Hallucinogens evoke sensory, perceptual, affective, and cognitive effects that may be useful to understand the neurobiological basis of mood and psychotic disorders. The present chapter reviews preclinical research carried out in recent years in order to better understand the action of psychotomimetic agents such as the noncompetitive NMDA receptor (NMDA-R) antagonists and serotonergic hallucinogens. Our studies have focused on the mechanisms through which these agents alter cortical activity. Noncompetitive NMDA-R antagonists, such as phencyclidine (PCP) and MK-801 (dizocilpine), as well as the serotonergic hallucinogens DOI and 5-MeO-DMT, produce similar effects on cellular and population activity in prefrontal cortex (PFC); these effects include alterations of pyramidal neuron discharge (with an overall increase in firing), as well as a marked attenuation of the low frequency oscillations (0.2-4 Hz) to which neuronal discharge is coupled in anesthetized rodents. PCP increases c-fos expression in excitatory neurons from various cortical and subcortical areas, particularly the thalamus. This effect of PCP involves the preferential blockade of NMDA-R on GABAergic neurons of the reticular nucleus of the thalamus, which provides feedforward inhibition to the rest of thalamic nuclei. It is still unknown whether serotonergic hallucinogens also affect thalamocortical networks. However, when examined, similar alterations in other cortical areas, such as the primary visual cortex (V1), have been observed, suggesting that these agents affect cortical activity in sensory and associative areas. Interestingly, the disruption of PFC activity induced by PCP, DOI and 5-MeO-DMT is reversed by classical and atypical antipsychotic drugs. This effect suggests a possible link between the mechanisms underlying the disruption of perception by multiple classes of hallucinogenic agents and the therapeutic efficacy of antipsychotic agents.

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals. The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2S,6S;2R,6R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis. We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.

Substance induced psychotic disorders (SIPD) have been historically considered as associated with better clinical and functional outcomes than other psychotic diagnoses. As a result, treatments for those with SIPD are often considerably less intensive, yet this is not based on evidence. The present study aimed to examine whether differences exist between those with SIPD and other first episode psychosis (FEP) diagnoses in regards to demographic and clinical factors, and to determine the symptomatic, clinical and functional outcomes in those with SIPD.This study included all young people aged 15–24 who presented with a FEP to the Early Psychosis Prevention and Intervention Centre between 01/01/2011 and 31/12/2013. Group differences were analysed with independent samples t-tests and chi-square analyses and equivalent non-parametric tests as appropriate. Where applicable, odds ratios were calculated.544 young people presented with a FEP and 10.3% (N = 56) were diagnosed with SIPD. Individuals with SIPD were more likely to be male, unemployed, and have a comorbid substance use disorder. There were no significant differences between groups regarding duration of untreated psychosis, severity of psychotic symptoms, time to remission, or rates of relapse. Those with SIPD were less likely to be employed or engaged in study at discharge and 35.7% of those with SIPD had a change of diagnosis to a schizophrenia spectrum or bipolar disorder after a median of 84 weeks.Young people diagnosed with SIPD should be an important focus of early intervention services and receive comparable treatment to those with other psychotic diagnoses.

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10-17), negative (SMD=−0.29,p = 2.2 × 10-31) and total symptoms (SMD =−0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

Metacognition refers to a range of cognitive processes that allow one to form complex ideas of self and others and to use this information to navigate psychosocial challenges. Several studies in both early-phase and prolonged schizophrenia have demonstrated not only that significant deficits in metacognitive ability are present, but importantly that they are associated with significant functional impairment and decreased quality of life. In spite of the importance of metacognitive impairment in schizophrenia, relatively little is known about the biological substrates that may contribute to this dysfunction. In this study, we examined the relationship between resting state functional connectivity of the medial prefrontal cortex (mPFC), a structure shown in prior voxel-based morphometry studies to be associated with metacognition, with metacognitive function in an early-phase psychosis cohort (n=18). Analyses revealed a positive association of resting state functional connectivity between the mPFC and precuneus and posterior cingulate structures and metacognitive ability. These results provide evidence of disrupted resting state connectivity in structures relevant to metacognitive dysfunction in early-phase psychosis, which may have implications for pathophysiological models of complex cognitive deficits in this illness.

Vision and AHRS (attitude and heading reference system) sensors fusion strategy is prevalent in recent years for the legged robot's SLAM (Simultaneous Localization and Mapping), due to its low cost and effectiveness in the global positioning system. In this paper, a new adaptive estimation algorithm is proposed to achieve the robot SLAM by fusing binocular vision and AHRS sensors. A novel acceleration algorithm for SIFT implementation based on Compute Unified Device Architecture (CUDA) is presented to detect the matching feature points in 2D images. All the steps of SIFT were specifically distributed and implemented by CPU or GPU, according to the step's characteristics to make full use of computational resources. The registration of the 3D feature point cloud is performed by using the iterative closest point (ICP) algorithm. Our GPU-based SIFT implementation can run at the speed of 30 frames per second (fps) on most images with 900 × 750 resolution in the test. Compared to other methods, our algorithm is simple to implement and suitable for parallel processing. It can be easily integrated into mobile robot’s tasks like navigation or object tracking, which need the real-time localization information. Experiments results showed that in the unknown indoor environments, the proposed algorithm`s operation is stable and the positioning accuracy is high.

