Exacerbation of the credit assignment problem in rats with lesions of the medial prefrontal cortex is revealed by Bayesian analysis of behavior in the pre-solution period of learning.

Our internal models of the world help us to process information rapidly: in general model-based learning is more rapid than model-free learning. However, the cognitive flexibility required to overcome cognitive predispositions can let us down: it is not fully developed until adulthood; predispositions can be unconscious biases; and cognitive flexibility is impaired in many psychiatric and neurological conditions. To understand these limits to flexibility, we need to know how the brain generates predispositions and deploys flexibility. We performed a detailed analysis of the exploratory behavior of rats in the pre-solution period of a two-alternative forced choice discrimination learning task. Rats readily learn in which of two bowls, filled with differentially scented and textured digging materials, there is hidden bait. In a single session, they are presented with a series of discrimination learning and reversal stages. We performed a simple Bayesian analysis on the data from 68 rats, 33 of which had lesions of the medial prefrontal cortex, to examine patterns of responding in the pre-solution period. Control rats rapidly focussed on the relevant stimulus attributes and showed flexibility when required to learn about a different stimulus attribute. Rats with prefrontal cortex damage had reduced sensitivity to negative feedback. They were able to overcome this deficit and solve the credit assignment problem when there were limited alternatives or when attention was appropriately focused and predispositions matched the required response. However, the learning impairment presents as a problem with shifting attention due to the additional difficulty of solving the credit assignment problem when the attentional set is inconsistent with the required response.

More rapid reversal learning following overtraining in the rat is evidence that behavioural and cognitive flexibility are dissociable.

Cognitive flexibility is a term used to describe the brain processes underlying the phenomenon of adaptive change in behaviour in response to changed contingencies in the internal or external environment. Cognitive flexibility is often assessed in complex tasks measuring perceptual attentional shifting or response or task switching, but, arguably, reversal learning is a simple assay of cognitive flexibility. Reversal learning requires the detection of a changed outcome, the cessation of a previously-rewarded response and the selection of an alternative, previously-unrewarded, response. This study addressed the issue of the relationship between reversal learning and cognitive flexibility. In a single testing session, rats completed a series of 2-alternative forced-choice discriminations between digging bowls. The bowls differed according to both the medium within the bowl and the odor of the bowl. Having learned which cue (one of the odors or one of the digging media) indicated the food-baited bowl, half the rats were given additional trials of "over-training". To test reversal learning, the meaning of the cues predictive of reward/non-reward was then switched. There was a robust effect of over-training, with over-trained rats performing reversal learning in fewer trials than rats trained to criterion only. The pattern of errors supported the hypothesis that more rapid reversing results from the formation of an attentional set. This is the same attentional mechanism that results in less rapid shifting or switching. We conclude that the behavioural flexibility demonstrated in reversal learning does not provide a scale on which cognitive flexibility can be measured.

Food or friends? What motivates zebrafish (Danio rerio) performing a visual discrimination.

As a model organism, zebrafish have much to offer neuroscientific research and they are increasingly being used in behavioral neuroscience, for example to study the genetics of learning and memory. As fish are often considered "less clever" than mammals, it is important to understand how they learn and to establish optimal testing conditions. In this study, we compared the efficacy of food reinforcement and social stimuli in supporting Pavlovian conditioning, Pavlovian-to-instrumental transfer, and acquisition of a two-alternative forced choice visual discrimination. Although equally effective in conditioning and in motivating discrimination learning, fish responded with shorter latencies when they were anticipating food but responded for a greater number of trials when anticipating the social stimulus. After learning, the reward was changed: food-reinforcement was replaced with the social stimulus and vice versa. Performance accuracy did not change, but response latency did: the group previously rewarded with food, but now rewarded with the social stimulus, showed a decrease in response vigor. This is a negative contrast effect, which is well established in rats, but was thought to be absent in fish because they lacked goal representation. Our results show that zebrafish, like rats, do have goal representations. Furthermore, we have shown that whereas food has greater incentive salience than social stimuli, fish become satiated rapidly, but motivation to seek social stimuli is sustained. We conclude that zebrafish are well motivated by a mixed economy of social stimuli and food.

Oral dosing of rodents using a palatable tablet.

