Addiction Biology最新文献

Dopamine D2 receptor (D2R)-mediated signalling is involved in reward, motivation and alcohol use disorder. Perturbation of the D2R system may influence an individual's response to alcohol. Alternative splicing of the D2R gene generates two isoforms: D2 long form (D2L) and D2 short form (D2S). It is unclear whether differences in the expression of D2L and D2S influence alcohol's effects. Here we examined if altered expression levels of either D2R isoform would influence alcohol effects on reward-related behaviour and relevant signalling pathways using knockout (KO) mice expressing either D2R isoform. We found that D2L KO mice (expressing only D2S) displayed a strong alcohol conditioned place preference (CPP) compared to WT mice and D2S KO mice (expressing only D2L). Alcohol exposure caused a downregulation of cannabinoid 1 receptors (CB1R) expression but an upregulation of cannabinoid 2 receptors (CB2R) expression in the striatum of D2L KO mice but not in WT and D2S KO mice. In addition, alcohol exposure resulted in decreased Akt phosphorylation selectively in D2L KO mice. Furthermore, the gene expressions of tyrosine hydroxylase (TH), Arc and RETN were also selectively downregulated in D2L KO mice following chronic alcohol exposure. Our results indicated that an alteration in the expression of D2S vs. D2L had significant impacts on alcohol-induced reward and gene expression changes in the striatum. These findings suggest that the increased expression level of D2S to D2L may be a pathophysiological mechanism for developing alcoholism, possibly through triggering a cascade of changes in the cannabinoid-Akt signalling pathway and relevant signalling network.

Alcohol misuse remains a leading cause of preventable death worldwide, prompting research into novel pharmacotherapies for alcohol use disorder (AUD). This study investigated the therapeutic potential of full agonism or positive allosteric modulation of the serotonin 2C receptor (5-HT_2CR) in addressing alcohol binge drinking and seeking behaviours in mice. Using a drinking-in-the-dark paradigm and a context-induced reinstatement model following punishment-imposed abstinence, we assessed the acute effects of 5-HT_2CR ligands lorcaserin, CYD-1-79, VA012 and CTW0415 on alcohol intake and seeking behaviours in mice. Results showed that while lorcaserin effectively reduced both alcohol consumption and seeking behaviours, the 5-HT_2CR positive allosteric modulators (PAMs) did not significantly alter these behaviours over the range of doses examined. These findings suggest that 5-HT_2CR PAMs, at the tested doses, may lack intrinsic efficacy in modulating alcohol use. However, our lorcaserin data demonstrate that targeting 5-HT_2CR remains a valid approach to reduce behaviours associated with AUD.

Problematic use of short video (PUSV) refers to a psychological dependency on short-video applications, characterized by an intense attachment and inability to control usage, resulting in typical addiction symptoms. Although PUSV shares similarities with substance addiction, its clinical presentation exhibits significant differences. Notably, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the International Classification of Diseases, 11th Revision (ICD-11), have not yet officially classified PUSV as an addiction disorder. However, the profound impact of short-video platforms on individuals' physical, mental and daily lives necessitates attention to PUSV. To enable more in-depth and standardized research on this issue, synthesizing and organizing existing studies on its theoretical foundations and mechanisms is crucial. This paper aims to integrate and evaluate existing research on PUSV from four perspectives: qualitative analysis, underlying mechanisms, negative effects and measurement tools, providing a more systematic understanding and approach to this emerging issue.

This narrative review examines recent advances in understanding the epigenetic and transcriptional dynamics of the central–medial amygdala across different stages of ethanol use. It covers the various models and protocols of ethanol administration, emphasizing their strengths and limitations in helping understand ethanol-induced changes in brain and behaviour. The findings from protocols utilizing acute, chronic-intermittent ethanol (CIE) and chronic-continuous ethanol (CCE) exposure are summarized into a proposed mechanism of epigenetic dysregulation and neuroadaptation, spanning from initial ethanol exposure to withdrawal and its influence on gene expression and neuronal activity. This review also explores potential epigenetic targets for therapeutic intervention. Understanding the mechanisms that underlie histone remodelling during initial ethanol exposure, chronic exposure, and withdrawal has the potential to elucidate novel cessation strategies tailored to specific stages of alcohol use disorder (AUD).

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.