Anhedonia, the loss of pleasure from previously rewarding activities, is implicated in several neuropsychiatric conditions, including major depressive disorder (MDD). In order to accelerate drug development for mood disorders, quantitative approaches are needed to objectively measure responsiveness to reward as a means to identify deficits. One such approach, the probabilistic reward task (PRT), uses visual discrimination methodology to quantify reward learning. In this computerized task, humans make visual discriminations, and probabilistic contingencies are arranged such that correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy participants consistently develop a response bias in favor of the rich alternative. However, participants with MDD typically exhibit lower response biases, and this blunting correlates with current and future anhedonia. The present studies validated a touchscreen-based PRT in rodents with formal and functional similarity to the human task. First, rats were trained to discriminate between two lines that differed in length. Next, parametric manipulations of probabilistic contingencies, line-length stimuli, and drug treatment (amphetamine, 0.32–3.2 mg/kg; scopolamine, 0.1–1.0 mg/kg; oxycodone, 0.1–1.0 mg/kg) on response bias were evaluated. Results demonstrated orderly shifts in bias and discriminability that varied as a function of, respectively, the asymmetry of rich/lean probabilities and disparity in line lengths. Drugs that enhance reward responsiveness (amphetamine and scopolamine, but not oxycodone) increased bias, verifying pharmacological task sensitivity. Finally, performance outcomes under optimized conditions were replicated in female rats. Collectively, the touchscreen-based rodent PRT appears to have high preclinical value as a quantitative assay of reward learning.

The staggering incidence of untreated pain is a worldwide crisis.On top of this, the implementation of opiates as a frontline therapeutic strategy has heavily contributed to the current opioid abuse and overdose epidemic in the United States. Improved strategies for treating chronic pain with safer side effect profiles carry an enormous potential payoff for pain patients (Volkow & Collins, 2017).Currently, the clinical management of chronic pain remains a significant challenge given the heterogeneity of underlying causes, and the limited efficacy and/or significant detrimental side effects of many current medications. The cognate receptors for both exogenous opioids and other current pharmacological pain treatments are located not only in the known pain pathways but also in brain reward circuits and brainstem breathing pattern generators (Corder et al., 2018) Therefore, comprehensive strategies that provide substantive relief across pain types, and with reduced abuse and death liabilities, are needed (Davis et al., 2020).

Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3’UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. The breadth of utility of this new tool will greatly facilitate the study of opioid biology under varying conditions.

Background Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias. Methods The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0–10.0 mg/kg), a US Food and Drug Administration-approved rapid-acting antidepressant, and phencyclidine (0.01–0.1 mg/kg), a pharmacologically similar N-methyl-D-aspartate receptor antagonist with no known antidepressant efficacy, were evaluated. Results Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability. Conclusions Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.

Background Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a shortage of animal models. Methods The present studies characterized the responses of the squirrel monkey to pharmacologically diverse emetic drugs. Subjects were administered nicotine (0.032‐0.56 mg/kg), lithium chloride (150‐250 mg/kg), arecoline (0.01‐0.32 mg/kg), or apomorphine (0.032‐0.32 mg/kg) and observed for emesis and prodromal hypersalivation. Results Nicotine rapidly produced emesis and hypersalivation. Lithium chloride produced emesis with a longer time course without dose‐dependent hypersalivation. Arecoline produced hypersalivation but not emesis. Apomorphine failed to produce emesis or hypersalivation. Conclusions The squirrel monkey is sensitive to drug‐induced emesis by a variety of pharmacological mechanisms and is well‐positioned to examine antiemetic efficacy and clinically important side effects of candidate antiemetic pharmacotherapies.