Addiction Biology最新文献

Evidence indicates that the activity of the infralimbic cortex (IL), as well as its projections to the nucleus accumbens shell (NAshell) and amygdala, following an unreinforced lever press is critical for cocaine extinction learning and retention. It is unclear whether the same neural circuitry is involved in extinction encoding for other classes of addictive drugs, including opioids. In this study, we used a behaviour-controlled optogenetic approach in female and male Sprague–Dawley rats to examine the role of the IL and its projections in the extinction of heroin seeking. Rats first underwent 12+ days of 6- or 3-h heroin self-administration sessions, followed by 12 days of extinction training. Optogenetic inhibition of the IL, IL-NAshell or IL-amygdala pathway was given for 20 s immediately following an unreinforced lever press during the first 5 days of extinction. Unlike cocaine extinction, these manipulations had no effect on lever pressing during extinction training, nor on the retention of extinction learning, as assessed during the subsequent 7 days of extinction without optogenetic inhibition. These results suggest that the extinction of heroin seeking does not involve the same infralimbic mechanisms that are critical for the extinction of cocaine seeking. Although extinction learning did not differ by sex, analyses of self-administration data revealed that females self-administered more heroin than males in 3 h, but not 6 h, self-administration sessions, indicating session length-dependent sex differences in heroin taking.

Family history (FH) of substance use disorders (SUDs) and stressful life events (SLEs) are known risk factors for SUDs in adolescents and young adults. Cross-sectional studies suggest that FH and SLEs affect adolescent white matter (WM) development and form abnormal WM patterns. Here, we examined the effects of FH, SLEs and their interaction on WM integrity in youths in the Adolescent Cognitive Brain Development (ABCD) study at baseline and 2- and 4-year follow-ups. ABCD youths (N = 8939, age ± SD = 9.9 ± 0.6 years, 4302 female) completed baseline diffusion tensor imaging, of which 5661 repeated the scan at 2-year follow-up (age ± SD = 12.0 ± 0.7 years, 2634 female) and 2177 at 4-year follow-up (age ± SD = 14.1 ± 0.7 years, 1007 female). FH was measured as the weighted sum of biological parents and grandparents with alcohol and/or drug problems. SLEs were measured with parental report of life events. WM integrity was measured with fractional anisotropy (FA) of 23 WM tracts. Linear mixed effect models were used to examine the effects of FH, SLEs and their interaction on FA at baseline and longitudinally, modelling family and study site as random intercepts and correcting for multiple comparisons with false discovery rate (FDR) q = 0.05. At baseline, there were no significant effects of FH, SLEs and their interaction on FA after multiple comparison correction when controlling for race, family income and parental education. From baseline to 4-year follow-up, FH significantly negatively interacted with newly occurred SLEs on FA in 19 out of 23 tracts, so that FA at 4-year was lower in youths with both FH and newly occurred SLEs when controlling for baseline FA (β_interaction = −0.049 − −0.018, p_FDR = 6.2 × 10⁻⁵ − 4.7 × 10⁻²). These negative interactions were not significant with shorter time spans (baseline to 2-year follow-up and 2- to 4-year follow-up). In conclusion, we replicated findings from cross-sectional cohorts of the effects of FH and SLEs on lower WM integrity in youths. The study utilized Big Data longitudinal design to show that FH-by-SLE interaction, rather than their independent effects was responsible for developmental WM changes associated with FH of SUDs and life stressors.

Alcohol use disorder (AUD) is associated with a loss of control over alcohol use, putatively driven by maladaptive changes in neural circuitries, including the basolateral amygdala (BLA). The BLA, known for its role in emotional regulation and associative learning, contributes to the reinforcement of alcohol-related behaviours, making it a critical target for understanding the underlying mechanisms of vulnerability to AUD. To further outline the role of BLA neurotransmission in AUD, we combined a multisymptomatic 0/3 criteria rodent model with electrophysiological whole-cell recordings to identify the association between neurophysiological parameters in the BLA and vulnerability to AUD-like progression. Our results demonstrate that when assessed after 4 months of voluntary alcohol consumption, rats can be subcategorized as resilient or vulnerable to AUD-like behaviour. Electrophysiological recordings, performed directly after alcohol self-administration, demonstrated that rats manifesting an AUD-like vulnerable phenotype presented a reduced frequency and amplitude of spontaneous excitatory post-synaptic currents (sEPSCs), indicating suppressed activation via glutamatergic inputs. Disinhibition induced by GABAA receptor antagonist did not differ between groups, and field potential recordings demonstrated reduced stimulus/response curves further supporting a hypoglutamatergic state. Additionally, the intrinsic excitability of BLA neurons was selectively decreased in vulnerable rats compared to both resilient and water control rats. Importantly, addiction score correlated with both synaptic transmission and intrinsic excitability of BLA neurons. Overall, our findings suggest that hypoexcitability of BLA neurons may represent a neurobiological underpinning that contributes to the development and persistence of alcohol addiction-like behaviours following protracted alcohol exposure.

