European Neuropsychopharmacology (v.27, #2)

Contents (OBC).

Hippocampal–prefrontal connectivity as a translational phenotype for schizophrenia by Florian Bähner; Andreas Meyer-Lindenberg (93-106).
Finding novel biological targets in psychiatry has been difficult, partly because current diagnostic categories are not defined by pathophysiology and difficult to model in animals. The study of species-conserved systems-level mechanisms implicated in psychiatric disease could be a promising strategy to address some of these difficulties. Altered hippocampal–prefrontal (HC-PFC) connectivity during working memory (WM) processing is a candidate for such a translational phenotype as it has been repeatedly associated with impaired cognition in schizophrenia patients and animal models for psychiatric risk factors. Specifically, persistent hippocampus-dorsolateral prefrontal cortex (HC-DLPFC) coupling during WM is an intermediate phenotype for schizophrenia that has been observed in patients, healthy relatives and carriers of two different risk polymorphisms identified in genome-wide association studies. Rodent studies report reduced coherence between HC and PFC during anesthesia, sleep and task performance in both genetic, environmental and neurodevelopmental models for schizophrenia. We discuss several challenges for translation including differences in anatomy, recording modalities and WM paradigms and suggest that a better understanding of HC-PFC coupling across species can be achieved if translational neuroimaging is used to control for task differences. The evidence for potential neurobiological substrates underlying HC-PFC dysconnectivity is evaluated and research strategies are proposed that aim to bridge the gap between findings from large-scale association studies and disease mechanisms.
Keywords: Hippocampus; Prefrontal cortex; Functional neuroimaging; Schizophrenia; Short-term memory;

Despite new insights into the pathophysiology of schizophrenia and clinical trials with highly selective drugs, no new therapeutic breakthroughs have been identified. We present a semi-mechanistic Quantitative Systems Pharmacology (QSP) computer model of a biophysically realistic cortical-striatal-thalamo-cortical loop. The model incorporates the direct, indirect and hyperdirect pathway of the basal ganglia and CNS drug targets that modulate neuronal firing, based on preclinical data about their localization and coupling to voltage-gated ion channels. Schizophrenia pathology is introduced using quantitative human imaging data on striatal hyperdopaminergic activity and cortical dysfunction. We identified an entropy measure of neuronal firing in the thalamus, related to the bandwidth of information processing that correlates well with reported historical clinical changes on PANSS Total with antipsychotics after introduction of their pharmacology (42 drug-dose combinations, r 2=0.62). This entropy measure is further validated by predicting the clinical outcome of 28 other novel stand-alone interventions, 14 of them with non-dopamine D2R pharmacology, in addition to 8 augmentation trials (correlation between actual and predicted clinical scores r 2=0.61). The platform predicts that most combinations of antipsychotics have a lower efficacy over what can be achieved by either one; negative pharmacodynamical interactions are prominent for aripiprazole added to risperidone, haloperidol, quetiapine and paliperidone. The model also recapitulates the increased probability for psychotic breakdown in a supersensitive environment and the effect of ketamine in healthy volunteers.This QSP platform, combined with similar readouts for motor symptoms, negative symptoms and cognitive impairment has the potential to improve our understanding of drug effects in schizophrenia patients.
Keywords: Schizophrenia; Systems pharmacology; Drug treatment; PANSS Total; Combination therapy; Information bandwidth;

Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: New insight into the benefits of antidepressant drug treatment by Katarzyna Głombik; Joanna Ślusarczyk; Ewa Trojan; Katarzyna Chamera; Bogusława Budziszewska; Władysław Lasoń; Agnieszka Basta-Kaim (120-131).
A growing body of evidence supports the involvement of disturbances in the brain insulin pathway in the pathogenesis of depression. On the other hand, data concerning the impact of antidepressant drug therapy on brain insulin signaling remain scare and insufficient. We determinated the influence of chronic treatment with antidepressant drugs (imipramine, fluoxetine and tianeptine) on the insulin signaling pathway of the brain of adult prenatally stressed rats. 3-month-old prenatally stressed and control rats were treated for 21 days with imipramine, fluoxetine or tianeptine (10 mg/kg/day i.p.).The impact of chronic antidepressant administration was examined in forced swim test. In the frontal cortex and hippocampus, the mRNA and protein expression of insulin, insulin receptor, insulin receptor substrates (IRS-1,IRS-2) and adaptor proteins (Shc1, Grb2) before and after drugs administration were measured.Rats exposed prenatally to stressful stimuli displayed depressive-like disturbances, which were attenuated by antidepressant drug administration. We did not reveal the impact of prenatal stress or antidepressant treatment on insulin and the insulin receptor expression in the examined structures. We revealed that diminished insulin receptor phosphorylation evoked by the prenatal stress procedure was attenuated by drugs treatment. We demonstrated that the favorable effect of antidepressans on insulin receptor phosphorylation in the frontal cortex was mainly related with the normalization of serine312 and tyrosine IRS-1 phosphorylation, while in the hippocampus, it was related with the adaptor proteins Shc1/Grb2. It can be suggested that the behavioral effectiveness of antidepressant drug therapy may be related with the beneficial impact of antidepressant on insulin receptor phosphorylation pathways.
Keywords: Insulin; Insulin receptor; Prenatal stress; Antidepressant drugs; Brain;

