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Findings from animal experiments are often difficult to transfer to humans. In this perspective article I discuss two questions. First, why are the results of animal experiments often so difficult to transfer to humans? And second, what can be done to improve translation from animal experiments to humans? Translation failures are often the result of poor methodology. It is not merely the fact that low statistical power of basic and preclinical studies undermine a “real effect,” but the accuracy with which data from animal studies are collected and described, and the resulting robustness of the data is generally very low and often does not allow translation to a much more heterogeneous human condition. Equally important is the fact that the vast majority of publications in the biomedical field in the last few decades have reported positive findings and have thus generated a knowledge bias. Further contributions to reproducibility and translation failures are discussed in this paper, and 10 points of recommendation to improve reproducibility and translation are outlined. These recommendations are: (i) prior to planning an actual study, a systematic review or potential preclinical meta-analysis should be considered. (ii) An a priori power calculation should be carried out. (iii) The experimental study protocol should be pre-registered.

Background Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events. Methods We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools. Results In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD − 0.5[CI − 0.62, − 0.38] high grade) and Parkinsonism (− 0.41[CI − 0.75, − 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (− 0.31[CI − 0.46, − 0.15]), appetite (− 0.51[CI − 0.87, − 0.15]) and Tourette (− 1.01[CI − 1.58, − 0.44]) and moderate evidence for nabiximols on chronic pain (− 0.25[− 0.37, − 0.14]), spasticity (− 0.36[CI − 0.54, − 0.19]), sleep (− 0.24[CI − 0.35, − 0.14]) and SUDs (− 0.48[CI − 0.92, − 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid. Conclusions Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.

Impaired neurotransmitter clearance in the amygdala is implicated in alcoholism More than 2 billion people worldwide regularly drink alcohol. Alcohol is a component cause of more than 200 diseases and causes ∼3.3 million deaths per year globally ( 1 ). The major disease burden comes from harmful alcohol consumption and alcohol dependence. Not everyone who regularly consumes alcohol becomes dependent: ∼15% become engaged in harmful and compulsive alcohol drinking ( 2 ). Patients suffering from alcohol dependence no longer have the freedom to choose between alternative rewards because alcohol drinking dictates what should be done next, namely, shaping activities for the next drink. On page 1321 of this issue, Augier et al. ( 3 ) demonstrate that aberrant choice behavior—that is, choosing alcohol over an alternative reward—is a key driver for the transition from controlled to compulsive alcohol use. They also provide a mechanistic understanding of this aberrant choice behavior that could lead to new treatment opportunities.

Recently we identified a deficiency in metabotropic glutamate receptor 2 (mGlu2) function in the corticoaccumbal pathway, as a common pathological mechanism underlying alcohol-seeking and relapse behavior. Based on this mechanism, we hypothesized that mGlu2/3 agonists and mGlu2 positive allosteric modulators (PAMs) may be effective in reducing relapse-like behavior. Two mGlu2/3 agonists, LY379268 and LY354740 (a structural analog of LY379268 six-fold more potent in activating mGlu2 over mGluR3), were tested in a well-established rat model of relapse, the alcohol deprivation effect (ADE) with repeated deprivation phases. Since these agonists do not readily discriminate between contributions of mGlu2 and mGluR3, we also tested LY487379, a highly specific PAM that potentiates the effect of glutamate on the mGlu2 with less specificity on other mGlu receptor subtypes. Both LY379268 and LY354740 significantly and dose-dependently reduced the expression of the ADE. No significant changes in water intake, body weight and locomotor activity were observed. Importantly, repeated administration of mGlu2/3 agonist did not lead to tolerance development. mGlu2 PAM LY487379 treatment significantly reduced expression of the ADE in both male and female rats. Combination treatment of mGlu2/3 agonist and PAM had similar effect on relapse-like drinking to that seen in mGlu2/3 agonist treatment alone. Together with other preclinical data showing that PAMs can reduce alcohol-seeking behavior we conclude that mGlu2 PAMs should be considered for clinical trials in alcohol-dependent patients.

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.

