Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats.

Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.

Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats.

BACKGROUND: Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. METHODS: Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. RESULTS: Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). CONCLUSIONS: Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.

Various factors can influence the development of alcohol addiction, but studying these factors in humans over the long-term is challenging and costly. With modern sensing technologies, rodents can be monitored throughout the lifespan, providing detailed information obtained under controlled conditions. Previous research suggests sex- and age-dependent differences in addiction processes, with female rats consuming more alcohol and age at first drink resulting in heavier later consumption, but a better characterization of these is needed. Using a rodent model of addiction and relapse, collecting high-resolution longitudinal drinking data in a computerized system over ~ 11 months, we studied differences in the development of addiction and compulsive-like drinking in male vs female as well as adult vs adolescent rats. Female rats drank more alcohol than male rats during the whole experiment, drinking much more weaker alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats in an aversive taste challenge, displaying more compulsive-like drinking. Increased consumption in females compared to males was driven by larger amounts consumed per approach. Little effect of age of onset of drinking was observed. Our results suggest sex-specific differences in the development of drinking patterns and solution preference, not only in terms of total amount consumed. These findings highlight the importance of awareness of sex-specific factors when developing models of addiction, as well as eventual treatment strategies and interventions.

A shea butter-based ketamine ointment: The antidepressant effects of transdermal ketamine in rats.

The delayed onset of monoaminergic antidepressants and disadvantages of traditional administration routes created the need for alternative non-invasive delivery methods with rapid onset therapeutic effect. Ketamine attracted attention as a fast-acting glutamatergic antidepressant with ideal physiochemical properties for alternative routes of administration. However, there is no sufficient data for its transdermal use in depression. In this proof-of-concept study, we investigated the antidepressant effects of transdermal ketamine delivered via a novel ointment with skin protective, emulsifying and permeation enhancing properties. A shea butter-based 5% (w/w) ketamine ointment or a drug-free vehicle ointment were applied to the shaved dorsal skin of male Wistar rats for 2 days, twice a day. Behavioral despair, locomotor activity and anxiety-like behavior were respectively assessed in the forced swim test (FST), open field test (OFT), and elevated plus maze (EPM). The pharmacokinetic profile of the ointment was analyzed with high-performance liquid chromatography. Transdermal ketamine ameliorated behavioral despair without altering general locomotor activity and anxiety-like behavior, showing that skin-friendly drug carriers like shea butter may constitute promising alternatives to current routes of delivery for ketamine. Tested transdermal method aims to provide more sustainable drug delivery for long-term treatment schedules. Future studies can investigate its long-term use, side effects and abuse liability.

Alcohol solution strength preference predicts compulsive-like drinking behavior in rats.

BACKGROUND: Understanding compulsive drinking behavior is key to improving outcomes in the treatment of addiction. In the present study, we investigated compulsive-like drinking in alcohol-addicted rats using the alcohol deprivation effect (ADE) model of relapse behavior, which involves repeated deprivation and reintroduction phases; the latter approximate relapse. METHODS: High-resolution longitudinal drinking and locomotor data were measured while rats (n = 30) underwent a four-bottle (water, 5%, 10%, 20% alcohol v/v) free-choice ADE paradigm. Alcohol bottles were adulterated with the bitter compound quinine during a reintroduction phase to test for compulsive behavior. We characterized how drinking and locomotor behavior during ADE + quinine differed from a regular ADE and how, at the individual level, behavioral parameters extracted from the regular ADE related to compulsive-like drinking. Associations of drinking with locomotor activity were also examined. RESULTS: In the ADE with quinine, we observed reduced consumption of alcohol and a shift to preference for stronger alcohol. Quinine acted by decreasing both the access size and frequency of drinking of 5% alcohol while increasing the frequency of consumption of 20% alcohol. Preference for higher alcohol concentrations prior to the quinine challenge was associated with greater compulsive-like drinking behavior; higher baseline consumption of 20% alcohol correlated with more drinking of quinine-adulterated solutions while high frequency and amount of 5% alcohol consumption at baseline were correlated with being more strongly affected by quinine. Associations between locomotor activity and drinking behavior were observed at the hourly level. These associations reflected changing preferences across experimental phases. CONCLUSION: Drinking patterns, and specifically solution preference, may offer insights into the presentation of compulsive-like drinking. The findings provide a preclinical basis for observations from epidemiological studies that link higher risk and burden of alcohol-related disease to stronger alcohol concentrations and encourage further translational studies to better understand the underlying mechanisms.

Adverse social experiences in adolescent rats result in persistent sex-dependent effects on alcohol-seeking behavior.

BACKGROUND: Accumulating clinical evidence suggests that women with prior exposure to adverse childhood experiences are more susceptible to heavy drinking and other health-related behaviors. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to the unavailability of valid animal models and a shortage of studies that compare effects in males and females. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion, and reward sensitivity in male and female rats. METHODS: We recently developed a rat model for childhood/adolescent peer rejection that allows us to study the long-term consequences of ASEs. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or within a group of Wistar rats (control). Wistar rats housed with Fischer 344 rats do not reciprocate social play in adolescence. This reduced play across adolescence mimics peer rejection and results in chronic dysregulation of social and pain-related behaviors. We tested adult male and female rats in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption long after the termination of the peer rejection condition. RESULTS: Peer rejection induced persistent sex-dependent changes in alcohol cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. Sex differences were observed in locomotor activity or reward sensitivity to sucrose. CONCLUSIONS: Peer rejection has long-lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population in which to study relapse-like behaviors that are similar to clinical findings, while males seem to buffer the peer rejection effect and demonstrate resilience to later life alcohol-seeking behaviors, as measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.

Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse.

For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run. Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model. In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention. In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.