Although the angiotensin II type 1 receptor (AT1R), a pivotal component of the renin-angiotensin system (RAS), is associated with cardiovascular and renal homeostasis, burgeoning evidence implicates its critical role in neuropsychiatric disorders, particularly addiction. Beyond regulating haemodynamics, AT1R activation in the central nervous system (CNS) modulates neuroinflammatory cascades, dopaminergic signalling plasticity, and stress-responsive neural circuit processes central to addiction pathophysiology. Notably, preclinical studies reveal that AT1R blockade attenuates drug-seeking behaviours by normalizing mesolimbic dopamine dysregulation and reducing glutamatergic excitotoxicity in the nucleus accumbens. This review systematically integrates contemporary evidence elucidating the dual pathophysiological roles of AT1R in CNS disorders, with particular emphasis on neurodegenerative diseases and psychiatric conditions. Crucially, we delineate two mechanistically distinct yet interconnected functions of AT1R: (1) serving as a critical mediator of maladaptive neuroplasticity during protracted exposure to addictive substances and (2) functioning as a regulator of blood-brain barrier (BBB) integrity, thereby potentiating neurotoxicant infiltration in substance use disorders. Building upon these mechanistic insights, we propose a translational framework for repurposing clinically approved AT1R antagonists as novel pharmacotherapies targeting addiction-related neurocircuitry dysregulation. By bridging molecular insights with translational opportunities, this work positions AT1R as a novel therapeutic target to address unmet clinical needs in addiction.

Drug addiction is characterized by compulsive drug use despite negative consequences, reflecting maladaptive changes in brain circuits. Elucidating the underlying neural mechanisms relies on animal models that capture core features of the disorder. Here, we review optogenetic mimicry mouse models that leverage a defining core of addictive drugs-their ability to elevate mesolimbic dopamine. Analogous to gold-standard pharmacological self-administration paradigms, these models allow animals to self-induce dopamine transients either directly, via optogenetic activation of ventral tegmental area dopamine neurons, or indirectly, via optogenetic inhibition of midbrain GABA interneurons. Both protocols are robustly reinforcing and induce lasting behavioral and synaptic adaptations. We compare these adaptations with those observed in established rodent models of psychostimulant and opioid addiction. We argue that optogenetic mimicry of drug-evoked mesolimbic dopamine transients recapitulates key features of addiction while uniquely enabling cell-type- and circuit-specific mechanistic investigations of reinforcement and maladaptive plasticity.

Our prior research revealed that dietary nitrate (NO₃⁻) may mitigate alcohol-induced cognitive impairment through oral microbiota modulation and attenuation of inflammatory responses in mice. While alcohol use disorder (AUD) is known to associate with cognitive decline and gut dysbiosis, the therapeutic potential of nitrate supplementation in ameliorating these effects remains to be elucidated. In this randomized, double-blind, placebo-controlled pilot trial (NCT05963659), 70 AUD patients received either nitrate-rich beetroot juice or placebo for 14 days. Primary outcomes were spatial memory measured by Cambridge Neuropsychological Test Battery. Oral and gut microbiota were analyzed before and after intervention by 16S rRNA sequencing. To establish causality, germ-free (GF) mice were colonized with pre- and post-nitrate intervention saliva samples from AUD patients, followed by microbiota profiling across gastrointestinal regions. The mean difference in Delayed Matching to Sample (all delays) change between the nitrate consumption group and the placebo group after intervention was 9.784 (95%[CI], 1.85-17.72, P = 0.016), as analyzed using a generalized linear mixed model. Nitrate supplementation induced distinct shifts in oral microbiota, while gut microbiota exhibited less pronounced changes. GF mice receiving pre-intervention microbiota exhibited elevated Klebsiella abundance throughout the gut. Mechanistically, nitrate attenuated systemic inflammation, enhanced intestinal barrier integrity, and improved cognitive performance in mice. Dietary nitrate enhances cognitive function in AUD patients, partially mediated by ectopic colonization of oral microbiota. Our findings identify specific oral bacteria (e.g., Klebsiella) as key contributors to alcohol-induced cognitive impairment and suggest promising therapeutic potential for microbiota-targeted interventions in AUD.

