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
power calculation should be carried out. (iii) The experimental study protocol should be pre-registered. (iv) The execution of the study should be in accordance with the most recent ARRIVE guidelines. (v) When planning the study, the generalizability of the data to be collected should also be considered (e.g., sex or age differences). (vi) "Method-hopping" should be avoided, meaning that it is not necessary to use the most advanced technology but rather to have the applied methodology under control. (vii) National or international networks should be considered to carry out multicenter preclinical studies or to obtain convergent evidence. (viii) Animal models that capture DSM-5 or ICD-11 criteria should be considered in the context of research on psychiatric disorders. (ix) Raw data of publication should be made publicly available and should be in accordance with the FAIR Guiding Principles for scientific data management. (x) Finally, negative findings should be published to counteract publication bias. The application of these 10 points of recommendation, especially for preclinical confirmatory studies but also to some degree for exploratory studies, will ultimately improve the reproducibility and translation of animal research.
Aberrant choice behavior in alcoholism Spanagel, Rainer
Science (American Association for the Advancement of Science),
06/2018, Letnik:
360, Številka:
6395
Journal Article
Recenzirano
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.
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 - 0.5CI - 0.62, - 0.38 high grade) and Parkinsonism (- 0.41CI - 0.75, - 0.08 moderate grade). There is moderate evidence for dronabinol for chronic pain (- 0.31CI - 0.46, - 0.15), appetite (- 0.51CI - 0.87, - 0.15) and Tourette (- 1.01CI - 1.58, - 0.44) and moderate evidence for nabiximols on chronic pain (- 0.25- 0.37, - 0.14), spasticity (- 0.36CI - 0.54, - 0.19), sleep (- 0.24CI - 0.35, - 0.14) and SUDs (- 0.48CI - 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. Keywords: Cannabinoids, Pharmacology, Medical conditions, Neuropsychiatry, Clinical trial, Efficacy, Adverse events
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract 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.
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.
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.
Abstract Cue reactivity to natural and social rewards is essential for motivational behavior. However, cue reactivity to drug rewards can also elicit craving in addicted subjects. The degree to which ...drug and natural rewards share neural substrates is not known. The objective of this study is to conduct a comprehensive meta-analysis of neuroimaging studies on drug, gambling and natural stimuli (food and sex) to identify the common and distinct neural substrates of cue reactivity to drug and natural rewards. Neural cue reactivity studies were selected for the meta-analysis by means of activation likelihood estimations, followed by sensitivity and clustering analyses of averaged neuronal response patterns. Data from 176 studies (5573 individuals) suggests largely overlapping neural response patterns towards all tested reward modalities. Common cue reactivity to natural and drug rewards was expressed by bilateral neural responses within anterior cingulate gyrus, insula, caudate head, inferior frontal gyrus, middle frontal gyrus and cerebellum. However, drug cues also generated distinct activation patterns in medial frontal gyrus, middle temporal gyrus, posterior cingulate gyrus, caudate body and putamen. Natural (sexual) reward cues induced unique activation of the pulvinar in thalamus. Neural substrates of cue reactivity to alcohol, drugs of abuse, food, sex and gambling are largely overlapping and comprise a network that processes reward, emotional responses and habit formation. This suggests that cue-mediated craving involves mechanisms that are not exclusive for addictive disorders but rather resemble the intersection of information pathways for processing reward, emotional responses, non-declarative memory and obsessive–compulsive behavior.
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.
Animal models of addiction Spanagel, Rainer
Dialogues in clinical neuroscience,
09/2017, Letnik:
19, Številka:
3
Journal Article
Odprti dostop
In recent years, animal models in psychiatric research have been criticized for their limited translational value to the clinical situation. Failures in clinical trials have thus often been ...attributed to the lack of predictive power of preclinical animal models. Here, I argue that animal models of voluntary drug intake-under nonoperant and operant conditions-and addiction models based on the Diagnostic and Statistical Manual of Mental Disorders are crucial and informative tools for the identification of pathological mechanisms, target identification, and drug development. These models provide excellent face validity, and it is assumed that the neurochemical and neuroanatomical substrates involved in drug-intake behavior are similar in laboratory rodents and humans. Consequently, animal models of drug consumption and addiction provide predictive validity. This predictive power is best illustrated in alcohol research, in which three approved medications-acamprosate, naltrexone, and nalmefene-were developed by means of animal models and then successfully translated into the clinical situation.
