European Neuropsychopharmacology (v.17, #9)

Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia by M.P.M. Boks; T. Rietkerk; M.H. van de Beek; I.E. Sommer; T.J. de Koning; R.S. Kahn (567-572).
We review the role of two susceptibility genes; G72 and DAAO in glutamate neurotransmission and the aetiology of schizophrenia. The gene product of G72 is an activator of DAAO (D-amino acid oxidase), which is the only enzyme oxidising D-serine. D-serine is an important co-agonist for the NMDA glutamate receptor and plays a role in neuronal migration and cell death. Studies of D-serine revealed lower serum levels in schizophrenia patients as compared to healthy controls. Furthermore, administration of D-serine as add-on medication reduced the symptoms of schizophrenia. The underlying mechanism of the involvement of G72 and DAAO in schizophrenia is probably based on decreased levels of D-serine and decreased NMDA receptor functioning in patients. The involvement of this gene is therefore indirect support for the glutamate dysfunction hypothesis in schizophrenia.
Keywords: Schizophrenia;; Glutamate;; DAAO;; G72;; D-Serine;

Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder by Lena Brundin; Maria Björkqvist; Åsa Petersén; Lil Träskman-Bendz (573-579).
Orexins are neuropeptides selectively expressed in a small number of neurons in the lateral–posterior hypothalamus. We measured orexin-A in the cerebrospinal fluid (CSF) of 66 patients with major depressive disorder (MDD), dysthymia and adjustment disorder after a suicide attempt. Blood samples confirmed that the patients were free from antidepressive and neuroleptic medication at the time of the lumbar punctures. CSF levels of orexin-A were significantly lower in patients with MDD than in patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF levels of somatostatin, delta sleep inducing peptide-like immunoreactivity (DSIP-LI) and corticotrophin releasing factor (CRF), but not with leptin or vasopressin. Plasma levels of thyroid-stimulating hormone (TSH) were not reduced in MDD patients, and did not correlate with CSF-orexin. Our results suggest that suicidal patients with MDD have distinct neurobiological features, involving compromised levels of hypothalamic peptides regulating the state of arousal.
Keywords: Orexin; Hypocretin; Suicide; Depression; Hypothalamus; CSF;

The purpose of this study was to investigate the effects of the 5-HT1B receptor antagonist NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) on cholinergic, glutamatergic and GABA-ergic neurotransmission in the rat brain in vivo. Extracellular levels of acetylcholine, glutamate and GABA were monitored by microdialysis in the frontal cortex (FC) and ventral hippocampus (VHipp) in separate groups of freely moving rats. NAS-181 (1, 5 or 10 mg/kg, s.c.) caused a dose-dependent increase in ACh levels, reaching the maximal values of 500% (FC) and 230% (VHipp) of controls at 80 min post-injection. On the contrary, NAS-181 injected at doses of 10 or 20 mg/kg s.c. had no effect on basal extracellular levels of Glu and GABA in these areas. The present data suggest that ACh neurotransmission in the FC and VHipp, the brain structures strongly implicated in cognitive function, is under tonic inhibitory control of 5-HT1B heteroreceptors localized at the cholinergic terminals in these areas.
Keywords: Acetylcholine; Frontal cortex; Hippocampus; 5-HT1B receptor; Microdialysis; NAS-181;

How do genes exert their role? Period 3 gene variants and possible influences on mood disorder phenotypes by Paola Artioli; Cristina Lorenzi; Adele Pirovano; Alessandro Serretti; Francesco Benedetti; Marco Catalano; Enrico Smeraldi (587-594).
The action of multiple liability genes is responsible for complex phenotypes at the same time, a single gene, could control several phenotypic features. This is the case of human period 3 gene (hper3), mainly involved in the setting of the biologic clock. Some variants of this gene, besides being associated with the Delayed Sleep Phase Syndrome, showed a key role in determining evening preference rather than morning one. According to this rationale, we hypothesized that this gene could influence circadian mood fluctuations, in mood disorders. Our study demonstrated that rare genetic variants of hper3 are significantly associated to a number of mood disorders features, such as age of onset, response to SSRIs treatment, circadian mood oscillations and characteristics of temperament. These preliminary results could shed further light on the involvement of circadian genes in various aspects of physiological and psychopathological mechanisms of the brain.
Keywords: Period 3 gene; Mood disorders; Antidepressants; Depressive symptomatology; Circadian rhythms; Temperament and Character Inventory;