Methamphetamine (METH) addiction is associated with progressive cognitive decline and maladaptive behaviors, but the molecular mechanisms bridging proteostatic dysfunction to neural circuit degeneration remain poorly defined. We hypothesized that METH hijacks chaperone-mediated autophagy (CMA), a lysosomal quality-control pathway, to drive neurodegeneration through ferroptosis. Using chronic METH self-administration models, hippocampal neurons, and CMA-targeted approaches, we demonstrated that METH coerces CMA components (HSC70-LAMP2A) to recognize a non-canonical 124NVKFD128 degron on glutathione peroxidase 4 (GPX4), resulting in its lysosomal degradation. This CMA-dependent GPX4 depletion disrupted glutathione recycling, unleashing lethal lipid peroxidation and hippocampal ferroptosis. Critically, neuronal CMA ablation rescued spatial memory deficits and reduced compulsive drug-seeking behaviors, establishing CMA hyperactivity as a causal driver of addiction-related neuropathology. Our findings extend the oxidative stress-centric model of METH toxicity by revealing CMA as a pathological switch that converts physiological proteostasis into a self-destructive cascade. The CMA-GPX4 axis, mechanistically linking protein quality control failure, iron-dependent cell death, and behavioral dysfunction, represents a druggable target, with CMA inhibitors showing preclinical efficacy in mitigating METH-induced neuropsychiatric deterioration. By redefining addiction-associated neurodegeneration as a disorder of hijacked proteostasis, this work provides a unified framework for targeting shared mechanisms in substance use disorders and neurodegenerative diseases.

AIM:This cross-sectional study was designed to investigate potential differences in the prevalence of suicidal ideation and its associated factors between young and elderly patients with chronic schizophrenia (SCZ). METHODS:A total of 812 chronic SCZ inpatients were recruited, and information regarding their sociodemographic and clinical characteristics was gathered. Patients were classified into two age groups: young (18-49 years, n = 430) and elderly (50 years and above; n = 382). The Beck Suicide Ideation Scale-Chinese Version (BSI-CV) was used to evaluate the presence of suicidal ideation. RESULTS:The prevalence of suicidal ideation observed among individuals with chronic SCZ stood at 21.18 %. The prevalence of suicidal ideation was markedly elevated in the young group compared to the elderly group (26.05 % VS 15.71 %, χ2 = 12.954, p < 0.001). The PANSS depression factor score was notably elevated in the young group than in the elderly group (p = 0.002). Binary logistic regression analysis indicated that the presence of suicidal ideation in young group was associated with severe PANSS depression factor, severe PANSS positive symptom and poor sleep quality. In the elderly group, the presence of suicidal ideation was only associated with severe PANSS depression factor. CONCLUSION:The results indicate that young SCZ patients experienced more pronounced suicidal ideation compared to their elderly counterparts, and the clinical factors associated with suicidal ideation differed between these two groups. These findings hold important potential clinical implication for developing prevention strategies tailored to SCZ patients of different age groups.

Propofol addiction represents a significant clinical challenge with no approved pharmacotherapy. While cognitive decline is a hallmark of substance use disorders, its underlying mechanisms in propofol addiction remain unclear. This study investigates whether propofol abuse induces neuronal senescence and cognitive impairment and explores the involved molecular pathways. We found that propofol administration in mice led to significant learning and memory deficits, which were associated with p16INK4a-dependent neuronal senescence in the hippocampus. Knockdown of p16INK4a alleviated both senescence and cognitive decline. Mechanistically, propofol triggered autophagic degradation of ADAR1 via LC3-binding motifs, leading to reduced SIRT1 expression and subsequent upregulation of p16INK4a. Both neuronal-specific and systemic inhibition of autophagy attenuated propofol-induced senescence, cognitive impairment, and addictive behaviors. Our findings reveal a novel ADAR1-SIRT1- p16INK4a pathway mediated by autophagy in propofol addiction, suggesting that targeting autophagy or senescence may offer therapeutic strategies for treating propofol use disorder.