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
Alcohol consumption is an integral part of daily life in many societies. The benefits ...associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societies. The World Health Organization ranks alcohol as one of the primary causes of the global burden of disease in industrialized countries. Alcohol-related diseases, especially alcoholism, are the result of cumulative responses to alcohol exposure, the genetic make-up of an individual, and the environmental perturbations over time. This complex gene x environment interaction, which has to be seen in a life-span perspective, leads to a large heterogeneity among alcohol-dependent patients, in terms of both the symptom dimensions and the severity of this disorder. Therefore, a reductionistic approach is not very practical if a better understanding of the pathological processes leading to an addictive behavior is to be achieved. Instead, a systems-oriented perspective in which the interactions and dynamics of all endogenous and environmental factors involved are centrally integrated, will lead to further progress in alcohol research. This review adheres to a systems biology perspective such that the interaction of alcohol with primary and secondary targets within the brain is described in relation to the behavioral consequences. As a result of the interaction of alcohol with these targets, alterations in gene expression and synaptic plasticity take place that lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, alcohol-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior.
1 The terms alcohol and ethanol are used interchangeably throughout this review. However, the term ethanol is mostly used in the context of a specific effect, e.g., a specific pharmacological effect.
2 Note that the term dependence is avoided in this review. Addiction is a pathological behavioral syndrome that has to be strictly separated from physical dependence. Transient neuroadaptive processes underlie physical dependence to alcohol, whereas persistent changes within specific neuronal systems underlie addictive behavior. To avoid any confusion between clinicians, psychologists, and preclinicians, the term dependence should refer to a state of physical dependence.
3 For historical reasons, blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of 500 mg/dl corresponds to 4.06 .
4 For reference, a low intoxicating BAL of 50 mg/dl is equivalent to an ethanol concentration of 10.6 mM.
5 N265M: the in vivo action of general anesthetics is strongly attenuated by this point mutation (227).
6 Various alcohol-preferring and nonpreferring rat lines have been developed within the last 50 yr. Depending on the line, preferring rats consume 5–9 g·kg –1 ·day –1 ethanol, whereas the nonpreferring lines consume less than 1 g·kg –1 ·day –1 . These lines are very powerful animal models in the study of the neurochemical substrates of alcohol reinforcement. A comprehensive overview of the different lines has recently been reported (31, 83, 93, 382, 354, 454).
7 In addition, a functional cross-talk between the endocannabinoid and opioid systems has been found in the mutual modulation of drug/alcohol reinforcement and reward processes (143, 401).
8 Differences in gene expression can arise from cis -regulatory changes that affect transcription initiation, transcription rate, and/or transcript stability in an allele-specific manner, or from trans -regulatory changes that modify the activity or expression of factors that interact with cis -regulatory sequences.
9 Type II people tend to become alcohol dependent at an early age and have a high family risk of alcoholism, more severe symptoms, and a negative perspective of life (59).
10 A four-bottle paradigm has the advantage of overcoming initial preference problems. Rats usually prefer lower concentrated alcohol solutions (<6%) over higher concentrated alcohol solutions. Following a period of taste adaptation, a shift towards preference for higher concentrated alcohol solutions is observed. Furthermore, individual sensitivities and preferences to alcohol solutions are usually observed. The free choice presentation of various concentrated alcohol solutions bypasses the problem of individual preferences; in this model a rat is allowed to drink what it likes most. Indeed, in a four-bottle paradigm, high alcohol intake and preference in common stock rats are observed during the acquisition of alcohol drinking behavior in male (444) as well as in female rats (147). In conclusion, a four-bottle paradigm results in a higher daily alcohol intake and preference compared with a two-bottle choice paradigm with a fixed alcohol concentration of 10% which has been used in most of the studies on alcohol drinking behavior in the rat performed to date.
11 Overall, female rats in our studies consume greater amounts of alcohol than male rats (147). This is in accordance with previous studies reporting that there is a sex difference in ethanol ingestion (7, 258) and that female rats consume significantly greater amounts of alcohol. Such a sex difference is also seen in other species such as mice and monkeys (25, 362). At first glance, this appears to be in stark contrast to observations in humans, since epidemiological and clinical studies demonstrate that women consume less alcohol than men. However, we have recently reported that if alcohol intake in humans were to be calculated on a g/kg basis instead of the number of drinks consumed, consumption in females would be much the same or even more compared with that in males (239). Contrasting sex differences in humans and animals are mainly related to social barriers in different populations and to an artifact in calculating exact alcohol intake. The reasons for sex differences in alcohol consumption are still poorly understood. However, it is obvious that intrinsic sex differences in brain organization and the actions of circulating gonadal steroids may contribute to the enhanced voluntary alcohol intake observed in female animals (7).
12 In the large-scale study COMBINE (11), over 1,300 patients were treated with either naltrexone or placebo. While half the patients received a low-dose standard supportive therapy (Medical Management), the other half received a more intensive psychotherapy, i.e., cognitive-behavioral intervention (CBI). All groups showed a substantial reduction in drinking. During treatment, those patients receiving naltrexone plus medical management, CBI plus medical management and placebo, or both naltrexone and CBI plus medical management had a higher percentage of abstinent days than the group receiving placebo and medical management only, which is indicative of a significant naltrexone x behavioral intervention interaction.
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