Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats.

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

Behavioral domains in compulsive rats: implications for understanding compulsive spectrum disorders.

Introduction: Compulsive behavior has been proposed as a transdiagnostic trait observed in different neuropsychiatric disorders, such as obsessive-compulsive disorder, autism, and schizophrenia. Research Domain Criteria (RDoC) strategy could help to disentangle the neuropsychological basis of compulsivity for developing new therapeutic and preventive approaches. In preclinical research, the selection of high-drinker (HD) vs. low-drinker (LD) animals by schedule-induced polydipsia (SIP) is considered a putative model of compulsivity, which includes a well-differentiated behavioral pattern. Methods: The purpose of this research was to assess the cognitive control and the negative valence system domains in a phenotype of compulsive HD rats. After the selection of animals as HD or LD, we assessed behavioral inflexibility by probabilistic spatial reversal learning (PSRL), motor and cognitive impulsivity by variable delay-to-signal (VDS), and risky decision-making by rodent gambling task (rGT). Results: HD rats performed fewer reversals and showed less probability of pressing the same lever that was previously reinforced on PSRL, more premature responses after the exposure to longer delays on VDS, and more disadvantageous risky choices on rGT. Moreover, HD animals performed more perseverative responses under the punishment period on rGT. Discussion: These results highlight that HD compulsive phenotype exhibits behavioral inflexibility, insensitivity to positive feedback, waiting impulsivity, risky decision-making, and frustrative non-reward responsiveness. Moreover, these findings demonstrate the importance of mapping different behavioral domains to prevent, treat, and diagnose compulsive spectrum disorders correctly.

Avoidance and inhibitory control are possible transdiagnostic traits? A systematic review in animal models.

In clinical research, aberrant avoidance behavior and inhibitory control deficit have a high comorbidity in different psychopathological disorders. Therefore, avoidance and impulsive and/or compulsive behaviors might be classified as transdiagnostic traits, where the assessment through animal models could address evidence of their contribution as neurobehavioral mechanisms in psychopathology. The objective of the present review has been to assess the avoidance trait and the implication of inhibitory control behaviors, through studies using passive and active avoidance tests in rodents, and a preclinical model using selective breeding of high- or low-avoidance Roman rats (RHA, RLA). A systematic search strategy was carried out in the PubMed and Web of Science databases, where a total of 40 studies were accepted in the qualitative synthesis. The results of the different studies reviewed pointed to a relation between a reduced avoidance profile in passive avoidance (PA) with impulsive decision making and novelty-seeking behaviors; an increased avoidance profile in PA with compulsive drinking; a high active avoidance profile, including RHA rats, with different types of impulsivity and novelty- seeking behaviors; and regarding compulsivity depending on its measure, a low active avoidance profile, including RLA rats, has been associated with increased anxiety in the EPM and increased grooming, while a high active avoidance profile, including RHA rats, has been associated with increased rearing, compulsive drinking including alcohol, and cognitive inflexibility. The results have been discussed in terms of environmental factors and the underlying mechanisms between these possible transdiagnostic traits in psychopathology.

Differential Neurobiological Markers in Phenotype-stratified Rats Modeling High or Low Vulnerability to Compulsive Behavior: A Narrative Review.

Compulsivity is a key manifestation of inhibitory control deficit and a cardinal symptom in different neuropsychopathological disorders such as obsessive-compulsive disorder, schizophrenia, addiction, and attention-deficit hyperactivity disorder. Schedule-induced polydipsia (SIP), is an animal model to study compulsivity. In this procedure, rodents develop excessive and persistent drinking behavior under different food-reinforcement schedules, that are not related to homeostatic or regulatory requirements. However, there are important individual differences that support the role of high-drinker HD rats as a compulsive phenotype, characterized in different paradigms by inhibitory response deficit, cognitive inflexibility, and resistant to extinction behavior; with significant differences in response to pharmacological challenges, and relevant neurobiological alterations in comparison with the control group, the non-compulsive low drinker LD group on SIP. The purpose of this review is to collate and update the main findings on the neurobiological bases of compulsivity using the SIP model. Specifically, we reviewed preclinical studies on SIP, that have assessed the effects of serotonergic, dopaminergic, and glutamatergic drugs; leading to the description of the neurobiological markers, such as the key role of the serotonin 5-HT2A receptor and glutamatergic signaling in a phenotype vulnerable to compulsivity as high drinker HD rats selected by SIP. The review of the main findings of HD rats on SIP helps in the characterization of the preclinical compulsive phenotype, disentangles the underlying neurobiological, and points toward genetic hallmarks concerning the vulnerability to compulsivity.

