Increased reactivity of the paraventricular nucleus of the hypothalamus and decreased threat responding in male rats following psilocin administration.

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior.

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:tdTomato Transgenic Rats.

In 2021, 131 million adult Americans reported drinking alcohol in the last month, despite the well-known consequences of alcohol consumption. While alcohol use disorders (AUDs) are associated with both mood and chronic pain disorders, the relationship between alcohol drinking and affective and nociceptive behaviors remains unclear. Corticotropin releasing factor receptor-1 (CRF1) has been implicated in alcohol drinking, affective states, and pain sensitivity, often in a sex-dependent manner. In order to probe the effects of alcohol drinking on activity of CRF1+ cells and to also test the hypothesis that alcohol drinking is associated with both basal and subsequent affective and nociceptive readouts, we put male and female CRF1:cre:tdTomato rats through a battery of behavioral tests before and after intermittent access to alcohol. Following baseline testing, rats began alcohol (or water) drinking. Females consumed more alcohol in the first week, but there was no effect of sex on overall alcohol intake. Following three to four weeks of drinking, behavioral tests were repeated. Alcohol drinking decreased mechanical sensitivity, but no other effects of alcohol drinking were observed between experimental groups. Individual alcohol intake correlated with affective behavior in both sexes but only correlated with thermal sensitivity in males. There were no main effects of alcohol drinking or sex on CRF1+ neuronal activity in the medial prefrontal cortex (PFC) but final session alcohol intake correlated with activity in CRF1+ neurons in the infralimbic (IL) subregion. Together, our results suggest complex interplay between affective state, alcohol drinking, and the role of prefrontal CRF1+ neurons in mediating these behaviors.

Effects of buprenorphine, methadone, and cariprazine on economic choice between remifentanil and food in squirrel monkeys.

We recently reported an economic choice task in which squirrel monkeys chose between differing amounts of remifentanil, a fast-acting opioid, or a food reward to develop a preclinical screen for evaluating potential pharmacotherapies for opioid dependence. Herein, two known opioid addiction treatments are evaluated using this task, as well as a potential new agent, cariprazine, a dopamine D2/D3 receptor partial agonist currently used to treat bipolar disorder and schizophrenia. Preclinical rodent studies suggest this class of compounds may reduce opiate self-administration. Squirrel monkeys were pretreated daily with clinically relevant doses of each compound during the five days of treatment evaluation using the economic choice task. Shifts in drug preference were measured as changes in subjects' indifference values, where the probability of drug and milk choice are equivalent. Buprenorphine produced a significant shift in indifference value between baseline and treatment weeks, indicating a decrease in drug preference. Subjects treated with methadone and cariprazine did not show any significant shift in drug preference. Differences between the buprenorphine and methadone results likely reflect a lack of opioid dependence in the subjects. The cariprazine results suggest that it does not alter opioid reward in non-dependent primates over a five day period.

Economic choice between remifentanil and food in squirrel monkeys.

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Potential Value of the Insights and Lived Experiences of Addiction Researchers With Addiction.

People in remission from substance use disorders (SUDs) have a history of using their own experience (also referred to as "experiential knowledge" or "expertise") to support those in or seeking SUD remission. In recent years, people with this experiential knowledge are being incorporated into research protocols to better guide research questions and inform the real-world uptake of SUD treatments and recovery supports. In these research contexts, however, those with research expertise and addiction rarely speak freely about these overlapping perspectives. The aim of this commentary is to increase awareness regarding the existence of this group (addiction researchers with addiction) and to explore the possibility that their expertise may help advance addiction science while helping to reduce stigma.

Reinforcement learning modeling reveals a reward-history-dependent strategy underlying reversal learning in squirrel monkeys.

Insight into psychiatric disease and development of therapeutics relies on behavioral tasks that study similar cognitive constructs in multiple species. The reversal learning task is one popular paradigm that probes flexible behavior, aberrations of which are thought to be important in a number of disease states. Despite widespread use, there is a need for a high-throughput primate model that can bridge the genetic, anatomic, and behavioral gap between rodents and humans. Here, we trained squirrel monkeys, a promising preclinical model, on an image-guided deterministic reversal learning task. We found that squirrel monkeys exhibited two key hallmarks of behavior found in other species: integration of reward history over many trials and a side-specific bias. We adapted a reinforcement learning model and demonstrated that it could simulate squirrel monkey-like behavior, capture training-related trajectories, and provide insight into the strategies animals employed. These results validate squirrel monkeys as a model in which to study behavioral flexibility. (PsycInfo Database Record (c) 2022 APA, all rights reserved).