European Neuropsychopharmacology (v.19, #9)

Contents (IBC).

Farewell message from the Founding Editors by Stuart A. Montgomery; Jan M. van Ree (609).

Welcome message from the new editor by Michael Davidson (610).

We review reports published over the past 5 years on positron emission tomography (PET) of neurotransmission in depressive disorders. The molecular tools of PET neuroimaging are compounds labeled with a positron-emitting nuclide. PET radioligands have been used in recent years to study several aspects of monoaminergic and cholinergic neurotransmission in the brain of depressed subjects and healthy controls. The value of kinetic parameters of certain PET radioligands has often been reported to be lower in depressed subjects than in healthy ones, but there is usually no reliable relationship between the binding potential of the neuroreceptor or transporter and the clinical condition of depressed subject. In addition, many recent PET studies have noted either higher binding potentials in depressed subjects or no difference between binding potentials of depressed and healthy subjects. In our view, recent research has neither proved nor refuted the idea that neuromolecular processes that can be assessed by the radioligands currently available for PET studies of humans are causally related to depressive disorders. The future success of PET research for understanding molecular mechanisms in depressive disorders may therefore require the invention and development of further molecular tools for studying a wider range of neuronal events in the living human brain.
Keywords: Depression; Major depressive disorder; Unipolar depression; Bipolar depression; Positron emission tomography; PET brain imaging; Neuroreceptor; Neurotransmission; Human;

Antipsychotics in children and adolescents: Increasing use, evidence for efficacy and safety concerns by Benedetto Vitiello; Christoph Correll; Barbara van Zwieten-Boot; Alessandro Zuddas; Mara Parellada; Celso Arango (629-635).
Second-generation antipsychotics (SGA) are increasingly used to treat children and adolescents. The European College of Neuro-psychopharmacology convened an expert panel to review relevant efficacy and safety data, and identify needs for further research. Controlled studies support the short-term efficacy of several SGA for treating psychosis, mania, and aggression within certain diagnostic categories. Except for clozapine, no clinically significant superiority in efficacy has been demonstrated for any specific antipsychotic, including both first- and second-generation agents, in children and adolescents. Major differences exist, however, with respect to type and severity of adverse effects; therefore the choice of treatment is primarily guided by tolerability and safety considerations. Children appear to be at higher risk than adults for a number of adverse effects, such as extrapyramidal symptoms and metabolic and endocrine abnormalities. While the safety profile during acute and intermediate treatment has been evaluated, the distal benefit/risk ratio during long-term treatment remains to be determined. Research is also needed to understand the mechanisms underlying antipsychotic-induced toxicities in order to develop effective preventive and treatment strategies.
Keywords: Antipsychotics; Children; Adolescents; Safety; Efficacy;

Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer's type (SDAT) by Tauheed Ishrat; Md Nasrul Hoda; M. Badruzzaman Khan; Seema Yousuf; Muzamil Ahmad; Mohd. Moshahid Khan; Ajmal Ahmad; Fakhrul Islam (636-647).
Recent evidence indicates that curcumin (CUR), the principal curcuminoid of turmeric, exhibits antioxidant potential and protects the brain against various oxidative stressors. The aim of the present study was to examine the modulating impacts of CUR against cognitive deficits and oxidative damage in intracerebroventricular–streptozotocin (ICV–STZ) infused rats. Rats were injected bilaterally with ICV–STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with CUR (80 mg/kg) for three weeks. After two weeks of ICV–STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks and then sacrificed for biochemical and histopathological assays. ICV–STZ rats showed significant cognitive deficits, which were significantly improved by CUR supplementation. CUR supplementation significantly augmented increased 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC) and oxidized glutathione (GSSG); decreased levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) in the hippocampus and cerebral cortex; and increased choline acetyltransferase (ChAT) activity in the hippocampus of ICV–STZ rats. The study suggests that CUR is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimer's type (SDAT).
Keywords: Alzheimer's disease; Curcumin; Streptozotocin; Oxidative stress; Cognitive deficits; Choline acetyltransferase;

Prenatal viral infection of mice at E16 causes changes in gene expression in hippocampi of the offspring by S. Hossein Fatemi; Timothy D. Folsom; Teri J. Reutiman; Hao Huang; Kenichi Oishi; Susumu Mori (648-653).
The hippocampus governs memory formation and emotional regulation, and there is widespread evidence of hippocampal dysfunction in psychiatric disorders, including schizophrenia and autism. There is abundant evidence that prenatal viral infection may play a role in the development of these two disorders. In the current study, we have examined gene expression and structural changes of the hippocampi of exposed neonates following maternal infection at embryonic day (E) 16 (middle second trimester). We observed significant changes in gene expression in the offspring at postnatal day (P) 0 (birth), P14 (childhood), and P56 (adulthood), including a number of candidate genes for autism and schizophrenia. qRT-PCR verified the direction and magnitude of change for 5 of the genes from the microarray data set and revealed mRNA changes for additional genes associated with schizophrenia and autism. MRI revealed a decrease in hippocampal volume at P35 (adolescence). Our results demonstrate altered gene expression and reduced hippocampal volume in the offspring following prenatal viral infection at E16.
Keywords: Schizophrenia; Autism; Viral model; Mouse; DNA microarray; Hippocampus;