Alcohol use disorder (AUD) represents a significant challenge in mental health. Severe AUD is characterized by uncontrolled alcohol consumption and is associated with dysregulation in brain circuits responsible for reward, motivation, decision-making, affect, and stress response. Mindfulness is known to positively influence those dysregulations and may enhance abstinence-related self-efficacy (confidence in resisting alcohol consumption), which is one of the best predictors for abstinence following inpatient treatment. Large-scale networks underlie mindfulness, including the default mode and salience network. This study aims to investigate the role of the cingulum bundle (CB) in patients with AUD, which bridges these two networks in relation to mindfulness and abstinence-related self-efficacy. We conducted a study with 39 recently abstinent inpatients with AUD and 18 healthy controls. Mindfulness and self-efficacy were assessed using standardized and validated self-report questionnaires. Structural and resting state functional magnetic resonance imaging (MRI) data were acquired to examine structural and functional connectivity of the cingulate cortex. Our findings showed reduced structural and functional connectivity of the CB in AUD patients with a highly positive association between these metrics. Overall, mindfulness correlated strongly with abstinence-related self-efficacy. We found no association of trait mindfulness and structural and functional findings of the cingulate cortex. However, exploratory analyses suggest a positive association between CB number of streamlines and mindfulness factors ‘acceptance’ and ‘decentring’, and abstinence-related self-efficacy. This is the first study indicating that patients with AUD have structural and functional impairments of the CB. These alterations could be associated with reduced mindfulness and self-efficacy.

Cocaine use disorder (CUD) lacks FDA-approved treatments, partly due to the difficulty of creating therapeutics that target behaviour-related neural circuits without disrupting signalling throughout the brain. One promising candidate for circuit-selective neuromodulation is pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with pleiotropic behavioural actions whose signalling network spans the gut–brain axis. Here, we investigated the potential existence and function of an endogenous PACAP signalling network within the nucleus accumbens core (NAcc), which is a structure that integrates emotional, cognitive and reward processes underlying behaviour. We found that PACAP and its cognate receptor, PAC1R, are endogenously expressed in the rat NAcc and that PACAP mRNA is present in medial prefrontal cortical projections to the NAcc. Behaviourally, intra-NAcc infusions of PACAP_1–38 (450 ng/500 nL) did not induce seeking behaviour. Instead, it blocked cocaine-primed reinstatement (10 mg/kg, intraperitoneal [ip]). Intra-NAcc PACAP_1–38 (450 ng/500 nL) also blocked reinstatement driven by coinfusion of the D1-like dopamine receptor agonist (SKF81297, 3 μg/500 nL) but not the D2-like dopamine receptor agonist (sumanirole, 100 ng/500 nL). These findings are notable because previous studies have shown D1-like and D2-like dopamine receptors in the NAcc regulate distinct processes and circuits. Collectively, these studies provide novel insights into the behaviour-modulating actions of central PACAP signalling within the NAcc. Taken together with prior findings, the results underscore the need for additional research to reveal the precise behavioural processes and mechanisms that can be regulated by the full PACAP signalling network, which may reveal how to target this system to develop targeted therapeutics.

Valproate may hold promise as a treatment for addiction. However, there are limited studies examining the effects of magnesium valproate (VPA-Mg) on methamphetamine (MA) addiction, and the relevant mechanisms have not been thoroughly discussed. This study aims to explore the potential therapeutic effects of VPA-Mg on MA addiction and to investigate its possible mechanisms. The effects of VPA-Mg on MA addiction were investigated using conditioned place preference (CPP) and behavioural sensitisation models in rats. VPA-Mg was administered during CPP formation and extinction phases to evaluate its effects on MA-induced CPP formation and reinstatement. Behavioural sensitisation assessed the impact of VPA-Mg during sensitisation induction and expression phases, with spontaneous activity and MA dosing optimised beforehand. Furthermore, western blotting was performed on brain regions including the prefrontal cortex (PFC), hippocampus (Hip), nucleus accumbens (NAc) and ventral tegmental area (VTA) to measure glycogen synthase kinase 3 beta (GSK-3β) and dopamine transporter (DAT) protein levels. VPA-Mg did not exhibit a significant impact on MA-induced CPP formation. VPA-Mg significantly reduced the establishment and expression of MA-induced behavioural sensitisation (p < 0.01). Pre-treatment with VPA-Mg for 3 days before the expression period also inhibited sensitisation (p < 0.05). In addition, the ratio of p-GSK-3β to t-GSK-3β in the PFC, Hip and VTA of rats with behavioural sensitisation significantly decreased, and the expression of DAT decreased significantly (p < 0.01). VPA-Mg can reverse the increase in GSK-3β activity in the Hip and the decrease in DAT in the PFC and Hip caused by repeated MA use (p < 0.05). VPA-Mg exhibits anti-addictive effects on MA dependence and relapse prevention. GSK-3β activation and DAT downregulation in addiction-related brain regions (PFC, Hip, VTA) are closely linked to MA addiction, suggesting potential therapeutic targets. VPA-Mg may exert its effects by modulating these pathways, particularly in the PFC and Hip.

