Assessing the motivational effects of ethanol in mice using a discrete-trial current-intensity intracranial self-stimulation procedure.

BackgroundAlcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice.MethodsMale and female C57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg; n = 5-7 per dose), using a Latin square design.ResultsA 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds). Ethanol doses from 1 to 1.75 g/kg increased response latencies as compared to saline treatment.ConclusionsThe discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice

Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou

Loss of pleasure (clinically referred to as anhedonia), impairments in other reward-related processes such as reward learning, motivation, and reward valuation, and blunted affect characterize several mood and other psychiatric disorders. Despite the availability of many therapeutic options for these disorders, reward-related impairments remain challenging to treat and often persist despite alleviation of other symptoms. Lack of animal models of reward-related impairments and affect that have high construct and predictive validity is a key obstacle to developing novel treatments. This review highlights 1) guidelines to consider when developing translatable animal models; and 2) recent efforts to develop new reward-related assessments in humans and nonhuman animals that have been translated or back-translated from one species to another. The procedures described in this review are used to assess aspects of reward learning, motivated behavior, reward valuation, and affect. In several cases, researchers have attempted to implement task parameters that are as identical as possible to the parallel parameters used in existing cross-species tasks, with the goal of improving the translation of preclinical drug discovery findings to the clinic. In this regard, Dr. Athina Markou, who worked tirelessly throughout her career to understand and treat reward-related impairments across several psychiatric disorders, had great influence on conceptualizing the development and use of translational animal models of reward-related processes

Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation.

Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials

Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning

Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning

Dysregulation of reward responsiveness during nicotine withdrawal and nicotine re-exposure in rats using a translational task

Abstinence from smoking is associated with depression-like symptoms, including deficits in reward processing, which are hypothesized to play an important role in relapse. Reward responsiveness (i.e., the ability to modulate behavior as a function of reinforcement history) is disrupted in major depressive disorder. We determined whether reward responsiveness was affected during nicotine withdrawal and subsequent nicotine re-exposure in male Wistar rats using a novel behavioral task that was recently developed to be analogous to an objective clinical assessment of reward responsiveness. Withdrawal from chronic nicotine (6.32 mg/kg/day, base; sc; 28 days; n=19), but not saline (n=20), administration diminished reward responsiveness. Two to eight weeks after termination of chronic nicotine, acute nicotine administration (0, 0.125, 0.25, 0.5 mg/kg, base; sc; administered in a Latin-square design) dose-dependently increased reward responsiveness. Conversely, acute nicotine administration in previously salinetreated rats dose-dependently decreased reward responsiveness. These results suggest that chronic nicotine exposure induces a long-lasting dysregulation of the processing of natural rewards. The disruption of reward responsiveness during immediate withdrawal may contribute to the depression-like state associated with withdrawal, while the nicotine-induced enhancement of reward responsiveness after withdrawal may contribute to relapse to tobacco smoking in order to re-instate responsiveness to natural rewards. Thus, treatment of deficits in reward responsiveness in abstinent smokers may facilitate smoking cessation

Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research

Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long–Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg−1, subcutaneous) or the psychostimulant amphetamine (0.5 mg kg−1, intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species

Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning