Addiction Biology最新文献

Alcohol exposure affects brain structure, but the extent to which its effects differ across development remains unclear. Several countries are considering changes to recommended guidelines for alcohol consumption, so high-quality evidence is needed. Many studies have been conducted among small samples, but recent efforts have been made to acquire large samples to characterize alcohol's effects on the brain on a population level. Several large-scale consortia have acquired such samples, but this evidence has not been synthesized across the lifespan. We conducted a systematic review of large-scale neuroimaging studies examining effects of alcohol exposure on brain structure at multiple developmental stages. We included studies with an alcohol-exposed sample of at least N = 100 from the following consortia: ABCD, ENIGMA, NCANDA, IMAGEN, Framingham Offspring Study, HCP and UK BioBank. Twenty-seven studies were included, examining prenatal (N = 1), adolescent (N = 9), low-to-moderate-level adult (N = 11) and heavy adult (N = 7) exposure. Prenatal exposure was associated with greater brain volume at ages 9–10, but contemporaneous alcohol consumption during adolescence and adulthood was associated with smaller volume/thickness. Both low-to-moderate consumption and heavy consumption were characterized by smaller volume and thickness in frontal, temporal and parietal regions, and reductions in insula, cingulate and subcortical structures. Adolescent consumption had similar effects, with less consistent evidence for smaller cingulate, insula and subcortical volume. In sum, prenatal exposure was associated with larger volume, while adolescent and adult alcohol exposure was associated with smaller volume and thickness, suggesting that regional patterns of effects of alcohol are similar in adolescence and adulthood.

Frontloading is an alcohol drinking pattern where intake is skewed towards the onset of access. This study aimed to identify brain regions involved in frontloading. Whole brain imaging was performed in 63 C57Bl/6J (32 female, 31 male) mice that underwent 8 days of binge drinking using drinking-in-the-dark (DID). On Days 1–7 mice received 20% (v/v) alcohol or water for 2 h. Intake was measured in 1-min bins using volumetric sippers. On Day 8 mice were perfused 80 min into the DID session and brains were extracted. Brains were processed to stain for Fos protein using iDISCO+. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect Fos+ cells. For network analyses, Day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a change-point analysis. Functional correlation matrices were calculated for each group from log₁₀ Fos values. Euclidean distances were calculated from these R values and clustering was used to determine modules (highly connected groups of brain regions). In males, alcohol access decreased modularity (three modules in both frontloaders and non-frontloaders) as compared to water (seven modules). In females, an opposite effect was observed. Alcohol access (nine modules for frontloaders) increased modularity as compared to water (five modules). Further, different brain regions served as hubs in frontloaders as compared to control groups. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females and we identify several brain-wide signatures of frontloading.

A. Ghaderi, H.R. Banafshe, N. Mirhosseini, M, Motmaen, F. Mehrzad, F. Bahmani, E. Aghadavod, M.A. Mansournia, R.J. Reiter, M-A. Karimi, and Z. Asemi, “The Effects of Melatonin Supplementation on Mental Health, Metabolic and Genetic Profiles in Patients Under Methadone Maintenance Treatment,” Addiction Biology 24, no. 4 (2019): 754-764, https://doi.org/10.1111/adb.12650.

This Expression of Concern is for the above article, published online on 27 June 2018 in Wiley Online Library (wileyonlinelibrary.com), and has been published by agreement between the journal Editor-in-Chief, Rainer Spanagel, Society for the Study of Addiction, and John Wiley & Sons Ltd. The Expression of Concern has been agreed due to concerns raised regarding the integrity of the research and discrepancies in reporting. An investigation has been conducted by the National Committee for Ethics in Biomedical Research Iran, in coordination with Kashan University of Medical Sciences (KAUMS). However, without the verification of clinical records there remain sufficient doubts about the feasibility and integrity of the research undertaken. As a result, the journal has decided to issue an Expression of Concern to alert readers.

Heinz et al. (2024) recently criticised habit/compulsion theory of human addiction but nevertheless concluded that ‘habit formation plays a significant role in drug addiction’. To challenge this causal claim, the current article develops four further methodological criticisms, that publications supporting the habit/compulsion account of human addiction: (1) under-report contradictory observations; (2) exaggerate the process purity of positive observations; (3) under-emphasise the low quality of epidemiological support for a causal hypothesis; (4) recapitulate the social injustice of racial intelligence era by prematurely attributing lower task performance to drug user group membership (endophenotype) without having adequately tested social, psychological, economic and environmental inequalities. Methodological guidelines are recommended to address each concern, which should raise evidence standards, incorporate social justice and improve accuracy of estimating any specific effect of addiction history on task performance. Given that construing drug users as intellectually impaired could promote stigma and reduce their recovery potential, it is recommended that scientific discourse about habit/compulsive endophenotypes underpinning addiction is avoided until these higher evidence standards are met.