Unique populations of basolateral amygdala (BLA) neurons regulate anxiety and reward through projections targeting downstream regions like the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAC). We showed previously that withdrawal from chronic ethanol exposure (CIE/WD) produced population- and sex-specific alterations to distinct glutamatergic inputs. The current study examined GABAergic function in these distinct populations (BLA^NAC and BLA^BNST neurons). We found that CIE/WD diminished feed-forward GABA release from lateral paracapsular cells (LPCs) specifically onto male BLA^NAC neurons. Pharmacological manipulations showed this dysregulation was caused by the enhanced activity of μ-opioid receptors. CIE/WD did not alter evoked GABA release from local interneurons onto either population. However, females expressed greater GABA release from these local interneurons compared to males. Immunostaining and confocal microscopy revealed lower colocalization between the GABA vesicular transporter, vGAT and parvalbumin in females, indicating that greater GABA releases from local interneurons in this sex may be a compensatory response to lower levels of perisomatic innervation by PV⁺ interneurons. Consistent with this, there were no sex differences related to spontaneous GABAergic synaptic events although CIE/WD decreased their frequency specifically in BLA^BNST neurons from both sexes. Altogether, these findings demonstrate that CIE/WD dynamically alters GABAergic function in an input-, sex- and population-specific fashion. Moreover, there are basal sex differences in both the anatomy of BLA GABAergic synapses and their function.

Alcohol use disorder (AUD) is associated with chronic inflammation and immune dysregulation, yet no validated immune-based markers exist to support assessment or monitoring. This study identifies interleukin-1 beta (IL-1β) in whole blood as a promising candidate biomarker of AUD risk, based on Alcohol Use Disorders Identification Test (AUDIT) scores. Twenty-eight non–treatment-seeking adults, with AUDIT scores between 2 and 22, provided whole blood samples. We aimed to identify biomarkers that signal immune changes associated with early AUDIT score risk, where interventions may be most effective. Luminex multiplex immunoassays quantified 14 immune-related mediators in combined cell lysates and supernatants. IL-1β, IL-18, IL-7 and CCL11 were significantly elevated in individuals with higher AUDIT scores. IL-1β showed the largest effect size (Cohen's d) and was the most consistent predictor of both AUDIT and AUDIT-Consumption (AUDIT-C) scores across random forest and linear regression analyses. Moderated multiple regression (MMR) confirmed that IL-1β predicted both scores independent of other immune mediators. Receiver operating characteristic (ROC) analyses demonstrated discriminative potential, with IL-1β achieving an AUC of 0.81 (good discrimination) for AUDIT ≥ 6 (true positive rate [TPR] = 0.71; false positive rate [FPR] = 0.14) and an AUC of 0.94 (excellent discrimination) for AUDIT-C thresholds (TPR = 0.80; FPR = 0.00). Principal component analysis (PCA) revealed greater immune variability in the high-risk group, particularly among proinflammatory mediators, suggesting immune dysregulation. This study demonstrates the utility of integrating whole blood immune profiling with high-sensitivity multiplex immunoassays, and applying both traditional statistical methods and machine learning to explore potential biomarkers for AUD risk. IL-1β is a statistically robust and clinically relevant candidate biomarker of AUD risk assessed by AUDIT scores. These findings require replication in larger, independent samples to determine their translational potential in addiction medicine.

This study aimed to investigate the role of LVV-hemorphin-7 (LVV-H7) in alcohol dependence. LVV-H7 is a short peptide derived from the cleavage of haemoglobin chains that binds to opioid receptors and plays diverse roles in various physiological and pathological processes. Additionally, LVV-H7 is cleaved at higher concentrations in the presence of alcohol. We conducted behavioural experiments in animal models and performed proteomic analyses of CNS tissues from alcohol-addicted rats to identify LVV-H7 binding partners. Using fluorescent microscopy, we confirmed the blood–brain barrier (BBB) permeability of synthesized LVV-H7 and its releasing enzyme inhibitor, pepstatin. Our results revealed a dose-dependent correlation between LVV-H7 quantities and alcohol levels. Mass spectrometry-based analyses identified LVV-H7's protein-binding targets in CNS tissues of addicted rats and the enzymes responsible for their degradation. These findings highlight the significant role of LVV-H7 in the mechanisms underlying alcohol dependence and indicate the potential role of hemorphin as a therapeutic target.