RATIONALE: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents. OBJECTIVES: To demonstrate a novel administrative technique-palatable gelatine tablets-as a stress-free route of oral delivery. METHODS: Twenty-four male Lister hooded rats were sacrificed for brain tissue analysis at varying time-points after jelly administration of 30 mg/kg of the wake-promoting drug modafinil. A second group of 22 female rats were tested on locomotor activity after 30 mg/kg modafinil, or after vehicle jellies, with the locomotor data compared to the brain tissue concentrations at the corresponding times. RESULTS: Modafinil was present in the brain tissue at all time-points, reducing in concentration over time. The pattern of brain tissue modafinil concentration is comparable to previously reported results following oral gavage. Modafinil-treated rats were more active than control rats, with greater activity during the later time-periods-similar to that previously reported following intraperitoneal injection of 40 mg/kg modafinil. CONCLUSIONS: Palatable jelly tablets are an effective route of administration of thermally stable orally bioavailable compounds, eliminating the stress/discomfort and health risk of oral gavage and presenting as an alternative to previously reported palatable routes of administration where high protein and fat levels may adversely affect appetite for food reward, and uptake rate in the gastrointestinal tract.

Assessment of intradimensional/extradimensional attentional set-shifting in rats.

The rat intradimensional/extradimensional (ID/ED) task, first described by Birrell and Brown 18 years ago, has become the predominant means by which attentional set-shifting is investigated in rodents: the use of rats in the task has been described in over 135 publications by researchers from nearly 90 universities and pharmaceutical companies. There is variation in the protocols used by different groups, including differences in apparatus, stimuli (both stimulus dimensions and exemplars within), and also the methodology. Nevertheless, most of these variations seem to be of little consequence: there is remarkable similarity in the profile of published data, with consistency of learning rates and in the size and reliability of the set-shifting and reversal 'costs'. However, we suspect that there may be inconsistent data that is unpublished or perhaps 'failed experiments' that may have been caused by unintended deviations from effective protocols. The purpose of this review is to describe our approach and the rationale behind certain aspects of the protocol, including common pitfalls that are encountered when establishing an effective local protocol.

Understanding the relationship between suicidality, current depressed mood, personality, and cognitive factors.

OBJECTIVES: Links between suicidality and depressed mood are well established. There is, however, little information about the emotional regulation processes that underlie the relationship between suicidality and current low mood, and how these processes differ between groups of never-suicidal (NS), suicidal ideators, and suicide attempters. As suicidality and depression are heterogeneous constructs, this study aimed to conduct within- and between-group comparisons of known suicide risk factors that are associated with emotion regulation (neuroticism, trait aggression, brooding, impulsivity, and overgeneral autobiographical memories). DESIGN: Correlational design using between- and within-group comparisons from self-report measures. METHODS: Inter- and intragroup differences were identified using Pearson's correlation coefficients and tests of difference. An analysis of indirect effects was used to investigate whether the relationship between suicidality and current low mood was mediated by neuroticism, trait aggression, brooding, impulsivity, and overgeneral autobiographical memories, and if this relationship varied according to group type. RESULTS: Brooding appeared to be a consistent feature of all three groups and was closely related to current low mood. Compared to the NS group, the relationship between suicide attempts and current low mood showed greater associations with brooding, trait aggression, and overgeneral autobiographical memories. Compared to the NS group, the suicidal ideation group showed stronger associations with neuroticism and impulsivity, but these factors did not correlate with low mood. CONCLUSION: These results suggest a need for larger studies to focus on heterogeneity within suicidal populations and consider how different combinations of risk factors may heighten or reduce suicide risk. PRACTITIONER POINTS: It is well known that the severity and intensity of suicide and depressed presentations vary because of underlying dispositional and contextual factors (Fried & Nesse, ) which, in turn, affect how events are interpreted and responded to. Despite this, there is little research about how these mechanisms operate in different types of suicide groups, and their influence on the relationship between suicidality and current low mood. Understanding interrelationships that affect current low mood is of clinical significance because past suicidal history and deteriorations in already negative mood are linked to repeated suicide attempts and completion. Our findings show that ruminative brooding, defined as a tendency to repeatedly think about emotional aspects of an event, consistently correlates with current low mood across different types of suicidal groups (NS, suicidal ideators, and suicide attempters), and across analyses. Findings also show that suicidal ideation and attempt groups were associated with specific personality characteristics that increased the propensity of emotional responding and interpretation compared to the NS group. The relationship between suicide attempt and current low mood had a higher propensity to be influenced by trait aggression, brooding, and overgenerality compared to the NS group. In contrast, although the suicidal ideation group correlated more strongly with neuroticism and impulsivity, these factors did not influence current low mood. In terms of clinical practice, these findings imply that specific styles of interpretation and thinking may maintain the relationship between suicidality and current low mood. Given the cross-sectional nature of the study, however, it is not possible to imply causality. Nevertheless, the findings obtained provide some support for transdiagnostic models of cognitive-behavioural processes that could be developed further.

Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a 'cost' of set-shifting - the ED stage was completed in fewer trials than the ID stage - and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

Attentional Set-Shifting Across Species.

Attentional set-shifting, as a measure of executive flexibility, has been a staple of investigations into human cognition for over six decades. Mediated by the frontal cortex in mammals, the cognitive processes involved in forming, maintaining and shifting an attentional set are vulnerable to dysfunction arising from a number of human neurodegenerative diseases (such as Alzheimer's, Parkinson's and Huntington's diseases) and other neurological disorders (such as schizophrenia, depression, and attention deficit/hyperactivity disorder). Our understanding of these diseases and disorders, and the cognitive impairments induced by them, continues to advance, in tandem with an increasing number of tools at our disposal. In this chapter, we review and compare commonly used attentional set-shifting tasks (the Wisconsin Card Sorting Task and Intradimensional/Extradimensional tasks) and their applicability across species. In addition to humans, attentional set-shifting has been observed in a number of other animals, with a substantial body of literature describing performance in monkeys and rodents. We consider the task designs used to investigate attentional set-shifting in these species and the methods used to model human diseases and disorders, and ultimately the comparisons and differences between species-specific tasks, and between performance across species.

Attentional set-shifting in rodents: a review of behavioural methods and pharmacological results.

Attentional set-shifting tasks have been used as a measure of human fronto-executive function for over 60 years. The major contribution these tasks have made has been the quantification of cognitive deficits associated with human pathologies such as schizophrenia, attention deficit/hyperactivity disorder and dementias related to Parkinson's, Huntington's and Alzheimer's diseases. Thirteen years ago an intradimensional/extradimensional attentional set-shifting task was developed for rats. Since then, there have been over 70 publications detailing the effects of various manipulations on task performance in rats, and 17 publications describing adaptations of the task for mice. Much of this literature has focused on animal models of neuropathology and cognitive deficits associated with schizophrenia and other human conditions. Altogether, these results have elucidated the roles of multiple neurotransmitters in the manifestation of cognitive deficits, and their subsequent amelioration, including dopamine, serotonin, acetylcholine and noradrenaline. However, the fundamental promise of the attentional set-shifting task, to measure cognitive flexibility in humans and rodents in a formally analogous way, has often been under investigated and over simplified. This review explores the research that led to the development of the rat attentional set-shifting task, and how subsequent use of the task has expanded our understanding of the psychological and neurological underpinnings of discrimination and reversal learning, as well as the formation, maintenance and shifting of attentional set.

Stratified medicine for mental disorders.

There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders. While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders.

Tacrine improves reversal learning in older rats.

Age-related decline has been reported in most cognitive domains, including executive function: in particular, attentional set-shifting and reversal learning, as measures of executive control, are impaired in aged populations of both humans and rats. Despite the importance of the cholinergic system in age-related cognitive decline, no data are available on the effects of cholinergic enhancement on age-related performance deficits in tests of attentional set-shifting. We investigated the effects of the cholinesterase inhibitor tetrahydroacridin-9-amine (tacrine) on reversal learning and attentional set-shifting in older rats (aged 16-21 months) using the rodent version of the intradimensional/extradimensional attentional set-shifting task in a repeated-measures design. Discrimination acquisition was not impaired, but age-related impairments in reversal learning were persistent between tests, and ameliorated by the 3 mg/kg dose of tacrine. No age-related impairments in set-shifting were seen, but there was a tendency for tacrine to reduce the cost of shifting set. Given the lack of previous evidence for a role of cortical acetylcholine in attentional set-shifting tasks, it is likely that altered neurotransmitter interactions in striatum underlie this improvement.