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder.

Background The prevalence of youth depression is rising, making the identification of reliable biomarkers for early detection increasingly challenging. This study explores potential biomarkers in youth experiencing their first depressive episode, with comorbid anxiety, and metabolic or thyroid imbalances. Methods We recruited 399 participants and measured thyroid stimulating hormone (TSH), triiodothyronine (FT3), free thyroxine (FT4), fasting blood glucose (FBG), cholesterol levels, body mass index (BMI), and blood pressure. Results Participants with abnormal TSH levels exhibited longer durations of depression, higher rates of suicidal behavior, increased anxiety, and more severe psychotic symptoms. Significant differences were observed in FBG, cholesterol levels, blood pressure, and BMI. Suicidal behavior was associated with higher TSH levels, anti-thyroglobulin antibodies (A-TG), and total cholesterol (TC), as well as lower high-density lipoprotein cholesterol (HDL-C) and BMI. Conclusions Our findings indicate a higher incidence of suicidal behaviors in youth with major depressive disorder (MDD) and comorbid anxiety symptoms. Elevated TSH levels, abnormal TC and HDL-C levels, and metabolic dysfunctions are significant risk factors. These findings underscore the importance of monitoring these biomarkers in managing youth with MDD.

Background Polypharmacy increases the risk of potential drug-drug interactions (pDDIs). This retrospective analysis was conducted to detect pDDIs and adverse drug reactions (ADRs) among older adults with psychiatric disorder, and identify pDDIs with clinical significance. Methods A retrospective analysis was carried out based on the medical records of older adults with psychiatric disorders. Data on demographic characteristics, substance abuse, medical history, and medications were extracted. The Lexi-Interact online database was used to detect pDDIs. The minimal clinically important difference (MCID) was set as the change in the Treatment Emergent Symptom Scale (TESS) score between admission and discharge. The median and interquartile ranges were used for continuous variables, and frequencies were calculated for dichotomous variables. Poisson regression was implemented to determine the factors influencing the number of ADR types. The influencing factors of each ADR and the clinical significance of the severity of the ADR were analysed using binary logistic regression. P < 0.05 was considered statistically significant. Results A total of 308 older adults were enrolled, 171 (55.52%) of whom had at least 1 pDDI. Thirty-six types of pDDIs that should be avoided were found, and the most frequent pDDI was the coadministration of lorazepam and olanzapine (55.5%). A total of 26 ADRs induced by pDDIs were identified, and the most common ADR was constipation (26.05%). There was a 9.4 and 10.3% increase in the number of ADR types for each extra medical diagnosis and for each extra drug, respectively. There was a 120% increase in the number of ADR types for older adults hospitalized for 18-28 days compared with those hospitalized for 3-17 days. There was an 11.1% decrease in the number of ADR types for each extra readmission. The length of hospitalization was a risk factor for abnormal liver function (P < 0.05). The use of a large number of drugs was a risk factor for gastric distress (P < 0.05) and dizziness and fainting (P < 0.05). None of the four pDDIs, including coadministrations of olanzapine and lorazepam, quetiapine and potassium chloride, quetiapine and escitalopram, and olanzapine and clonazepam, showed clinical significance of ADR severity (P > 0.05). Conclusions pDDIs are prevalent in older adults, and the rate is increasing. However, many pDDIs may have no clinical significance in terms of ADR severity. Further research on assessing pDDIs, and possible measures to prevent serious ADRs induced by DDIs is needed to reduce the clinical significance of pDDIs.

