Rates of opioid use disorder (OUD) and overdose deaths have increased dramatically in recent years. Currently approved medications for OUD include the opioid agonists methadone and buprenorphine, and the opioid antagonist naltrexone. However, relapse rates are high due to an impaired ability for addicts to control their urge to consume due to strong cravings, and the extreme severity of withdrawal symptoms. Additionally, the nature of the agonists can lead to abuse of those compounds as well. Non-opioid targets, such as glutamate receptors, are potentially ideal for developing intervention strategies with the goal of reducing OUD, relapse, and overdose death. NYX-783 is a small molecule positive allosteric modulator for the glutamate receptor NMDA. It has been shown to modulate learning and memory, both of which are impaired in drug addicts, and known play a role in relapse. Using mice, we have conducted preclinical studies to evaluate the potential for NYX-783 as a therapeutic for OUD with assessment of several outcomes: 1) respiratory depression, 2) consumption during maintenance of regular consumption as well as post-abstinence reinstatement, 3) motivation for consumption, 4) somatic withdrawals, and 5) the development of aversion to withdrawal symptoms. For respiratory depression studies, mice were pretreated 1h prior with NYX-783 and respiratory rates were monitored for 15min after each escalating dose of oxycodone. No effects were seen for any dose of NYX-783. To test for effects on drug consumption, mice were trained to orally self-administer oxycodone and then treated every two days with different doses of NYX-783 or entering an abstinence phase prior to testing with NYX-783. No effect on intake at clinically-relevant doses was observed during regular maintenance or post-abstinence intake. Additionally, we used a progressive ratio to assess the motivation self-administering mice had for reward acquisition, and no effect of NYX-783 was observed on rewards earned. We next evaluated withdrawal using two separate paradigms to test for effects of NYX-783 on, 1) for somatic withdrawal symptoms, 2) aversion to the state of withdrawal. For somatic withdrawal, using higher doses of naloxone (1 mg/kg), NYX-783 did not attenuate jumping behavior. For aversion to withdrawal, three aversion pairings were completed that consisted of oxycodone treatment, followed by NYX-783 preceding a low dose of naloxone (0.1mg/kg ip) immediately before pairing in a specific context. These alternated with neutral (saline) pairings daily. We observed a significant improvement in aversion scores in female mice treated with NYX-783, and a trending significant improvement in males. This suggests a potential therapeutic use for NYX-783 in reducing the negative state of withdrawal that can drive relapse in OUD.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three -choice probabilistic reversal learning task following excitotoxic lesions of the MDmc ( n = 3) or OFC ( n = 3) and compared performance with that of unoperated monkeys ( n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose -stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Initial results of a prostate cancer study investigating whether multiparametric MRI (MP-MRI), involving diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI, can predict or assess tumour response to radiotherapy (RT) and potentially support adaptive radiotherapy for high-risk patients. Adaptive radiotherapy is a treatment technique utilised to minimise radiation related toxicity. For some cancers it is possible to adapt radiotherapy according to physical changes that occur during treatment. This is not appropriate for prostate cancer treatment since observable changes are generally due to rectal movement, however it may be possible to use multiparametric MRI (MP-MRI) to measure treatment response.

Background Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females. Methods Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [ 18 F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female). Results Overall, FE rats displayed greater fear generalization as compared with CON ( p < .001). Further, greater mGlu5 receptor availability at baseline ( p = .003) and post-test ( p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility ( p = .01), and had lower baseline mGlu5 availability ( p = .03) relative to their FE male rat counterparts. Conclusion Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder.

Background:Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females.Methods:Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [18F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female).Results:Overall, FE rats displayed greater fear generalization as compared with CON (p < .001). Further, greater mGlu5 receptor availability at baseline (p = .003) and post-test (p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility (p = .01), and had lower baseline mGlu5 availability (p = .03) relative to their FE male rat counterparts.Conclusion:Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder.

