Overshadowing and salience attribution in relation to cannabis use.

Aberrant attentional salience has been implicated in the cannabis-psychosis association. Here, history and frequency of cannabis use were examined against changes in overshadowing (OS), a cue competition paradigm that involves salience processing. Additionally, we examined the association between OS and alternative measures of aberrant salience, as well as schizotypy, in a non-clinical adult sample.

A new era for schizophrenia drug development - Lessons for the future.

For many patients and their treating clinicians, the pharmacological management of psychotic symptoms centres on trying to find a regime that balances efficacy and quality of life-impairing side effects associated with dopamine antagonism. Recent reports of a positive Phase III study from Karuna Therapeutics indicate that the first primarily non-dopamine-based treatment for schizophrenia may come to market soon with the potential for substantially reduced or differentiated side effects. Against a background of repeated failures, Karuna's success promises a desperately needed new treatment option for patients.

Latent inhibition, aberrant salience, and schizotypy traits in cannabis users.

Aberrant salience processing may underlie the link between cannabis and psychosis, as posited in individuals with schizophrenia or high schizotypy. We investigated the relative effects of cannabis use, schizotypy status, and self-reported aberrant salience experiences on salience processing, measured using a latent inhibition (LI) task (Granger et al., 2016), in a non-clinical population.

Cannabis Use, Schizotypy and Kamin Blocking Performance.

Cannabis use has been associated with increased risk for a first episode of psychosis and inappropriate assignment of salience to extraneous stimuli has been proposed as a mechanism underlying this association. Psychosis-prone (especially schizotypal) personality traits are associated with deficits in associative learning tasks that measure salience allocation. The aim of this study was to examine the relationship between history of cannabis use and Kamin blocking (KB), a form of selective associative learning, in a non-clinical sample.

High Schizotypy Predicts Emotion Recognition Independently of Negative Affect.

Deficits in Emotion Recognition (ER) contribute significantly to poorer functional outcomes in people with schizophrenia. However, rather than reflecting a core symptom of schizophrenia, reduced ER has been suggested to reflect increased mood disorder co-morbidity and confounds of patient status such as medication. We investigated whether ER deficits are replicable in psychometrically defined schizotypy, and whether this putative association is mediated by increased negative affect.

Effects of 7.5% Carbon Dioxide and Nicotine Administration on Latent Inhibition.

Stratified medicine approaches have potential to improve the efficacy of drug development for schizophrenia and other psychiatric conditions, as they have for oncology. Latent inhibition is a candidate biomarker as it demonstrates differential sensitivity to key symptoms and neurobiological abnormalities associated with schizophrenia. The aims of this research were to evaluate whether a novel latent inhibition task that is not confounded by alternative learning effects such as learned irrelevance, is sensitive to (1) an in-direct model relevant to psychosis [using 7.

Does cannabis use predict psychometric schizotypy via aberrant salience?

Cannabis can induce acute psychotic symptoms in healthy individuals and exacerbate pre-existing psychotic symptoms in patients with schizophrenia. Inappropriate salience allocation is hypothesised to be central to the association between dopamine dysregulation and psychotic symptoms. This study examined whether cannabis use is associated with self-reported salience dysfunction and schizotypal symptoms in a non-clinical population.

Olfactory threshold selectively predicts positive psychometric schizotypy.

Olfactory impairment might be useful as a non-invasive pre-morbid biological marker of psychosis. People with schizophrenia show consistent impairments, but an association between olfaction and schizotypy in non-clinical populations is inconclusive and has been somewhat controversial. This is important as impairment in patients may be artefacts of antipsychotic medication.

Pharmacology of cognition: a panacea for neuropsychiatric disease?

This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies.

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1.

Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line.

Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice.

Background: In addition to cognitive decline, Alzheimer's Disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and have been referred to as 'sundowning'. They are especially difficult for carers and there are no specific drug treatments.

Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations.

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models.

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models.

Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2)-deficient mice: do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI.

Dopaminergic function in relation to genes associated with risk for schizophrenia: translational mutant mouse models.

Mutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action.

A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors.

Despite their physiological importance, selective interactions between nuclear receptors (NRs) and their cofactors are poorly understood. Here, we describe a novel signature motif (F/YSXXLXXL/Y) in the developmental regulator BCL11A that facilitates its selective interaction with members of the NR2E/F subfamily. Two copies of this motif (named here as RID1 and RID2) permit BCL11A to bind COUP-TFs (NR2F1;NR2F2;NR2F6) and Tailless/TLX (NR2E1), whereas RID1, but not RID2, binds PNR (NR2E3).

Genetic models of schizophrenia and related psychotic disorders: progress and pitfalls across the methodological "minefield".

The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia.

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats.

Rationale: Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia.

Objective: This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model.

Method: Forty-five male Lister hooded rats were housed in groups of 3-4 (n = 16) or singly (n = 29) for 4 weeks immediately after weaning on postnatal day (PND) 22-24.

Kamin blocking is associated with reduced medial-frontal gyrus activation: implications for prediction error abnormality in schizophrenia.

The following study used 3-T functional magnetic resonance imaging (fMRI) to investigate the neural signature of Kamin blocking. Kamin blocking is an associative learning phenomenon seen where prior association of a stimulus (A) with an outcome blocks subsequent learning to an added stimulus (B) when both stimuli are later presented together (AB) with the same outcome. While there are a number of theoretical explanations of Kamin blocking, it is widely considered to exemplify the use of prediction error in learning, where learning occurs in proportion to the difference between expectation and outcome.

Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology.

Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder.

Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges.

Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges.

Phencyclidine withdrawal disrupts episodic-like memory in rats: reversal by donepezil but not clozapine.

Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder.

Mutant mouse models: genotype-phenotype relationships to negative symptoms in schizophrenia.

Negative symptoms encompass diminution in emotional expression and motivation, some of which relate to human attributes that may not be accessible readily in animals. Additionally, their refractoriness to treatment precludes therapeutic validation of putative models. This review considers critically the application of mutant mouse models to the study of the pathobiology of negative symptoms.