The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive.
Keywords: Behaviour; Cannabidiol; THC; Mesolimbic pathway; Epigenetic; Neuroadaption;

Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains by Cristóbal Río-Álamos; Ignasi Oliveras; Maria Antonietta Piludu; Cristina Gerbolés; Toni Cañete; Gloria Blázquez; Silvia Lope-Piedrafita; Esther Martínez-Membrives; Rafael Torrubia; Adolf Tobeña; Alberto Fernández-Teruel (146-158).
The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes.
Keywords: Anxiety; Sensorimotor gating; Hippocampus volume; Amygdala volume; Roman high- and low-avoidance rats; Neonatal handling;

Anything goes? Regulation of the neural processes underlying response inhibition in TBI patients by Laura Moreno-López; Anne E. Manktelow; Barbara J. Sahakian; David K. Menon; Emmanuel A. Stamatakis (159-169).
Despite evidence for beneficial use of methylphenidate in response inhibition, no studies so far have investigated the effects of this drug in the neurobiology of inhibitory control in traumatic brain injury (TBI), even though impulsive behaviours are frequently reported in this patient group. We investigated the neural basis of response inhibition in a group of TBI patients using functional magnetic resonance imaging and a stop-signal paradigm. In a randomised double-blinded crossover study, the patients received either a single 30 mg dose of methylphenidate or placebo and performed the stop-signal task. Activation in the right inferior frontal gyrus (RIFG), an area associated with response inhibition, was significantly lower in patients compared to healthy controls. Poor response inhibition in this group was associated with greater connectivity between the RIFG and a set of regions considered to be part of the default mode network (DMN), a finding that suggests the interplay between DMN and frontal executive networks maybe compromised. A single dose of methylphenidate rendered activity and connectivity profiles of the patients RIFG near normal. The results of this study indicate that the neural circuitry involved in response inhibition in TBI patients may be partially restored with methylphenidate. Given the known mechanisms of action of methylphenidate, the effect we observed may be due to increased dopamine and noradrenaline levels.
Keywords: Traumatic brain injury; Response inhibition; Functional connectivity; Methylphenidate;

Prenatal maternal infection represents a risk factor for the development of psychopathologic conditions later in life. Clinical evidence is also supported by animal models in which the vulnerability to develop a schizophrenic-like phenotype likely originates from inflammatory processes as early as in the womb. Prenatal immune challenge, for example, induces a variety of long-term behavioral alterations in mice, such as deficits in recognition and spatial working memory, perseverative behaviors and social impairments, which are relevant to different symptom clusters of schizophrenia.Here, we investigated the modulation of GABAergic markers in the dorsal and ventral hippocampus of adult mice exposed to late prenatal immune challenge with the viral mimetic Poly(I:C) (polyriboinosinic-polyribocytidilic-acid) at gestational day 17, and we evaluated the ability of chronic treatment with the multi-receptor antipsychotic lurasidone to modulate the alterations produced by maternal infection. Poly(I:C) mice show a significant reduction of key GABAergic markers, such as GAD67 and parvalbumin, specifically in the dorsal hippocampus, which were normalized by chronic lurasidone administration. Moreover, chronic drug administration increases the expression of the pool of brain derived neurotrophic factor (BDNF) transcripts with the long 3’-UTR as well as the levels of mature BDNF protein in the synaptosomal compartment, selectively in dorsal hippocampus.All in all, our findings demonstrate that lurasidone is effective in ameliorating molecular abnormalities observed in Poly(I:C) mice, providing further support to the neuroplastic properties of this multi-receptor antipsychotic drug.
Keywords: Poly(I:C); Infection; GABA; Hippocampus; Lurasidone; BDNF;

The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia by Roger Prades; Eva Munarriz-Cuezva; Leyre Urigüen; Itziar Gil-Pisa; Lídia Gómez; Laura Mendieta; Soledad Royo; Ernest Giralt; Teresa Tarragó; J. Javier Meana (180-191).
Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5 mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.
Keywords: Schizophrenia; Prolyl oligopeptidase; Cognition; Peptidomimetic; Animal model;

Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers by Jessica A. Waller; Joseph A. Tamm; Aicha Abdourahman; Alan L. Pehrson; Yan Li; Manuel Cajina; Connie Sánchez (192-203).
The multimodal antidepressant vortioxetine displays an antidepressant profile distinct from those of conventional selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and possesses cognitive-enhancing properties in preclinical and clinical studies. Recent studies have begun to investigate molecular mechanisms that may differentiate vortioxetine from other antidepressants. Acute studies in adult rats and chronic studies in a middle-aged mouse model reveal upregulation of several markers that play a central role in synaptic plasticity. However, the effect of chronic vortioxetine treatment on expression of neuroplasticity and neurodevelopmental biomarkers in naïve rats has not been evaluated. In the present study, we demonstrate that vortioxetine at a range of doses regulates expression of genes associated with plasticity in the frontal cortex, hippocampus, region encompassing the amygdala, as well as in blood, and displays similar effects relative to the SSRI fluoxetine in adult naïve rats. These genes encode immediate early genes (IEGs), translational regulators, and the neurodevelopmental marker Sema4g. Similar findings detected in brain regions and in blood provide a potential translational impact, and vortioxetine appears to consistently regulate signaling in these networks of neuroplasticity and developmental markers.
Keywords: Multimodal; Neuroplasticity; Neurodevelopment; Immediate early gene; Transcription regulation;