Explore the vast range of titles available.

Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated ‘treatments’ may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.Recent advances in animal addiction models have emphasized translational challenges. In this Review, Venniro and colleagues introduce a reverse translational approach that may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.

Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.

Differentiation between self-produced tactile stimuli and touch by others is necessary for social interactions and for a coherent concept of “self.” The mechanisms underlying this distinction are unknown. Here, we investigated the distinction between self- and other-produced light touch in healthy volunteers using three different approaches: fMRI, behavioral testing, and somatosensory-evoked potentials (SEPs) at spinal and cortical levels. Using fMRI, we found self–other differentiation in somatosensory and socio-cognitive areas. Other-touch was related to activation in several areas, including somatosensory cortex, insula, superior temporal gyrus, supramarginal gyrus, striatum, amygdala, cerebellum, and prefrontal cortex. During self-touch, we instead found deactivation in insula, anterior cingulate cortex, superior temporal gyrus, amygdala, parahippocampal gyrus, and prefrontal areas. Deactivation extended into brain areas encoding low-level sensory representations, including thalamus and brainstem. These findings were replicated in a second cohort. During self-touch, the sensorimotor cortex was functionally connected to the insula, and the threshold for detection of an additional tactile stimulus was elevated. Differential encoding of self- vs. other-touch during fMRI correlated with the individual self-concept strength. In SEP, cortical amplitudes were reduced during self-touch, while latencies at cortical and spinal levels were faster for other-touch. We thus demonstrated a robust self–other distinction in brain areas related to somatosensory, social cognitive, and interoceptive processing. Signs of this distinction were evident at the spinal cord. Our results provide a framework for future studies in autism, schizophrenia, and emotionally unstable personality disorder, conditions where symptoms include social touch avoidance and poor self-vs.-other discrimination.

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

Key Points Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine. The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use. Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus. Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone. Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence. Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use. Genetic variation that influences the functional activity of the CRF system has been found in rats, non-human primates and humans, and has been shown to be associated with various alcohol use phenotypes in all three species. This suggests that pharmacogenetic effects may need to be considered when CRF receptor 1 (CRF 1 ) antagonists are developed for the treatment of alcoholism. GABAergic and serotonergic transmission are also involved in the pathophysiology of alcoholism, and pharmacogenetic effects of variants within both these systems have also been suggested. A potential implication of these findings is that pharmacogenetic effects may turn out to be the rule rather than the exception, and that much more attention will have to be paid to personalizing pharmacotherapy of addictive disorders. Current addiction pharmacotherapies have limited success. Focusing on alcohol addiction, Heilig and colleagues review the evidence that genetic heterogeneity in the opioid, corticotropin-releasing factor, GABA and serotonin systems may underlie differential treatment responses, and that personalized therapies tailored to patient genotype may lead to more successful treatment for alcohol addiction. Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.

The stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice. By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol. Our data suggest that central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders.

Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation, but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging in a childhood maltreatment–exposed and –nonexposed mixed population, combined with human and rodent fear-conditioning models. Here we show that 2-AG levels were inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increased the proportion of neurons that respond to, and the similarity of neuronal representations for, both threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical–amygdala resting-state connectivity was inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder-susceptibility endophenotype.

Defensive responses to threat-associated cues are commonly evaluated using conditioned freezing or suppression of operant responding. However, rats display a broad range of behaviors and shift their defensive behaviors based on immediacy of threats and context. This study aimed to systematically quantify the defensive behaviors that are triggered in response to threat-associated cues and assess whether they can accurately be identified using DeepLabCut in conjunction with SimBA. We evaluated behavioral responses to fear using the auditory fear conditioning paradigm. Observable behaviors triggered by threat-associated cues were manually scored using Ethovision XT. Subsequently, we investigated the effects of diazepam (0, 0.3, or 1 mg/kg), administered intraperitoneally before fear memory testing, to assess its anxiolytic impact on these behaviors. We then developed a DeepLabCut + SimBA workflow for ethological analysis employing a series of machine learning models. The accuracy of behavior classifications generated by this pipeline was evaluated by comparing its output scores to the manually annotated scores. Our findings show that, besides conditioned suppression and freezing, rats exhibit heightened risk assessment behaviors, including sniffing, rearing, free-air whisking, and head scanning. We observed that diazepam dose-dependently mitigates these risk-assessment behaviors in both sexes, suggesting a good predictive validity of our readouts. With adequate amount of training data (approximately > 30,000 frames containing such behavior), DeepLabCut + SimBA workflow yields high accuracy with a reasonable transferability to classify well-represented behaviors in a different experimental condition. We also found that maintaining the same condition between training and evaluation data sets is recommended while developing DeepLabCut + SimBA workflow to achieve the highest accuracy. Our findings suggest that an ethological analysis can be used to assess fear learning. With the application of DeepLabCut and SimBA, this approach provides an alternative method to decode ongoing defensive behaviors in both male and female rats for further investigation of fear-related neurobiological underpinnings.

Only a minority of alcohol users develop alcohol use disorder (AUD), and the extent to which vulnerability to this condition depends on sex remains insufficiently explored in preclinical research. Using an established model that reverse-translates key diagnostic criteria for AUD, we investigated this question in male and female rats. Criteria for addiction-like behavior assessed were: (i) the inability to refrain from alcohol-seeking, (ii) high motivation for alcohol, and (iii) continued alcohol use despite negative consequences, assessed using footshock punishment. We found that a larger proportion of females (12.90%) met all three criteria compared to males (6.45%). Sex-differences observed were independent of alcohol consumption history, footshock sensitivity, or basal anxiety levels. Factor analysis results support the existence of both shared and sex-specific behavioral dimensions underlying addiction vulnerability. Notably, while persistence in alcohol-seeking and motivation loaded similarly onto “Factor 1” in both sexes, resistance to punishment showed opposite loadings on “Factor 3” in males and females. Moreover, this factor was differentially correlated with the global addiction score across sexes, indicating that this behavioral dimension may contribute differently to addiction-like behaviors in males and females. Notably, impulsivity was strongly correlated with the number of addiction-like criteria in both male and female rats, underscoring its broad role in shaping the risk. In contrast, neither anxiety-like behavior, locomotor activity in a novel environment, nor social dominance were predictors of addiction-like behaviors. These results emphasize the need for sex-specific approaches in AUD research, revealing complex behavioral traits that influence addiction risk.