Addiction Biology最新文献

Psychedelics have emerged as potential therapeutics for substance use disorders, yet preclinical data validating their efficacy remain limited. Here, we investigated the effects of a clinically inspired dose-escalation protocol of psilocybin and ibogaine on extinction and cue-induced reinstatement in Wistar male rats following intravenous cocaine self-administration (IVSA). Rats were trained on a fixed ratio 1 (FR1) schedule with cocaine dose-escalation during the acquisition phase (0.25 mg/kg/infusion, followed by 0.5 mg/kg/infusion). Following acquisition, animals were randomised into treatment groups and then subjected to 10 days of extinction. Psilocybin (1.25 mg/kg and 5 mg/kg) or ibogaine (10 mg/kg and 40 mg/kg) was administered subcutaneously and intraperitoneally, respectively, on extinction days 1 and 5. A cue-induced reinstatement test was conducted 6 days after the last treatment. Both treatments significantly modulated behaviour during extinction; psilocybin reduced active lever pressing 1 day after the second dose, with a nonsignificant reduction already apparent after the first dose, while the effect of ibogaine was significant even after the first administration. However, neither compound significantly altered reinstatement behaviour, although psilocybin showed a trend toward attenuation. The applied treatment had no side effects on general locomotor activity or anxiety-like behaviour, as measured in the open field test 24 h after each administration. These findings support a role for psilocybin and ibogaine in facilitating extinction learning and suggest possible protective effects against relapse, warranting further research into their antiaddictive efficacy.

Polysubstance use of opioids and stimulants is increasingly common among individuals with a substance use disorder, yet most researchers examine these substances in isolation. This gap limits our understanding of the effects of polysubstance use and how these differ from single substance use. Here, we examined the impact of single versus polysubstance exposure of fentanyl and methamphetamine on locomotor sensitisation and social behaviour in male and female rats. In addition, as recent evidence has suggested the potential for psychedelic compounds to decrease facets of both opioid and stimulant use disorders, we tested whether the psychedelic R-(-)2,5-dimethoxy-4-iodoamphetamine (DOI) can reverse drug withdrawal-induced social deficits. Baseline sociability was assessed in male and female Sprague-Dawley rats using DeepLabCut and Simple Behavioral Analysis (SimBA). Rats then received injections of saline, methamphetamine (1 mg/kg) and/or fentanyl (20 μg/kg) for 14 days, and locomotion was measured. All rats then underwent 10 days of withdrawal followed by a reassessment of sociability. The following day, all subjects received DOI (0.3 mg/kg; 30 min) and were reassessed for sociability. Our results indicate that the development of locomotor sensitisation and drug withdrawal-induced social deficits vary as a function of drug class, drug history and sex. In addition, acute DOI treatment is sufficient to reverse social deficits as well as enhance social interactions in females. The findings from these experiments suggest a potential therapeutic role of psychedelics in mitigating the social deficits that are associated with withdrawal from polysubstance use of opioids and stimulants.

The combined disease burden of excessive alcohol consumption and metabolic dysfunction (MD) is an escalating global concern. Although it is well established that both factors adversely impact health, the biological characteristics and comorbidities of their overlap remain understudied in the United States. The present study investigated whether concurrent MD and alcohol use disorder (AUD) is associated with worse liver-related and psychiatric health. A total of 1220 participants were recruited through the Natural History Protocol at the National Institutes of Health (NIH) and categorized into the following four groups: healthy controls (HC), individuals with MD (metHC), individuals with current AUD without MD (AUD) and those with both current AUD and MD (metAUD). Sociodemographic and clinical biomarkers, liver injury indices (Fibrosis-4 [FIB-4], LiverRisk, NAFLD fibrosis score [NFS]), liver enzymes and inflammatory markers (GGT, AST, ALT, CRP), liver function tests (albumin, bilirubin, PT-INR), psychiatric and substance use comorbidities as well as current smoking were assessed in the four groups using analysis of covariance (ANCOVA). In addition, the clinical biomarkers were compared across three groups: mild (< 3 MD criteria) and severe (≥ 3) metAUD, as well as AUD only. Liver enzymes, noninvasive liver fibrosis scores and liver function tests showed additive effects across metHC, AUD and metAUD compared to HC, with the largest effects in metAUD for GGT, AST, ALT, CRP, albumin, direct bilirubin, FIB-4, LiverRisk and NFS (p < 0.001). Psychiatric disorders also exhibited the most significant association with metAUD (p < 0.001). Within AUD, greater MD severity was associated with higher GGT, ALT, CRP, NFS and any DSM anxiety disorders (p < 0.05). These findings suggest that MD in the context of AUD is associated with greater liver dysfunction and psychiatric burden, supporting MD-targeted treatment strategies in clinical care for AUD.