NO synthase-positive striatal interneurons are decreased in schizophrenia by S. Fritzen; M. Lauer; A. Schmitt; T. Töpner; A. Strobel; K.-P. Lesch; A. Reif (595-599).
The gaseous messenger NO has repeatedly been suggested to play a role in the pathogenesis of psychoses. Following a pilot study, we investigated whether the number of nitrinergic neurons in the putamen of patients suffering from schizophrenia, bipolar disorder or major depression is altered. Post-mortem striatum sections of 15 brains from patients with either disease were examined by NADPH-diaphorase staining, which selectively labels NO synthase-positive interneurons. Quantification of these cells revealed significantly lower numbers of NO synthase-containing neurons in the putamen of schizophrenic patients. Our results suggest that striatal nitrinergic interneurons are involved in the pathophysiology of at least some forms of schizophrenia, such as e.g. catatonic schizophrenia.
Keywords: Schizophrenia;; Major depression;; Bipolar disorder;; Nitric oxide synthase;; Corpus putamen;; Striatum;; Histopathology NADPH diaphorase;

Involvement of IL-1β in acute stress-induced worsening of cerebral ischaemia in rats by Javier R. Caso; María A. Moro; Pedro Lorenzo; Ignacio Lizasoain; Juan C. Leza (600-607).
Stress is known to be one of the risk factors of stroke. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. However, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. We have used an acute stress protocol consisting of the exposure of male Fischer rats to an acute, single exposure immobilisation protocol (6 h) prior to permanent middle cerebral artery occlusion (MCAO), and we have found that stress worsens behavioural and neurological outcomes and increased infarct size after MCAO. The possible regulatory role of the TNFα and IL-1β was studied by looking at the release of these cytokines in brain. The results of the present study showed an increase in IL-1β release in cerebral cortex after exposure to acute stress. Brain levels of IL-1β are also higher in previously stressed MCAO rats than in MCAO animals without stress. Pharmacological blockade of IL-1β with an antibody anti-IL-1β led to a decrease in the infarct size as well as in neurological and behavioural deficits after MCAO. In summary, our results indicate that IL-1β, but not TNFα, accounts at least partly for the worsening of MCAO consequences in brain of rats exposed to acute stress.
Keywords: Stress; Stroke; IL-1β;

Positron emission tomography study of regional brain metabolic responses to a serotonergic challenge in major depressive disorder with and without comorbid lifetime alcohol dependence by Leo Sher; Matthew S. Milak; Ramin V. Parsey; Juan J. Carballo; Thomas B. Cooper; Kevin M. Malone; Maria A. Oquendo; J. John Mann (608-615).
This is the first study contrasting regional glucose metabolic rate (rCMRglu) responses to a serotonergic challenge in major depressive disorder (MDD) with and without comorbid alcohol dependence. In a university hospital, patients with MDD without a history of alcohol dependence (MDD only) and patients with MDD and comorbid alcohol dependence (MDD/ALC) were enrolled in this study. Subjects with comorbid borderline personality disorder were excluded. A bolus injection of approximately 5 mCi of 18fluorodeoxyglucose was administered 3 h after the administration of placebo or fenfluramine. We found an anterior medial prefrontal cortical area where MDD/ALC subjects had more severe hypofrontality than MDD only patients. This area encompassed the left medial frontal and left and right anterior cingulate gyri. This group difference disappeared after fenfluramine administration. The fact that the observed group difference disappeared after the fenfluramine challenge suggests that serotonergic mechanisms play a role in the observed differences between the groups.
Keywords: Depression; Alcohol dependence; Fenfluramine; Serotonin; Positron emission tomography;

This study examined the effects of subsequent, subchronic, treatment with choline uptake enhancer MKC-231 on the behavioral and cellular deficits induced by repeated PCP exposure in rats. Prior subchronic PCP exposure resulted in increased locomotion following an acute PCP or cocaine challenge, but resulted in decreased locomotor activity in response to a carbachol-challenge. MKC-231 significantly antagonized the alterations in the locomotor responses to cocaine and carbachol, but not to PCP. In the novel object recognition test, repeated PCP exposure caused cognitive deficits in rats, and the PCP-induced cognitive deficits were antagonized by MKC-231. In contrast, no effects of PCP exposure were shown in the repeated passive avoidance test. Furthermore, repeated PCP exposure decreased a number of choline acetyltransferase (ChAT)-positive cells in the medial septum and increased dynorphin A expression in the ventral striatum. Moreover, MKC-231 significantly antagonized the changes in septal ChAT-positive cells, but not the changes in ventrostriatal dynorphin A expression. These results suggest that MKC-231 could be a therapeutic drug for the treatment of schizophrenia.
Keywords: Choline; Phencyclidine; Cognition; Dynorphin; Cocaine; Choline acetyltransferase;