Methamphetamine(METH)is a powerful stimulant drug that can cause addiction and serious health problems.It is one of the most widely abused drugs in the world.However,the mechanisms of how METH affects the brain and leads to addiction are still unclear,and there are no effective treatments for METH addiction in clinical practice.Therefore,it is important to explore the new addiction mechanisms and treatment strategies of METH.METH addiction is a complex and chronic brain disorder that involves multiple brain regions and neurotransmitter systems.Neurotransmitters are chemical messengers that transmit signals between neurons(nerve cells)in the brain.Some of the main neurotransmitters involved in METH addiction are dopamine(DA),glutamate(Glu),norepinephrine(NE),and serotonin(SNRIS).These neurotransmitters regulate various aspects of brain function,such as reward,reinforcement,motivation,cognition,emotion,and behavior.When a person takes METH,it causes a surge of these neurotransmitters in the brain,especially in the prefrontal cortex(mPFC),ventral tegmental area(VTA),and nucleus accumbens(NAc).These brain regions form a circuit called the mesocorticolimbic system,which is responsible for mediating the rewarding and reinforcing effects of drugs and natural stimuli.The increased levels of neurotransmitters in this circuit make the person feel euphoric,alert,confident,and energetic.However,repeated or chronic use of METH can also cause negative effects,such as anxiety,paranoia,psychosis,depression,and cognitive impairment.The effects of METH on the brain are not only due to the changes in neurotransmitter levels,but also to the changes in gene expression.Gene expression is the process by which genes are turned on or off to produce proteins that perform various functions in the cells.Gene expression can be influenced by environmental factors,such as drugs,stress,diet,etc.One way that environmental factors can affect gene expression is through epigenetic mechanisms.Epigenetics is a branch of genetics that studies the heritable changes in gene expression that are not caused by changes in DNA sequence.Epigenetic mechanisms include histone modifications,DNA methylation,and non-coding RNA regulation.These mechanisms can modulate the chromatin structure and accessibility,thereby affecting the transcriptional activity of genes.Chromatin is a complex of DNA and proteins that forms the chromosomes in the nucleus of the cell.The chromatin structure can be altered by adding or removing chemical groups to histones(proteins that wrap around DNA)or DNA itself.These chemical groups can either activate or repress gene expression by changing the affinity of transcription factors(proteins that bind to DNA and initiate transcription)or other regulatory molecules.Non-coding RNAs are RNA molecules that do not code for proteins but can regulate gene expression by interacting with DNA,RNA,or proteins.Epigenetic mechanisms provide a link between environmental stimuli and gene expression,and play an important role in various physiological and pathological processes,including drug addiction.Recent studies have shown that epigenetic mechanisms are involved in the regulation of neurotransmitter systems and neural plasticity in response to METH exposure.Neural plasticity is the ability of neurons to change their structure and function in response to experience or injury.Neural plasticity is essential for learning,memory,adaptation,and recovery.The expression of some genes related to METH addiction is altered by epigenetic modifications,such as histone acetylation,methylation,ubiquitination,and non-coding RNA regulation.These epigenetic changes may affect the synaptic function and morphology,neuronal connectivity,and circuitry formation in the brain regions implicated in METH addiction.Moreover,some epigenetic modifications may persist for a long time after METH withdrawal,suggesting that they may contribute to the development and maintenance of METH addiction.In this article,we review the current literature on the epigenetic mechanisms of METH addiction.We will first introduce METH and its pharmacological effects,and then discuss the epigenetic regulation of neurotransmitter systems and neural plasticity by METH.We will focus on the changes of histone,DNA,and RNA during METH addiction,and the possible causes and consequences of their relationship with METH addiction.We will also provide some perspectives on the potential applications of epigenetic interventions for METH addiction treatment.

Macroautophagy, a universal cellular process, sends cellular material to lysosomes for breakdown and is often activated by stressors like hypoxia or drug exposure. It is vital for protein balance, neurotransmitter release, synaptic function, and neuron survival. The role of macroautophagy in substance use disorders is dual. On one hand, substances like cocaine, methamphetamine, opiates, and alcohol can activate macroautophagy pathways to degrade various neuroinflammatory factors in neuronal cells, providing a protective function. On the other hand, long-term and excessive use of addictive substances can inhibit macroautophagy pathways, obstructing the fusion of autophagosomes with lysosomes and losing the original protective function. This review first summarizes the key proteins and signaling pathways involved in macroautophagy, including mTORC1, AMPK, and endoplasmic reticulum stress, and suggests that the regulation of macroautophagy plays a central role in drug-rewarding behavior and addiction. Second, we focus on the interactions between macroautophagy and neuroinflammation induced by drugs, evaluating the potential of macroautophagy modulators as therapeutic strategies for substance use disorder (SUD), and identifying autophagy-related biomarkers that can be used for early diagnosis and monitoring of treatment response. Our review summarizes the important scientific basis involved in macroautophagy pathways for the development of new therapies for SUD.