The kinetochore drives chromosome segregation at cell division. It acts as a physical link between chromosomes and dynamic microtubules, and as a signaling hub detecting and processing microtubule attachments to control anaphase onset. The mammalian kinetochore is a large macromolecular machine that forms a dynamic interface with the many microtubules that it binds. While we know most of the kinetochore’s component parts, how they work together to give rise to its robust functions remains poorly understood. Here we highlight recent findings that shed light on this question, driven by an expanding physical and molecular toolkit. We present emerging principles that underlie the kinetochore’s robust microtubule grip, such as redundancy, specialization, and dynamicity, and present signal processing principles that connect this microtubule grip to robust computation. Throughout, we identify open questions, and define simple engineering concepts that provide insight into kinetochore function.

Vortioxetine Vortioxetine (VOR) is a multimodal antidepressant drug. VOR is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro-cognitive activity in animal models and beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14-day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with p-chlorophenylalanine -pCPA-, used as model of cognitive impairment) were fed with control food or with two doses of VOR-containing food. Four groups were implanted with minipumps delivering vehicle or ESC 10 mg/kg.day s.c. The two VOR doses enable occupation by VOR of SERT+5-HT3-R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 VOR mg/day, respectively. Putative pyramidal neurons (n = 985) were recorded extracellularly in the mPFC of anesthetized rats.Sub-chronic VOR administration (but not ESC) significantly increased neuronal discharge in standard and 5-HT-depleted conditions, with a greater effect of the low VOR dose in standard rats. VOR increased neuronal discharge in infralimbic (IL) and prelimbic (PrL) cortices. Hence, oral VOR doses evoking SERT occupancies similar to those in treated patients increase mPFC neuronal discharge. The effect in 5-HT depleted rats cannot be explained by an antagonist action of VOR at 5-HT3-R and suggests a non canonical interaction of VOR with 5-HT3-R. These effects may underlie the superior pro-cognitive efficacy of VOR compared with SSRIs in animal models. (C) 2016 Elsevier Ltd. All rights reserved.

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP) markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO, <4 Hz) that temporarily group neuronal discharge. These actions are mainly driven by PCP interaction with NMDA-R in GABAergic neurons of the thalamic reticular nucleus and likely underlie PCP psychotomimetic activity. Here we report that classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripripazole) antipsychotic drugs - but not the antidepressant citalopram - countered PCP-evoked fall of LFO in the medial prefrontal cortex (mPFC) of anesthetized rats. PCP reduces LFO by breaking the physiological balance between excitatory and inhibitory transmission. Next, we examined the role of different neurotransmitter receptors to reverse PCP actions. D2-R and D1-R blockade may account for classical antipsychotic action since raclopride and SCH-23390 partially reversed PCP effects. Atypical antipsychotic reversal may additionally involve 5-HT1A-R activation (but not 5-HT2A-R blockade) since 8-OH-DPAT and BAYx3702 (but not M100907) fully countered PCP effects. Blockade of histamine H1-R (pyrilamine) and alpha(1)-adrenoceptors (prazosin) was without effect. However, the enhancement of GABA(A)-R-mediated neurotransmission (using muscimol, diazepam or valproate) and the reduction of excitatory neurotransmission (using the mGluR2/3 agonist LY379268 and the preferential kainite/AMPA antagonist CNQX - but not the preferential AMPA/kainate antagonist NBQX) partially or totally countered PCP effects.Overall, these results shed new light on the neurobiological mechanisms used by antipsychotic drugs to reverse NMDA-R antagonist actions and suggest that agents restoring the physiological excitatory/inhibitory balance altered by PCP may be new targets in antipsychotic drug development. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.

Poster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (Espana)

Poster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (Espana)

The study of individual differences provides an important methodological approach to analyze the neurobehavioral spectrum of a given cohort in order to understand brain function and disease. Based on immobility time in the forced swimming test (FST) juvenile and adult rats were classified as subgroups with low and high immobility. Afterwards, we compared behavior, neurochemical parameters, and gene expression profiles in some brain areas of rats with low and high immobility only. No differences in the open field test (OFT) were observed between subgroups. Regarding neurochemistry, juvenile animals with low immobility showed higher accumbal dopamine turnover and lower hippocampal norepinephrine concentrations, whereas adult rats only differed for accumbal dopamine, although in an opposite direction from that observed in juveniles. Moreover, the expression of accumbal corticotrophin-releasing factor receptor 1 (CRFR1) was significantly different in animals with low and high immobility at both ages, with animals less immobile showing higher levels of CRFR1 mRNA levels. Taken together, our findings suggest that differences in monoaminergic neurotransmission and CRFR1 expression are associated with the coping strategy adopted by the animal and with the tendency to develop depression-related behaviors. Concerning monoaminergic neurotransmission such association is modulated by age, and such modulation could be related to the differential behavioral results observed between juvenile and adult rats.