Lesions of the dorsomedial striatum impair formation of attentional set in rats.

Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies. Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex. The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting. Rats were tested in two set-shifting tasks following quinolinic acid injections bilaterally into the DMS. When tested in a rodent version of the set-shifting task, rats with a DMS lesion displayed a greater number of errors during the reversal stages of the task than sham lesion controls but the nature of the errors did not differ between the two groups. Interestingly, when the rats were tested in a modified version of the set-shifting task, directly designed for measuring the formation of an attentional set, sham lesion controls displayed a pronounced shift-cost, evident of successful set-formation. In contrast, rats with DMS lesions failed to form an attentional set, showing no performance cost when a shift of attention was required. These results support previous reports of the importance of the DMS in behavioural flexibility but also suggest that this region is vital for the formation of set, possibly by extrapolating different perceptions into a unified representation of a dimension.

Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research.

Executive control is an aspect of cognitive function known to be impaired in schizophrenia. Previous meetings of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group have more precisely defined executive control in terms of two constructs: "rule generation and selection", and "dynamic adjustments of control". Next, human cognitive tasks that may effectively measure performance with regard to these constructs were identified to be developed into practical and reliable measures for use in treatment development. The aim of this round of CNTRICS meetings was to define animal paradigms that have sufficient promise to warrant further investigation for their utility in measuring these constructs. Accordingly, "reversal learning" and the "attentional set-shifting task" were nominated to assess the construct of rule generation and selection, and the "stop signal task" for the construct of dynamic adjustments of control. These tasks are described in more detail here, with a particular focus on their utility for drug discovery efforts. Presently, each assay has strengths and weaknesses with regard to this point and increased emphasis on improving practical aspects of testing, understanding predictive validity, and defining biomarkers of performance represent important objectives in attaining confidence in translational validity here.

Lesions of the orbital prefrontal cortex impair the formation of attentional set in rats.

In rats, reversal learning impairments are commonly reported after lesions of the orbital prefrontal cortex (OFC), in contrast to the effect of lesions of the medial prefrontal cortex, which impair attentional set-shifting. Comparable dissociations have also been reported in humans, monkeys and mice. However, these two manifestations of behavioural flexibility may share common cognitive processes. The present study tested the hypothesis that lesions of the OFC (an area that integrates expected and actual outcomes to signal which cues in the environment predict reward) would impair the formation of attentional set as well as impairing reversal learning. We compared the performance of lesioned and control rats on two set-shifting tasks. The first task we used, 'the 4ID task', had no reversal stages, but multiple intradimensional acquisitions before the extradimensional shift stage, to assess set-formation as well as set-shifting. The second task was the standard intradimensional/extradimensional '7-stage task', which includes reversal learning stages after each compound acquisition. Compared with controls, lesioned rats were slower to form attentional set on the 4ID task. When they did form a set, they required more trials to complete the extradimensional shift stage. On the 7-stage task, we replicated our previous finding of impaired reversal learning and reduced shift-costs. We interpret these findings as reflecting a single deficit in identifying relevant cues after unexpected outcomes, which supports recent models of OFC function. Our findings challenge the assumption that the contribution of the OFC to behavioural flexibility is limited to reversal learning.

Discrimination reversal and attentional sets in zebrafish (Danio rerio).

The potential of zebrafish as a comparative model in behavioural neuroscience is currently hampered only by the lack of reliable and validated behavioural assays available to researchers. In the present experiment, we describe the performance of zebrafish in a test of attentional set formation. The fish were initially trained on a two-choice colour discrimination. Upon reaching acquisition criterion, the reinforced alternative was switched to the previously unreinforced alternative. Again, upon reaching criterion, the cues were replaced with a novel pair of colours (intra-dimensional shift) and reversed again on reaching criteria. We found that zebrafish show a steady decrease in trials-to-criteria over the four phases of the experiment, suggesting that they are forming and maintaining an attentional set, as has previously been demonstrated with mammals. Reversal learning deficits have been implicated in a variety of human psychological disorders (e.g., disorders of impulse control) and as such, we propose that performance of zebrafish in this procedure may represent a useful comparative model to complement existing rodent models.

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia.

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.