Opioids have been used to manage pain for thousands of years, but they have significant potential for abuse. Prescription opioids, like oxycodone, are associated with 32% of overdoses, that have reached a total of 75,673 deaths in 2021. A major challenge is maximizing their therapeutic potential while minimizing the negative side effects including opioid use disorder (OUD). The Ketogenic Diet (KD) has been reported to reduce pain and decrease the severity of alcohol use disorder, yet its effects on oxycodone responses remain unknown. KD mice displayed increased oxycodone-induced locomotor activity and enhanced antinociceptive effects of oxycodone, suggesting a dietary effect on opiate sensitivity. Male KD mice exposed to chronic oxycodone exhibited increased naloxone-induced jumps, suggesting a sex-specific effect of diet on opioid withdrawal. Consistent with this, male KD mice self-administered less oxycodone while female KD mice did not differ from controls. Finally, no effect of KD on motivation to obtain oxycodone was observed during a progressive ratio schedule. These data suggest sex-biased effects of KD on responses to opioids that should be considered and potentially leveraged in both clinical pain management and treatment of OUD.

Background Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females. Methods Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [ 18 F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female). Results Overall, FE rats displayed greater fear generalization as compared with CON ( p < .001). Further, greater mGlu5 receptor availability at baseline ( p = .003) and post-test ( p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility ( p = .01), and had lower baseline mGlu5 availability ( p = .03) relative to their FE male rat counterparts. Conclusion Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder. Keywords positron emission tomography , metabotropic glutamate receptor 5 , post-traumatic stress disorder , stress-enhanced fear learning , sex-differences

Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research-particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations.

RATIONALE:While neural correlates of hallucinations are known, the mechanisms have remained elusive. Mechanistic insight is more practicable in animal models, in which causal relationships can be established. Recent work developing animal models of hallucination susceptibility has focused on the genesis of perceptual expectations and perceptual decision-making. Both processes are encompassed within mediated learning, which involves inducing a strong perceptual expectation via associative learning, retrieving that memory representation, and deciding whether this internally generated percept is predictive of an external outcome. Mediated learning in rodents is sensitive to many psychotomimetic manipulations. However, we do not know if these manipulations selectively alter learning of perceptual expectations versus their retrieval because of their presence throughout all task phases. OBJECTIVES:Here, we used mediated learning to study the targeted effect of a psychotomimetic agent on the retrieval of perceptual expectation. METHODS:We administered (R,S)-ketamine to rats selectively during the devaluation phase of a mediated learning task, when the representation of the expected cue is retrieved, to test the hypothesis that internally generated perceptual experiences underlie this altered mediated learning. RESULTS:We found that ketamine increased only mediated learning at a moderate dose in rats, but impaired direct learning at the high dose. CONCLUSIONS:These results suggest that ketamine can augment retrieval of perceptual expectations and thus this may be how it induces hallucination-like experiences in humans. More broadly, mediated learning may unite the conditioning, perceptual decision-making, and even reality monitoring accounts of psychosis in a manner that translates across species.

Suboptimal decision-making strategies have been proposed to contribute to the pathophysiology of addiction. Decision-making, however, arises from a collection of computational components that can independently influence behavior. Disruptions in these different components can lead to decision-making deficits that appear similar behaviorally, but differ at the computational, and likely the neurobiological, level. Here, we discuss recent studies that have used computational approaches to investigate the decision-making processes underlying addiction. Studies in animal models have found that value updating following positive, but not negative, outcomes is predictive of drug use, whereas value updating following negative, but not positive, outcomes is disrupted following drug self-administration. We contextualize these findings with studies on the circuit and biological mechanisms of decision-making to develop a framework for revealing the biobehavioral mechanisms of addiction.

Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based instrumental tasks parallel those engaged by pavlovian-based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, that is, sign- and goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within-subject design to assess sign-tracking and goal-tracking behaviors using a pavlovian conditioned approach task and then characterized behavior using an instrumental multistage decision-making (MSDM) task in male rats. We hypothesized that both pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states.SIGNIFICANCE STATEMENT Model-free and model-based computations that guide instrumental decision-making processes may also be recruited in pavlovian-based behavioral procedures. Here, we used a within-subject design to test the hypothesis that both pavlovian and instrumental learning processes were driven by common reinforcement-learning mechanisms. Sign-tracking and goal-tracking behaviors were assessed in rats using a pavlovian conditioned approach task, and then instrumental behavior was characterized using an MSDM task. We report that sign-tracking behavior was associated with greater model-free, but not model-based, learning in the MSDM task. These data suggest that pavlovian and instrumental behaviors may be driven by conserved reinforcement-learning mechanisms.

INTRODUCTION:Implementation of interprofessional education (IPE) is recognised as challenging, and well-designed programs can have differing levels of success depending on implementation quality. The aim of this review was to summarise the evidence for implementation of IPE, and identify challenges and key lessons to guide faculty in IPE implementation. METHODS:Five stage scoping review of methodological characteristics, implementation components, challenges and key lessons in primary studies in IPE. Thematic analysis using a framework of micro (teaching), meso (institutional), and macro (systemic) level education factors was used to synthesise challenges and key lessons. RESULTS:Twenty-seven primary studies were included in this review. Studies were predominantly descriptive in design and implementation components inconsistently reported. IPE was mostly integrated into curricula, optional, involved group learning, and used combinations of interactive and didactic approaches. Micro level implementation factors (socialisation issues, learning context, and faculty development), meso level implementation factors (leadership and resources, administrative processes), and macro level implementation factors (education system, government policies, social and cultural values) were extrapolated. Sustainability was identified as an additional factor in IPE implementation. CONCLUSION:Lack of complete detailed reporting limits evidence of IPE implementation, however, this review highlighted challenges and yielded key lessons to guide faculty in the implementation of IPE.

N-methyl-D-aspartate receptor (NMDAR) modulators have recently received increased attention as potential therapeutics for posttraumatic stress disorder (PTSD). Here, we tested a novel NMDAR-positive modulator, NYX-783, in the following two rodent models of PTSD: an auditory fear-conditioning model and a single-prolonged stress (SPS) model. We examined the ability of NYX-783 to reduce subsequent fear-based behaviors by measuring enhanced fear extinction and reduced spontaneous recovery (spontaneous return of fear) in male mice. NYX-783 administration significantly reduced spontaneous recovery in both PTSD models and enhanced fear extinction in the SPS model. Furthermore, NYX-783 increased the NMDA-induced inward currents of excitatory and inhibitory neurons in the infralimbic medial prefrontal cortex (IL mPFC) and that the GluN2B subunit of NMDARs on pyramidal neurons in the IL mPFC is required for its effect on spontaneous recovery. The downstream expression of brain-derived neurotrophic factor was required for NYX-783 to achieve its behavioral effect. These results elucidate the cellular targets of NYX-783 and the molecular mechanisms underlying the inhibition of spontaneous recovery. These preclinical findings support the hypothesis that NYX-783 may have therapeutic potential for PTSD treatment and may be particularly useful for inhibiting spontaneous recovery.

Objective: Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods to characterize the patterns of symptom clustering and how clusters relate to one another.Methods: We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) subjects from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all subjects, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. Principal component analysis (PCA) was applied to hallucination and delusions items. Results: MDS revealed relationships between items of the SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 negative symptom clusters. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. PCA revealed 5 latent components: 1) passivity delusions, 2) auditory hallucinations, 3) other hallucinations, 4) paranoid/negative affect delusions, and 5) grandiose/religious delusions. Conclusions: While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes apart. This has important implications, not only for treatment and prognosis, but also for experimental medicine. Our data should further inform the search for causal pathophysiological mechanisms.