposure was ineffective in inducing remission from a depression-like state.
Keywords: Electroconvulsive stimulation; ECT; Chronic mild stress; Depression; Anhedonia; Cognitive impairment;

NMDA receptor antagonist-enhanced high frequency oscillations: Are they generated broadly or regionally specific? by Maciej Olszewski; Wioleta Dolowa; Pawel Matulewicz; Stefan Kasicki; Mark J. Hunt (1795-1805).
Systemic administration of NMDA receptor antagonists, used to model schizophrenia, increase the power of high-frequency oscillations (130–180 Hz, HFO) in a variety of neuroanatomical and functionally distinct brain regions. However, it is unclear whether HFO are independently and locally generated or instead spread from a distant source. To address this issue, we used local infusion of tetrodotoxin (TTX) to distinct brain areas to determine how accurately HFO recorded after injection of NMDAR antagonists reflect the activity actually generated at the electrode tip. Changes in power were evaluated in local field potentials (LFPs) recorded from the nucleus accumbens (NAc), prefrontal cortex and caudate and in electrocorticograms (ECoGs) from visual and frontal areas. HFO recorded in frontal and visual cortices (ECoGs) or in the prefrontal cortex, caudate (LFPs) co-varied in power and frequency with observed changes in the NAc. TTX infusion to the NAc immediately and profoundly reduced the power of accumbal HFO which correlated with changes in HFO recorded in distant cortical sites. In contrast, TTX infusion to the prefrontal cortex did not change HFO power recorded locally, although gamma power was reduced. A very similar result was found after TTX infusion to the caudate. These findings raise the possibility that the NAc is an important neural generator. Our data also support existing studies challenging the idea that high frequencies recorded in LFPs are necessarily generated at the recording site.
Keywords: Rat; NMDAR antagonist; Nucleus accumbens; Cortex; High frequency oscillations; Tetrodotoxin; Local field potential;

Inhibition of inositol monophosphatase (IMPase) at the calbindin-D28k binding site: Molecular and behavioral aspects by Itzhak Levi; Yael Eskira; Miriam Eisenstein; Chaim Gilon; Amnon Hoffman; Yiftach Talgan; Joseph Fanous; Yuly Bersudsky; RH Belmaker; Galila Agam; Orna Almog (1806-1815).
Bipolar-disorder (manic-depressive illness) is a severe chronic illness affecting ∼1% of the adult population. It is treated with mood-stabilizers, the prototypic one being lithium-salts (lithium), but it has life threatening side-effects and a significant number of patients fail to respond. The lithium-inhibitable enzyme inositol-monophosphatase (IMPase) is one of the viable targets for lithium's mechanism of action. Calbindin-D28k (calbindin) up-regulates IMPase activity. The IMPase-calbindincomplex was modeled using the program MolFit. The in-silico model indicated that the 55–66 amino-acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys–Glu–Lys motif) and that the motif interacts with residues Asp24 and Asp26 of calbindin. We found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a linear peptide with the sequence of amino acids 58–63 of IMPase (peptide 1) and by six amino-acid linear peptides including at least part of the Lys–Glu–Lys motif. The three amino-acid peptide Lys–Glu–Lys or five amino-acid linear peptides containing this motif were ineffective. Mice administered peptide 1 intracerebroventricularly exhibited a significant anti-depressant-like reduced immobility in the forced-swim test. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic peptide and one linear pre-cyclic analog peptide inhibited calbindin-activated brain IMPase activity in-vitro. Our findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.
Keywords: Bipolar disorder; Inositol monophosphatase; Calbindin; Lithium; Protein–protein docking;

Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice by Jenny Molet; Denis Hervé; Marie-Hélène Thiébot; Michel Hamon; Laurence Lanfumey (1816-1825).
Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5 g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5 mg/kg) or morphine (10 mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20 mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.
Keywords: Adolescence; Ethanol; Conditioned place preference; Locomotion; Extracellular signal-regulated kinase; Mouse;