The radical relay provides an effective paradigm for intermolecular assembly to achieve functionalization across remote chemical bonds. Herein, we report the first radical relay 1,3-carbocarbonylation of alpha-carbonyl alkyl bromides across two separate C=C bonds. The reaction is highly chemo- and regioselective, with two C(sp(3))-C(sp(3)) bonds and one C=O bond formed in a single orchestrated operation. In addition, the synthesis method under mild conditions and using inexpensive copper as the catalyst allows facile access to structurally diverse 1,3-carbocarbonylation products. The plausible mechanism is investigated through a series of control experiments, including radical trapping, radical clock experiments, critical intermediate trapping, and O-18 labeling experiment.

Objective: Methamphetamine (METH) exposure commonly causes cognitive impairment. An angiotensin II receptor/neprilysin inhibitor (ARNI), LCZ696 has been demonstrated to inhibit inflammation, oxidative stress and apoptosis. The present study was designed to examine the effect of LCZ696 on METH-induced cognitive impairment and the underlying mechanism. Methods: Following daily treatment of either saline or METH (5 mg/kg) for 5 consecutive days, the cognitive function was tested using the Y-maze and the Novel Object Recognition (NOR) in Experiment 1. In Experiment 2, mice were initially treated with saline or LCZ696 (60 mg/kg) for 9 consecutive days, followed by LCZ696, METH or saline for 5 days. Cognitive testing was carried out as Experiment 1. In Experiment 3, SH-SY5Y cells were treated with either METH (2.5 Mm) or ddH2O for 12 h. The apoptosis and reactive oxygen species (ROS) level of SH-SY5Y were examined. In Experiment 4, SH-SY5Y cells were pretreated with either ddH2O or LCZ696 (70um) for 30 min, followed by ddH2O or METH treatment for 12 h. Nrf2 and HO-1 protein expression was examined in the ventral tegemental area (VTA) of all the animals and SH-SY5Y cells. Results: LCZ696 significantly improved METH-induced cognitive impairment, in conjunction with decreased apoptosis and ROS levels in VTA of METH-treated mice and SH-SY5Y cells. METH significantly decreased Nrf2 and HO-1 protein expression in VTA of mice and SH-SY5Y cells, which was reversed by LCZ696 treatment. Conclusion: LCZ696 yields a neuroprotective effect against METH-induced cognitive dysfunction via the Nrf2/ HO-1 signaling pathway.

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder

Rationale The rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R). Objectives This study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH. Methods C57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH. Results METH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc. Conclusion These results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.

Chronic exposure to methamphetamine (METH) has been suggested to cause METH use disorder and severe cognitive impairment. Paeoniflorin (PF) is a monoterpenoid glycoside with various beneficial effects, including anti-inflammatory, antioxidant and antidepressant. The current study was designed to investigate the effect of PF (30 mg/kg, i.p.) on the rewarding effect of METH (2.5 mg/kg, i.p.) and the associated cognitive impairment, using the animal model of conditioned place preference, new location reorganization test, new object reorganization test and Y-maze test. METH induced conditioned place preference, accompanied by increased expression of synapse-associated proteins in the ventral target areas (VTA) and nucleus accumbens (NAc). In addition, METH induced significant cognitive impairment and decreased the expression of synapse-associated proteins in the hippocampus (Hip). Administration of PF decreased the rewarding effect of METH and the expression of synapse-associated proteins in the VTA or NAc. PF was also effective to improve METH-induced cognitive impairment by upregulating the expression of synapse-associated proteins in the Hip. Therefore, PF could be a potential agent for the treatment of METH use disorder and the associated cognitive impairment.