Epidemiological studies suggest heavy adolescent binge drinking is strongly associated with later development of an alcohol use disorder (AUD). Alcohol tolerance (i.e., an acquired reduction in acute alcohol responsivity) is a universally recognized symptom of AUD, but the direct contribution of adolescent binge drinking to adult alcohol tolerance is poorly understood. To investigate the contributions of adolescent binge ethanol exposure to lasting acquisition of acute tolerance, we used our ethanol response battery (ERB) to assess intoxication rating, hypothermia, motor coordination and balance across cumulative ethanol doses (i.e., 0.0, 0.5, 1.0, 2.0 and 3.0 g/kg) in adult female Wistar rats following adolescent intermittent ethanol (AIE), lipopolysaccharide (LPS) and glycyrrhizic acid treatment following AIE. We report AIE confers lasting alcohol tolerance across cumulative ethanol doses and blunts acute ethanol-induced increases in proinflammatory HMGB1 plasma levels. Adolescent LPS (1.0 mg/kg, i.p.) treatment, which mimics AIE-induced HMGB1-mediated neuroinflammation, induces adult alcohol tolerance and blunts HMGB1 release across cumulative ethanol doses on the ERB. Assessment of proinflammatory HMGB1 involvement in AIE-induced acquisition of lasting alcohol tolerance showed that post-AIE administration of the HMGB1 inhibitor glycyrrhizic acid reversed the AIE-induced acquisition of alcohol tolerance in adulthood. These data reveal that (1) adolescent binge drinking confers long-lasting low ethanol responsivity (i.e., tolerance), (2) proinflammatory neuroimmune activation contributes to the development of alcohol tolerance and (3) blockade of proinflammatory HMGB1 signalling reverses AIE-induced acquisition of alcohol tolerance in adulthood. These findings suggest a potential mechanistic target for the development of novel therapeutics for the treatment of AUD.

Buprenorphine (BUP) offers a therapeutic approach for opioid use disorder (OUD) due to its unique pharmacodynamic properties, primarily as a partial agonist with high affinity for the mu-opioid receptor (MOR). BUP's partial agonism and ceiling effect on respiratory depression enhance its safety profile. However, BUP can induce precipitated withdrawal when administered after a full agonist, leading to severe withdrawal symptoms. This Perspective builds on prior work that has linked BUP's high-affinity partial agonism to precipitated withdrawal and low-dose induction strategies. We focus on how BUP's capacity to promote MOR externalization, together with its activity at the nociceptin opioid peptide (NOP) receptor, can help explain why it precipitates withdrawal when administered in the presence of full agonists yet relieves withdrawal once spontaneous withdrawal has begun. Understanding these mechanisms is critical for optimizing BUP protocols in OUD treatment and informs the potential development of new biased MOR agonists (i.e., ligands that preferentially activate specific signalling pathways) for addiction therapy.

Cannabis positive expectancies, favourable beliefs about cannabis effects, are a key risk factor for cannabis initiation and problematic use during adolescence. Prior research demonstrated a robust association between cannabis positive expectancies and increased use among adolescents, yet less is known about the developmental aetiology, biobehavioural mechanisms and cognitive context that contribute to these expectancies. The present study examines the intermediary role of negative urgency, a facet of impulsivity characterized by rash action under distress. Additionally, the study investigates whether anterior cingulate cortex (ACC) activation during emotional reward processing moderates this indirect effect. We conducted a longitudinal moderated mediation model with three waves of data from the Adolescent Brain and Cognitive Development (ABCD) study, analysing 6638 youths (baseline M_age = 10.1 years; 47.8% female). Family conflict at baseline predicted increased cannabis positive expectancies ΔT5T7 through increases in negative urgency at T5 (β = 0.017, p < 0.001, 95% CI [0.045, 0.069]). Heightened ACC activity at T5 (anticipatory large loss), including bilateral caudal and rostral regions, intensified negative urgency's impact on cannabis positive expectancy ΔT5T7: Left caudal (β = 0.081, p < 0.001, 95% CI [0.041, 0.122]), right caudal (β = 0.062, p = 0.004, 95% CI [0.020, 0.105]), right rostral (β = 0.041, p = 0.026, 95% CI [0.001, 0.081]) and left rostral (β = 0.052, p = 0.01, 95% CI [0.012, 0.092]). This study highlights how neural activity amplifies stress-related effects on adolescent substance use expectations, suggesting emotional decision-making as a target for prevention.