Peat depositional environments, the sites where and conditions under which peat accumulates, significantly influence a resultant coal's physical properties, chemical composition, and coal utilization behavior. Recognition of peat depositional environments for coal is a challenging endeavor because coal's observed compositional properties not only result from a variety of geological processes operating during peat accumulation, but also reflect the influence of adjoining or external depositional sedimentary environments and alteration during later diagenesis and/or epigenesis. The maceral or microlithotype composition of any one layer of peat can be the product of years or decades of plant growth, death, decay, and post-burial infiltration by roots in addition to the symbiotic, mutualistic, parasitic, and saprophytic relationships with non-plant biota, such as arthropods, fungi, and bacteria. The overprint of increasing thermal maturation and fluid migration through time on the resulting coal can make these relationships difficult to recognize. Therefore, published models based on maceral composition alone must be used with great caution. Lipid compositions, even from lipid-poor low-rank coals, can provide important information about depositional environments and paleoclimate, especially if combined with the results of organic petrography and paleontological studies. Just as sulfur derived from seawater provides environmental clues, the ratios of two particularly relevant trace elements rather than a single trace element can be used to interpret peat depositional environments. Epigenetic minerals, as well as their corresponding chemical compositions should not be used for such a purpose; similarly, resistant terrigenous minerals deposited during peat accumulation in many cases should be used with considerable caution. The interactions of the biota present in the peat-forming ecosystem, often determined using palynological and geochemical proxies, and their interpretation in the context of geography and paleoclimate are important means for deciphering peat depositional environments. Overall, a combination of evidence from geochemistry, mineralogy, palynology, and petrology of coal and from stratigraphy, sedimentology, and sedimentary facies of related rocks is necessary for accurate and comprehensive determination of depositional environments. The need for interdisciplinary studies is underscored by peat compositional properties, which have been greatly affected by various processes during the syngenetic, diagenetic or epigenetic stages of coal formation.

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5‐HT reuptake inhibitors (SSRI) and other 5‐HT‐enhancing drugs is compromised by a negative feedback mechanism involving 5‐HT1A autoreceptor activation by the excess 5‐HT produced by these drugs in the somatodendritic region of 5‐HT neurones. 5‐HT1A receptor antagonists augment antidepressant‐like effects in rodents by preventing this negative feedback, and the mixed β‐adrenoceptor/5‐HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5‐HT1A autoreceptors. However, it is unclear whether 5‐HT1A receptor antagonists not discriminating between pre‐ and post‐synaptic 5‐HT1A receptors would be clinically effective.EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5‐HT1A receptor antagonist DU‐125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double‐blind, randomized, 6 week placebo‐controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430).KEY RESULTS DU‐125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre‐ and post‐synaptic 5‐HT1A receptors in rat and human brain. It antagonized suppression of 5‐hydroxytryptaminergic activity evoked by 8‐OH‐DPAT and SSRIs in vivo. DU‐125530 augmented SSRI‐induced increases in extracellular 5‐HT as effectively as in mice lacking 5‐HT1A receptors, indicating a silent, maximal occupancy of pre‐synaptic 5‐HT1A receptors at the dose used. However, DU‐125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects.CONCLUSIONS AND IMPLICATIONS DU‐125530 is an excellent pre‐ and post‐synaptic 5‐HT1A receptor antagonist. However, blockade of post‐synaptic 5‐ HT1A receptors by DU‐125530 cancels benefits obtained by enhancing pre‐synaptic 5‐hydroxytryptaminergic function.

Background and purpose: F15599, a novel 5‐hydroxytryptamine (5‐HT) 1A receptor agonist with 1000‐fold selectivity for 5‐HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5‐HT 1A heteroreceptors. Experimental approach: In vivo single unit and local field potential recordings and microdialysis in the rat. Key results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg −1 i.v and reduced that of dorsal raphe 5‐hydroxytryptaminergic neurones at doses >10‐fold higher (minimal effective dose 8.2 µg·kg −1 i.v.). Both effects were reversed by the 5‐HT 1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5‐HT 1A receptors) with an ED 50 of 30 µg·kg −1 i.p., whereas it reduced hippocampal 5‐HT release (an effect dependent exclusively on 5‐HT 1A autoreceptor activation) with an ED 50 of 240 µg·kg −1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration‐dependent manner. All neurochemical responses to F15599 were prevented by administration of (±)WAY100635. Conclusions and implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5‐HT 1A receptors in PFC rather than somatodendritic 5‐HT 1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5‐HT 1A receptor agonists, which preferentially activate somatodendritic 5‐HT 1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.