The concept of “sugar addiction” is gaining increasing attention in both the lay media and scientific literature. However, the concept of sugar addiction is controversial and only a few studies to date have attempted to determine the “addictive” properties of sugar using rigorous scientific criteria. Here we set out to systematically test the addictive properties of sugar in male and female mice using established paradigms and models from the drug addiction field. Male and female C57BL/6N (8–10 weeks old) were evaluated in 4 experimental procedures to study the addictive properties of sugar: (i) a drinking in the dark (DID) procedure to model sugar binging; (ii) a long-term free choice home cage drinking procedure measuring the sugar deprivation effect (SDE) following an abstinence phase; (iii) a long-term operant sugar self-administration with persistence, motivation and compulsivity measures and (iv) intracranial self-stimulation (ICSS). Female mice were more vulnerable to the addictive properties of sugar than male mice, showing higher binge and long-term, excessive drinking, a more pronounced relapse-like drinking following deprivation, and higher persistence and motivation for sugar. No sex differences were seen in a compulsivity test or reward sensitivity measured using ICSS following extended sugar consumption. This study demonstrates the occurrence of an addictive-like phenotype for sugar in male and female mice, similar to drugs of abuse, and suggests sex-dependent differences in the development of sugar addiction.

Understanding the psychological mechanisms and underlying neurobiology of relapse behavior is essential for improving the treatment of addiction. Because the neurobiology of relapse behavior cannot be well studied in patients, we must rely on appropriate animal models. The alcohol deprivation effect (ADE) is a phenomenon in laboratory animals that models a relapse-like drinking situation, providing excellent face and predictive validity. In rodents, relapse-like behavior is largely influenced by the genetic make-up of an animal. It is not clear which other factors are responsible for variability of this behavior, but there seems to be no correlation between levels of baseline alcohol intake and the occurrence, duration, and robustness of the ADE. Rats that undergo long-term alcohol drinking for several months with repeated deprivation phases develop a compulsive drinking behavior during a relapse situation, characterized by insensitivity to taste adulteration with quinine, a loss of circadian drinking patterns during relapse-like drinking, and a shift toward drinking highly concentrated alcohol solutions to rapidly increase blood alcohol concentrations and achieve intoxication. Some mouse strains also exhibit an ADE, but this is usually of shorter duration than in rats. However, compulsive drinking in mice during a relapse situation has yet to be demonstrated. We extend our review section with original data showing that during long-term alcohol consumption, mice show a decline in alcohol intake, and the ADE fades with repeated deprivation phases. Furthermore, anti-relapse compounds that produce reliable effects on the ADE in rats produce paradoxical effects in mice. We conclude that the rat provides a better model system to study alcohol relapse and putative anti-relapse compounds.

RationaleIn classical conditioning, sign-tracking reflects behavior directed toward a conditioned stimulus (CS) in expectation of a reward (unconditioned stimulus, US); in contrast, goal-tracking describes behavior directed toward the location of delivery of a US. As cues previously paired with drugs of abuse promote drug-seeking and drug-taking behavior in both animals and humans and thus contribute to the severity of substance abuse, sign-tracking may represent a maladaptive cue-focused behavior that may increase addiction vulnerability as compared to goal-tracking. Recent studies do, in fact, support this possibility. Previous work in this area has focused primarily on paradigms using relatively limited exposure to drug rather than extended drug intake.ObjectivesHere, we used the DSM-IV–based 3-criteria (3-CRIT) model and examined whether a relationship exists between sign- or goal-tracking phenotypes and the prevalence of criteria associated with addiction-like behavior following extended cocaine self-administration as measured in this model.MethodsForty-six male Sprague Dawley rats underwent a Pavlovian conditioned approach (PCA) procedure and were characterized along a continuum as goal-trackers (GTs), intermediates (INTs), or sign-trackers (STs). The animals were subsequently trained to intravenous self-administer cocaine during 45 self-administration (SA) sessions and characterized for the 3 criteria outlined in the model: persistence of drug-seeking, motivation for cocaine-taking, and resistance to punishment.ResultsWe performed correlational analyses on the traits measured, finding no relationships between PCA score and addiction-like characteristics measured using the 3-CRIT model of addiction. However, STs showed significantly greater resistance to punishment than GTs.ConclusionsPhenotyping along a continuum of PCA scores may not be a valid predictor for identifying vulnerability to the addiction-like behaviors examined using the 3-CRIT model. However, PCA phenotype may predict a single feature of the 3-CRIT model, resistance to punishment, among those rats classified as either STs or GTs.

Rationale The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. Objectives In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. Methods An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse—the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour. Results Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048. Conclusions Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.

The authors combine electrophysiology and behavioral assays to show that the duration of cocaine-induced synaptic plasticity in the VTA of mice is gated by mGluR1. The lack of mGluR1 in vivo made VTA potentiation persistent and led to synaptic plasticity in the NAc, which is important for relapse. Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor–dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.