Refinement of the use of food and fluid control as motivational tools for macaques used in behavioural neuroscience research: report of a Working Group of the NC3Rs.

This report provides practical guidance on refinement of the use of food and fluid control as motivational tools for macaques used in behavioural neuroscience research. The guidance is based on consideration of the scientific literature and, where data are lacking, expert opinion and professional experience, including that of the members of a Working Group convened by the United Kingdom National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). The report should be useful to researchers, veterinarians and animal care staff responsible for the welfare of macaques used in food and fluid control protocols, as well as those involved with designing, performing and analysing studies that use these protocols. It should also assist regulatory authorities and members of local ethical review processes or institutional animal care and use committees concerned with evaluating such protocols. The report provides a framework for refinement that can be tailored to meet local requirements. It also identifies data gaps and areas for future research and sets out the Working Group's recommendations on contemporary best practice.

Attention to visual, but not tactile, properties of a stimulus results in activation of FOS protein in the visual thalamic reticular nucleus of rats.

Previous reports have suggested that the modality-specific sectors of the thalamic reticular nucleus (TRN) may become selectively activated as a result of attention being drawn to their respective sensory modalities. Here we used a task that required the discrimination of digging bowls on the basis of their visual (the colour of the bowl) or tactile (the external texture of the bowl) characteristics. We trained rats to perform both modality discriminations, ensuring the equity of exposure to both visual and tactile aspects of the stimuli. On the test day, animals had to perform only one of the modality discriminations for a 1-h period prior to being transcardially perfused and their brains removed and processed for Fos immunocytochemistry. We found that animals that performed the visual discrimination prior to sacrifice demonstrated a selective activation of cells in the visual TRN. On the other hand, animals that had performed the tactile discrimination, despite encountering the same stimuli and having received equal visual stimulation as the animals performing the visual discrimination, did not have activation of the visual TRN. This evidence suggests that activation of visual TRN is a function of visual selective attention, and not merely visual stimulation. Surprisingly, the same was not true for somatic TRN, which was not labeled in any animals. It is possible that this lack of a double dissociation is the result of modality-specific differences in the attentional demands of the two discrimination tasks.

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV. Application of bicuculline to wild-type (WT) VB neurones revealed a GABA(A)R-mediated tonic current of 92 +/- 19 pA, which was greatly reduced (13 +/- 5 pA) for VB neurones of delta(0/0) mice. Deletion of the delta- but not the alpha(1)-subunit dramatically reduced the THIP (1 mum)-induced inward current in these neurones (WT, -309 +/- 23 pA; delta(0/0), -18 +/- 3 pA; alpha(1) (0/0), -377 +/- 45 pA). Furthermore, THIP selectively decreased the excitability of WT and alpha(1) (0/0) but not delta(0/0) VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose-dependent manner. The effect of THIP on rotarod performance was blunted for delta(0/0) but not alpha(1) (0/0) mice. We previously reported that deletion of the alpha(1)-subunit abolished synaptic GABA(A) responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic delta-GABA(A)Rs vs. synaptic alpha(1)-subunit-containing GABA(A)Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.

Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions.

RATIONALE: Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat. OBJECTIVES: The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility. METHODS: The effect of subcutaneously administered asenapine (0.75, 7.5, 75 microg/kg) on ID/ED performance of controls or mPFC-lesioned rats was examined using a within-subjects, repeated-measures design. In a second experiment, lesioned and control rats were tested with or without asenapine in a modified version of the task, with multiple set-shifts, before brains were processed for Fos-immunoreactivity in the mPFC. RESULTS: The mPFC lesion-induced deficit in the ID/ED task was stable with repeated testing over more than two months. Asenapine (75 microg/kg s.c., p < 0.05) completely restored the performance of lesioned rats. Experiment 2 replicated both lesion and asenapine effects and demonstrated that it is possible to measure set-shifting multiple times within a test session. Asenapine (75 microg/kg s.c.) was associated with differential activation of the neurons in the anterior mPFC of lesioned animals, but was without effect in controls. CONCLUSION: Asenapine can ameliorate mPFC lesion-induced impairment in attentional set-shifting, and is associated with a greater activation of the spared neurons in the anterior mPFC. These data suggest that asenapine may benefit impaired cognitive flexibility in disorders such as schizophrenia.