Association between corneal temperature and mental status of treatment-resistant schizophrenia inpatients by Roni Shiloh; Lior Schapir; Danit Bar-Ziv; Rafael Stryjer; Shai Konas; Rachel Louis; Haggai Hermesh; Hanan Munitz; Abraham Weizman; Avi Valevski (654-658).
Preliminary point-prevalent data suggest that drug-free schizophrenia patients may exhibit increased body/corneal temperature, that antipsychotic drugs (APDs) may decrease body/core temperature and that patients' mental status might be associated with their body/corneal temperature. Hence, we hypothesized that treatment-resistant psychotic APD-treated schizophrenia patients' mental status may correlate with their corneal temperature during a continuous 6-week period.Corneal temperature of 12 treatment-resistant schizophrenia inpatients and 16 healthy volunteers was evaluated 2–3 times a week during 6 consecutive weeks using a flir thermal imaging camera.A significant and substantial correlation was found between inpatients' mean weekly Positive and Negative Syndrome Scale (PANSS)'s total scores and their mean weekly corneal temperature during the 6-week study period (r  = 0.82; n  = 6 weeks; p  = 0.043). There was no significant difference in mean 6-week corneal temperature between the patient group and the healthy subjects (34.25 ± 0.64 °C vs. 34.39 ± 0.69 °C, respectively; t  = 1.127, df  = 131, p  = 0.26).This study indicates that treatment-resistant overtly psychotic schizophrenia inpatients' mental status (as assessed by the PANSS) correlates with their corneal temperature. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying corneal temperature alterations and the possible role of temperature-modulating drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis merits further large-scale investigation in both medicated- and drug-free schizophrenia patients compared to matched controls.
Keywords: Schizophrenia; Corneal temperature; Antipsychotic drugs; Thermoregulation;

In this study, we investigated behavioral factors underlying conditioned place preference (CPP) induced by social interaction in adolescent rats. We found that the magnitude of socially-induced CPP depended on the social motivation of the animals and on the amount of training. After extinction, socially-induced CPP could be reinstated by a single reconditioning session. Treatment with methylphenidate, which disrupts social play behavior in adolescent rats, but not social exploratory behavior, prevented the development of socially-induced CPP. Interestingly, methylphenidate by itself induced CPP. These data demonstrate that: 1. social interaction is rewarding in adolescent rats; 2. appetitive and mnemonic factors influence the development of socially-induced CPP; 3. comparable to drug-induced CPP, socially-induced CPP can be extinguished and reinstated; 4. social play is likely to be the most rewarding aspect of social interaction in adolescent rats; 5. social context influences the subjective effects of methylphenidate.
Keywords: Social behavior; Adolescence; Place conditioning; Methylphenidate; Reward; Motivation; Reinstatement;

Modulation of the Ca2+ conductance of nicotinic acetylcholine receptors by Lypd6 by Martin Darvas; Marco Morsch; Ildiko Racz; Seifollah Ahmadi; Dieter Swandulla; Andreas Zimmer (670-681).
The agonist binding sensitivity and desensitization kinetics of nicotinic acetylcholine receptors (nAChRs) can be modulated by snake venom neurotoxins and related endogenous small proteins of the uPAR-Ly6 family. Here we identify Lypd6, a distantly related member of the u-PAR/Ly-6 family expressed in neurons as a novel modulator of nAChRs. Lypd6 overexpressed in trigeminal ganglia neurons selectively enhanced the Ca2+-component of nicotine-evoked currents through nAChRs, as evidenced by comparative whole-cell patch clamp recordings and Ca2+-imaging in wildtype and transgenic mice overexpressing Lypd6. In contrast, a knockdown of Lypd6 expression using siRNAs selectively reduced nicotine-evoked Ca2+-currents. Pharmacological experiments revealed that the nAChRs involved in this process are heteromers. Transgenic mice displayed behaviors that were indicative of an enhanced cholinergic tone, such as a higher locomotor arousal, increased prepulse-inhibition and hypoalgesia. These mice overexpressing Lypd6 mice were also more sensitive to the analgesic effects of nicotine. Transgenic mice expressing siRNAs directed against Lypd6 were unable to procreate, thus indicating a vital role for this protein. Taken together, Lypd6 seems to constitute a novel modulator of nAChRs that affects receptor function by selectively increasing Ca2+-influx through this ion channels.
Keywords: Transgenic mice; Allosteric modulator; Ion selectivity; Electrophysiology; Behavior; Receptor channel;