European Neuropsychopharmacology (v.21, #4)

Contents (OBC).

2-year course of bipolar disorder type I patients in outpatient care: Factors associated with remission and functional recovery by J.M. Haro; C. Reed; A. Gonzalez-Pinto; D. Novick; J. Bertsch; E. Vieta (287-293).
EMBLEM is a 2-year, prospective, observational study that enrolled patients initiating/changing oral treatment for an acute manic/mixed episode. This paper analysed remission and functional recovery in 1656 patients who entered the 2-year long-term phase. Cox models identified variables significantly associated with achieving remission and functional recovery at 2 years. Of these patients, 64% achieved remission and 34% achieved functional recovery. Patients with a higher CGI-BP overall score at baseline, who had depressive episodes in the year before inclusion and who had poor social functioning (work or social impairment, not living independently or without a spouse/partner) were less likely to achieve remission or recovery. Prescription of typical antipsychotics and prescription of antidepressants at the first visit of the long-term treatment phase (12 weeks) were independent predictors of lower remission and recovery rates. In conclusion, functional recovery occurred in approximately half of those who achieved remission. Impairment of work and social functioning was consistently associated with lower remission and recovery rates.
Keywords: Bipolar disorder; Europe; Mania; Observational studies; Longitudinal studies; Remission; Functional recovery;

Searching for functional SNPs or rare variants in exonic regions of DRD3 in risperidone-treated patients by Patricia Gassó; Sergi Mas; Cristina Oliveira; Miquel Bioque; Eduard Parellada; Miquel Bernardo; Gemma Trias; Joaquim Comeche; Amalia Lafuente (294-299).
Previously one intronic DRD3 SNP, rs167771, was associated with risperidone-induced extrapyramidal side-effects (EPS). The aim of the present study was to search hitherto unidentified common functional variants or rare variants, in DRD3 associated with risperidone-induced EPS. 126 subjects treated with risperidone participated in this study. We sequenced the seven exons of DRD3. After sequencing we localized five dbSNPs and four new rare variants. None of the dSNPs or rare variants seems to be functional after bioinformatics analysis. Our results suggest that, rather than exonic regions, regulatory regions and introns could be related to the associations reported for DRD3 and the incidence of locomotor side-effects.
Keywords: Risperidone; Extrapyramidal side-effects; Schizophrenia; DRD3; Single nucleotide polymorphism; Rare variant; Resequencing; Pharmacogenetics;

Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia by Jan-Willem Muntjewerff; Roel A. Ophoff; Jacobine E. Buizer-Voskamp; Eric Strengman; Martin den Heijer (300-305).
Season of birth – in particular winter birth – has been persistently related to increased schizophrenia risk. Variation in folate intake is among the explanations for this seasonal effect. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate mediated methylation transfer reactions. Interestingly, the MTHFR gene has been related to schizophrenia risk in various studies. We investigated a possible interaction between MTHFR 677 C>T polymorphism and winter birth in the development of schizophrenia in a group of 742 schizophrenia patients and 884 control subjects. All subjects were of Dutch ancestry. Winter birth (December up to and including February) was associated with a 20% increase in schizophrenia risk (odds ratio (OR) of 1.20 and 95% confidence interval (CI), 0.96–1.5; P  = 0.113). The MTHFR 677TT genotype was associated with an overall schizophrenia risk of 1.13 (95% CI, 0.82–1.57; P  = 0.454) compared with the MTHFR 677CC genotype. In the winter period the MTHFR 677TT genotype associated schizophrenia risk was 0.90 (95% CI, 0.47–1.70; P  = 0.744). In conclusion, neither winter birth nor MTHFR genotype were significantly associated with increased schizophrenia risk. There was no evidence for interaction between MTHFR 677TT genotype and winter birth in the development of schizophrenia.
Keywords: Schizophrenia;; MTHFR;; Seasonality;; Folate;; Neurodevelopmental disorders;

Involvement of dorsal raphe nucleus and dorsal periaqueductal gray 5-HT receptors in the modulation of mouse defensive behaviors by Roger L.H. Pobbe; Helio Zangrossi; D. Caroline Blanchard; Robert J. Blanchard (306-315).
Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqueductal gray (dPAG) serotonergic receptors in the mediation of defensive responses that are associated with specific subtypes of anxiety disorders. These studies have mostly been conducted with rats tested in the elevated T-maze, an experimental model of anxiety that was developed to allow the measurement, in the same animal, of two behaviors mentioned: inhibitory avoidance and one-way escape. Such behavioral responses have been respectively related to generalized anxiety disorder (GAD) and panic disorder (PD). In order to assess the generality of these findings, in the current study we investigated the effects of the injection of 5-HT-related drugs into the DRN and dPAG of another rodent species, mouse, on the mouse defense test battery (MDTB), a test of a range of defensive behaviors to an unconditioned threat, a predator. Male CD-1 mice were tested in the MDTB after intra-DRN administration of the 5-HT1A receptor antagonist WAY-100635 or after intra-dPAG injection of two serotonergic agonists, the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT2A/2C receptor agonist DOI. Intra-DRN injection of WAY-100635 did not change behavioral responses of mice confronted with a rat in the MDTB. In the dPAG, both 8-OH-DPAT and DOI consistently impaired mouse escape behavior assessed in the MDTB. Intra-dPAG infusion of 8-OH-DPAT also decreased measures of mouse risk assessment in the rat exposure test. In conclusion, the current findings are in partial agreement with previous results obtained with rats tested in the elevated T-maze. Although there is a high level of similarity between the behavioral effects obtained in rats (elevated T-maze) and mice (MDTB and RET) with the infusion of 5-HT agonists into the dPAG, the same is not true regarding the effects of blockade of DRN 5-HT1A receptors in these rodent species. These data suggest that there may be differences between mice and rats regarding the involvement of the DRN in the mediation of defensive behaviors.
Keywords: Serotonin; Anxiety; Dorsal raphe nucleus; Dorsal periaqueductal gray; Mouse defense test battery;

GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus by Andreas Papadopoulos; Yalini Chandramohan; Andrew Collins; Susanne K. Droste; David J. Nutt; Johannes M.H.M. Reul (316-324).
The activity of dentate gyrus granule neurons is under a strong GABAergic tonic inhibitory control which contributes to the sparse activation pattern of these neurons after environmental stimuli. Previously, we reported that in sparse dentate gyrus neurons such stimuli evoke Ser-10 (S10) phosphorylation and Lys-14 (K14) acetylation in the nucleosomal protein histone H3 (H3S10p-K14ac) resulting in the induction of c-Fos. We hypothesized that GABA is an important modulator of novelty stress-evoked epigenomic mechanisms in rat dentate neurons. As reported previously, exposure to novelty (30 min in new cage) evoked a significant increase in H3S10p-K14ac-and c-Fos-positive neuron numbers in the dentate gyrus. Pre-treatment of rats with the benzo Lorazepam, an indirect GABA-A receptor agonist, had no effects on baseline levels of H3S10p-K14ac and c-Fos but dose-dependently inhibited the novelty-induced epigenomic effects. At the applied doses (0.1–0.3 mg/kg), Lorazepam's effects on behavior were mainly anxiolytic-like. To examine the effects of attenuated GABAergic inhibition on dentate granule neurons we applied the partial inverse GABA-A agonist FG-7142. This drug profoundly enhanced baseline levels as well as novelty-induced increases in the number of H3S10p-K14ac- and c-Fos-positive dentate neurons. Furthermore, FG-7142 evoked behavior in the novel cage congruous with increased anxiety and hyper-vigilance. Interestingly, the FG-7142-evoked enhancements in epigenomic changes were completely blocked by the NMDA receptor antagonist MK-801. We conclude that GABA tonically controls epigenomic responses to psychologically salient events in dentate gyrus granule neurons. Furthermore, GABA appears to exert its controller activity through modulation of NMDA receptor function. These findings may be of significance for the elucidation of anxiety disorders especially PTSD.
Keywords: Chromatin; GABA; NMDA; Glucocorticoid; c-Fos; Histone; Stress; Anxiety; Memory;

Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam by Gian Marco Leggio; Vincenzo Micale; Bernard Le Foll; Carmen Mazzola; José N. Nobrega; Filippo Drago (325-332).
Dopamine D3 receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D3 −/−) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D3 −/− mice treated with diazepam (0.1 or 0.5 mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D3 −/− mice, but not in WT, 1 mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10 mg/kg) in combination with diazepam, in WT animals. D3 −/− mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [3H]flunitrazepam autoradiographic analysis revealed no significant changes in D3 −/− mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABAA changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D3 −/− mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects.
Keywords: Dopamine D3 dopamine receptor; Knock-out mice; Diazepam; Elevated plus maze test; Novelty-induced grooming sampling test; GABAA receptor binding;

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia by Samantha L. McLean; Ben Grayson; Nagi F. Idris; Anne S. Lesage; Darrel J. Pemberton; Claire Mackie; Jo C. Neill (333-343).
Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance.Sub-chronic PCP produced significant deficits in both cognitive tasks (P < 0.01–0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.001), and in novel object recognition at 10 mg/kg on day 1 (P < 0.01) and on day 15 (P < 0.001).These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.
Keywords: Reversal learning; Novel object recognition; α7 nACh receptor; Phencyclidine; Female rat; Cognition; Schizophrenia;

Mapping of CBV changes in 5-HT1A terminal fields by functional MRI in the mouse brain by Thomas Mueggler; Florence Razoux; Holger Russig; Anna Buehler; Tamara B. Franklin; Christof Baltes; Isabelle M. Mansuy; Markus Rudin (344-353).
Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT1A receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT1A receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT1A receptor antagonist WAY-100635, or in 5-HT1A knock-out mice, suggests that 5-HT1A receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT1A receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT1A receptor or the serotonergic system, including depression and anxiety.
Keywords: Functional MRI; 5-HT1A receptor; 8-OH-DPAT; WAY-100635; 5-HT1A receptor knockout mice;