Murillo Gonzalez, DJ, Hernandez Granados, BA, Sabandal, PR, Han, K-A. Social setting interacts with hyper dopamine to boost the stimulant effect of ethanol. Addiction Biology. 2024; 29(6):e13420, doi:10.1111/adb.13420.

The footnote, “Dilean J. Murillo Gonzalez and Bryan A. Hernandez Granados contributed equally to this work”, is incorrect and should be removed. Dilean J. Murillo Gonzalez is the sole first author.

There are three institutions listed in the affiliations, which is incorrect. All works reported in the paper were done entirely at the “Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA”. The other institutions are the authors' present addresses as noted below.

D.M.G.’s present address: Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.

B.H.G.’s present address: Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.

We apologize for these errors.

Heinz and colleagues provide interesting insights into the clinical presentation of drug-taking habits and the associated difficulties of breaking them. Although they do not question the existence of habits in addiction, they raise concerns about the psychological construct of habit and its role in the development of compulsivity in addiction.

The authors doubt that compulsive behaviour in addiction arises from a predominance of habits over goal-directed behaviour, as suggested by the habit theory.¹ Their arguments are based on descriptions of differences in clinical phenotypes of compulsivity in addicted patients and patients with obsessive-compulsive disorder (OCD), without mentioning the many commonalities. For example, they explain that avoidance behaviour in OCD patients is negatively reinforced through the relief of anxiety but do not say that hoarding behaviour in OCD patients is positively reinforced.² Likewise, they emphasise that the use of alcohol is positively reinforced by its pleasurable effects but do not mention the fact that negative reinforcement underlies chronic opioid use.³ Similar commonalities are also evident in the brain, as reflected by an overlapping neuropathology underlying self-reported compulsivity in both OCD and addiction.⁴ Focussing solely on different manifestations of orbitofrontal dysfunction (i.e., cases of overactivity or underactivity) distracts from the fact that the same system is impaired in both disorders but expressed in different ways. I wonder whether the authors' questioning of the role of compulsivity in addiction derives from an understanding that equates the psychological concept of compulsivity (i.e., the maladaptive continuation/perseveration of behaviour) with clinical symptoms of compulsions. Compulsive symptoms can of course be expressed in many different ways, as exemplified by the authors' clinical case of an OCD patient with comorbid compulsive alcohol use and gambling behaviour. Whilst there are variations of compulsive symptoms across different disorders, the psychological concept underpinning these behavioural manifestations is the same, namely, a reflection of ongoing actions that have become inappropriate to the immediate context.

Moreover, it is worth clarifying that the habit theory does not contradict their observations. Habits (including habitual drug use) do not necessarily develop into compulsions because most people are able to break their habits. If habits are, however, learned under the influence of drugs or stress, the formation of habits is facilitated. In people with impaired prefrontal inhibitory control (such as patients with OCD or addiction), habits run the risk of persisting even if they no longer produce the desirable effects or lead to adverse consequences. This only affects a minority of drug users, as just 15%–20% are thought to develop addiction.<

Approximately 50 million Americans suffer from chronic pain, and nearly a quarter of chronic pain patients have reported misusing opioid prescriptions. Repeated drug seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone-seeking behaviour and that the pain state would differentially increase intrinsic excitability in dmPFC drug-seeking ensemble neurons. TetTag mice self-administered intravenous oxycodone. After 7 days of forced abstinence, a drug-seeking session was performed, and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between the first and second seeking session. Following the second seeking session, we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug-seeking ensemble and non-ensemble neurons. SNI had no impact on sucrose seeking or intrinsic excitability of dmPFC neurons from these mice. In females, SNI increased oxycodone seeking and intrinsic excitability of non-ensemble neurons. In males, SNI had no impact on oxycodone seeking or neuron excitability. Data from females are consistent with clinical reports that chronic pain can promote drug craving and relapse and support the hypothesis that chronic pain itself may lead to neuroadaptations which promote opioid seeking.

While previous research has shown that compulsivity is related to an imbalance between goal-directed and habitual learning systems, very little is known about whether this effect is due to the impairment of a single system or the impairment of the arbitration mechanism that determines which system controls behaviour at any given moment; the current study aims to address this disagreement. Nineteen alcohol use disorder, 30 obsessive-compulsive disorder (OCD) and 20 major depressive disorder patients and corresponding sex- and age-matched controls performed two-choice, three-stage Markov decision-making paradigm. Model-based and mode-free reinforcement learning models were used to independently fitted their behavioural data. Alcohol use disorder and OCD patients showed less model-based strategy choice than healthy controls in task conditions where the model-based strategy was optimal. Only OCD patients showed higher behavioural control system switching in task conditions where model-free use was optimal. Major depressive disorder patients did not differ from the matched control in both. These findings suggest that dysfunction in arbitration control between dual systems may be the basis for diverse disorders involving compulsivity.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine-seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.