Smoking addiction is a common mental disorder, and numerous imaging studies have shown that adolescents with smoking addiction exhibit abnormalities in brain function and structure. This study aims to investigate changes in the topological characteristics of the white matter (WM) functional network in young smokers. Forty-two young smokers and 42 age-, gender-, and education-matched nonsmokers were included in the study. The functional connectome of white matter and graph theory were used to study these participants. Two-sample t-test were used for the detection of the abnormal graph properties in young smokers. Pearson correlation was applied for the correlation analyses between properties and clinical indicators of smoking. The global level WM functional network analyses showed that the $C_p$ and $E_{\text{local}}$ values were higher in young smokers than in the control group, and the $E_{\text{local}}$ was positively correlated with the age of first smoking. At the node level, five nodes of the WM functional network exhibited abnormal node properties in the WM regions of the bilateral hippocampal parahippocampal gyrus (CGH), bilateral superior longitudinal fasciculus (SLF), bilateral inferior frontal gyrus (IFO), middle cerebellar peduncle (MCP), and the bilateral anterior commissure (ACR) in young smokers. The node degree centrality value of MCP was positively correlated with age of first smoking. Our neuroimaging findings provide evidence of WM functional alterations associated with nicotine addiction, which may enhance our understanding of the neural mechanisms underlying smoking addiction in young smokers.

Cigarette smoking is a prevalent and critical global health issue, with inconsistent findings for its effects on endogenous progesterone concentrations. This large multicentre study investigated the associations between various markers of smoking behaviour and plasma progesterone concentrations using a sex-segregating approach. We studied 747 males aged 18-65 years and 158 peri-/postmenopausal females aged 50-65 years and assessed differences in plasma progesterone concentrations between smokers and never-smokers and associations of plasma progesterone concentrations with the Fagerström Test for Nicotine Dependence (FTND) score, cigarette pack years, age at onset of regular smoking, number of cigarettes smoked daily, exhaled carbon monoxide (CO), plasma cotinine and the Questionnaire of Smoking Urges (QSU) score. In models adjusted for age, body mass index (BMI), years of education, Alcohol Use Disorder Identification Test (AUDIT) scores, intake of any medication and study centre, and after correction for multiple hypothesis testing, there were no significant differences in plasma progesterone concentrations between smokers and never-smokers, and no significant associations between any of the mentioned markers of smoking behaviour and plasma progesterone concentrations in either males or females. The results suggest that smoking behaviour has no substantial effect on plasma progesterone concentrations and is not an important confounder in studies investigating progesterone.

While alcohol use disorder can be treated with pharmacological interventions, ketosis is a recently proposed treatment option. Ketosis, defined by elevated concentrations of ketone bodies such as β-hydroxybutyrate (BHB), can be induced by a ketogenic diet or by supplements. As a supplement, both the salt and ester formulation of BHB rapidly increase blood ketone levels. Although preclinical studies have revealed that a ketogenic diet or a mix of ketone supplements reduces alcohol intake and alleviates withdrawal symptoms, the impact of BHB supplements on alcohol-related responses remains to be defined. We first assessed the efficacy of BHB in ester versus salt formulation on general locomotor activity, exogenous ketosis and alcohol-induced locomotor stimulation in male mice. We then investigated the impact of the BHB salt on alcohol intake in male and female rats. In attempts to define mechanisms influenced by the BHB salt, monoamines and their metabolites were measured in the nucleus accumbens (NAc), a brain region associated with alcohol reward. Initial results indicate that the BHB salt had a greater impact on ketone levels, glucose-ketone index and inhibition of alcohol-induced locomotor stimulation compared to the BHB ester, without altering the general locomotor activity. We further found that BHB salt dose-dependently lowered alcohol intake in rats of both sexes and that females responded to lower doses than males. Moreover, BHB salt elevated dopamine and noradrenaline and their metabolites in the NAc of male mice. Overall, this study provides insight into the role of BHB salt in modulating rodent alcohol-related behaviours.