Negative valence system as a relevant domain in compulsivity: review in a preclinical model of compulsivity.

Compulsive behavior is observed in different neuropsychiatric disorders such as Obsessive-Compulsive Disorder (OCD), anxiety, phobia, schizophrenia and addiction. Compulsivity has been proposed as a transdiagnostic symptom, where the Research Domain Criteria (RDoC) strategy could help to understand its neuropsychological basis for a better understanding, and development of therapeutic and preventive strategies. However, research on compulsivity has been focused on the cognitive control domain, and the contribution of an altered negative valence system has been less considered. In this review, we collate the main findings in an animal model of compulsivity, the high drinker (HD) rats selected by Schedule-Induced Polydipsia (SIP) regarding these two research domains. This preclinical model of compulsivity has shown a phenotype characterized by a lack of behavioral inhibition, impulsive decision-making and cognitive inflexibility. Moreover, the results in compulsive HD rats, suggests that there is also a relevant alteration in the emotional dimension, linked to the negative valence system domain, as for example by: the increased perseverative responses in a withdrawal condition, associated with the behavioral construct of frustrative non-reward; and an inhibition or extinction deficit in memory retrieval associated with an alteration in the behavioral response to sustained threat. However, the precise nature of the link between these shared altered domains, cognitive control and negative valence system, remains unknown. These results point towards relevant behavioral aspects of the compulsive phenotype that should be taken into account when studying the vulnerability to compulsivity that could help in the development of a better transdiagnostic assessment, preventive and therapeutic strategies.

Socioemotional deficit and HPA axis time response in high compulsive rats selected by schedule-induced polydipsia.

Compulsivity is a failure to stop an ongoing behavior that has become inappropriate to the situation and is recognized as a transdiagnostic trait present in different neuropsychiatric disorders. The implication of motivation and emotion, as well as the stress response in compulsive population has not been fully understood. We assessed the motivation to reward and cues, the emotional response in different contexts and the hypothalamic-pituitary-adrenal (HPA) axis response in rats selected by a preclinical model of compulsive behavior. Firstly, high (HD) or low (LD) drinkers were selected according to their drinking behavior on schedule-induced polydipsia (SIP). Then, we assessed motivation by the propensity to attribute incentive salience to rewards on Pavlovian Conditioned Approach (PavCA) and motivation to gain reward on Progressive Ratio Schedule of Reinforcement (PRSR). Emotion was measured by Social Dominance on the Tube Test (SDTT) and emotional memory on Passive Avoidance (PA). Plasma corticosterone (CORT) levels in response to SIP were assessed. HD rats showed a socioemotional deficit by fewer victories on the SDTT, and an increased latency to enter the dark compartment on the PA. No differences were found between groups regarding to motivational assessment. Moreover, HD rats revealed a blunted time response in the increase of CORT levels at 45 min after SIP compared to LD rats. The findings show that the compulsive phenotype of HD rats exhibit less social dominance, more resistance to extinction and a differential CORT time response to SIP. These findings may contribute to highlight the relevance of assessing socioemotional behaviors and stress response for a better characterization of the vulnerability to compulsive spectrum disorders.

The Role of Social Stress in the Development of Inhibitory Control Deficit: A Systematic Review in Preclinical Models.

Inhibitory control deficit and impulsivity and compulsivity behaviours are present in different psychopathological disorders such as addiction, obsessive-compulsive disorders and schizophrenia, among others. Social relationships in humans and animals are governed by social organization rules, which modulate inhibitory control and coping strategies against stress. Social stress is associated with compulsive alcohol and drug use, pointing towards a determining factor in an increased vulnerability to inhibitory control deficit. The goal of the present review is to assess the implication of social stress and dominance on the vulnerability to develop impulsive and/or compulsive spectrum disorders, with the aid of the information provided by animal models. A systematic search strategy was carried out on the PubMed and Web of Science databases, and the most relevant information was structured in the text and tables. A total of 34 studies were recruited in the qualitative synthesis. The results show the role of social stress and dominance in increased drug and alcohol use, aggressive and impulsive behaviour. Moreover, the revised studies support the role of Dopaminergic (DA) activity and the alterations in the dopaminergic D1/D2 receptors as key factors in the development of inhibitory control deficit by social stress.