This article reviews scientific advances in the prevention and treatment of substance-use disorder and related developments in public policy. In the past two decades, research has increasingly supported the view that addiction is a disease of the brain. Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned, perhaps because the aberrant, impulsive, and compulsive behaviors that are characteristic of addiction have not been clearly tied to neurobiology. Here we review recent advances in the neurobiology of addiction to clarify the link between addiction and brain function and to broaden the understanding of addiction as a brain disease. We review findings on the desensitization of reward circuits, which dampens the ability to feel pleasure and the motivation to pursue everyday activities; the increasing strength of conditioned responses and stress reactivity, which results in increased cravings for alcohol and other drugs and negative emotions when these cravings are not sated; and the weakening of the brain regions involved in executive functions such as decision making, inhibitory control, and self-regulation that leads to repeated relapse. We also review the ways in which social environments, developmental stages, and genetics are intimately linked to and influence vulnerability and recovery. We conclude that neuroscience continues to support the brain disease model of addiction. Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance addictions and related behavioral addictions (e.g., to food, sex, and gambling) but may also improve our understanding of the fundamental biologic processes involved in voluntary behavioral control. In the United States, 8 to 10% of people 12 years of age or older, or 20 to 22 million people, are addicted to alcohol or other drugs. 1 The abuse of tobacco, alcohol, and illicit drugs in the United States exacts more than $700 billion annually in costs related to crime, lost work productivity, and health care. 2-4 After centuries of efforts to reduce addiction and its related costs by punishing addictive behaviors failed to produce adequate results, recent basic and clinical research has provided clear evidence that addiction might be better considered and treated as an acquired disease of the brain (see Box 1 for definitions of substance-use disorder and addiction). Research guided by the brain disease model of addiction has led to the development of more effective methods of prevention and treatment and to more informed public health policies. Notable examples include the Mental Health Parity and Addiction Equity Act of 2008, which requires medical insurance plans to provide the same coverage for substance-use disorders and other mental illnesses that is provided for other illnesses, 5 and the proposed bipartisan Senate legislation that From the National Institute on Drug Abuse (N.D.V.) and the National Institute of Alcohol Abuse and Alcoholism (G.F.K.) — both in Bethesda, MD; and the Treatment Research Institute, Philadelphia (A.T.M.). Address reprint requests to Dr. Volkow at the National Institute on Drug Abuse, 6001 Executive Bld., Rm. 5274, Bethesda, MD 20892, or at nvolkow@ nida . nih . gov.

Review Article: Neurobiologic Advances from the Brain Disease Model of Addiction

Background and Purpose Standard radiographic criteria for hematoma enlargement have not been established. We undertook this investigation to assess the incidence and time course of hematoma growth using objective cutoff values. Methods We reviewed the clinical records of 204 patients with spontaneous intracerebral hemorrhage treated nonsurgically who underwent initial computed tomography (CT) within 48 hours and repeat CT within 120 hours of the onset of symptoms. The consensus of five observers reading the CT films was considered the “gold standard” for hematoma enlargement. The discriminant values of the difference (V2−V1) or the ratio (V2/V1) of the hematoma volume on the initial (V1) and second (V2) CT scans were determined by use of receiver operating characteristic curves. We chose the cutpoint that had the highest sensitivity and specificity for identifying hematoma expansion. Results The cutpoint for hematoma enlargement was determined as V2−V1=12.5 cm3 or V2/V1=1.4 (sensitivity=94.4%, specificity...

Enlargement of Spontaneous Intracerebral Hemorrhage

Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy.

Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.

/pdf/dihydroartemisinin-induced-unfolded-protein-response-2wkay6qlfl.pdf

Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

Transcriptional control of midbrain dopaminergic neuron development

Human adipose-derived stem cells (huADSC) were generated from fat tissue of a 65-year-old male donor. Flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) analyses indicated that the huADSC express neural cell proteins (MAP2, GFAP, nestin and β-III tubulin), neurotrophic growth factors (BDNF and GDNF), and the chemotactic factor CXCR4 and its corresponding ligand CXCL12. In addition, huADSC expressed the characteristic mesenchymal stem cell (MSC) markers CD29, CD44, CD73, CD90, CD105 and HLA class I. The huADSC were employed, via a right femoral vein injection, to treat rats inflicted with experimental intracerebral hemorrhage (ICH). Behavioral measurement on the experimental animals, seven days after the huADSC therapy, showed a significant functional improvement in the rats with stem cell therapy in comparison with rats of the control group without the stem cell therapy. The injected huADSC were detectable in the brains of the huADSC treated rats as determined by histochemistry analysis, suggesting a role of the infused huADSC in facilitating functional recovery of the experimental animals with ICH induced stroke.

/pdf/human-adipose-derived-stem-cells-for-the-treatment-of-du37qhum1p.pdf

Human adipose-derived stem cells for the treatment of intracerebral hemorrhage in rats via femoral intravenous injection

The endoplasmic reticulum (ER) is an intracellular organelle that performs multiple functions, such as lipid biosynthesis, protein folding, and maintaining intracellular calcium homeostasis. Thus, conditions wherein the ER is unable to fold proteins is defined as ER stress, and an inbuilt quality control mechanism, called the unfolded protein response (UPR), is activated during ER stress, which serves as a recovery system that inhibits protein synthesis. Further, based on the severity of ER stress, the response could involve both proapoptotic and antiapoptotic phases. Intracerebral hemorrhage (ICH) is the second most common subtype of cerebral stroke and many lines of evidence have suggested a role for the ER in major neurological disorders. The injury mechanism during ICH includes hematoma formation, which in turn leads to inflammation, elevated intracranial pressure, and edema. A proper understanding of the injury mechanism(s) is required to effectively treat ICH and closing the gap between our current understanding of ER stress mechanisms and ICH injury can lead to valuable advances in the clinical management of ICH.

https://www.mdpi.com/2073-4409/9/3/750/pdf

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development. Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction. Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits. Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.

https://www.mdpi.com/2073-4409/8/11/1326/pdf

Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats

Objective Alcohol intoxication is associated with worse intracerebral hemorrhage (ICH) outcome, indicating the important role of alcohol in ICH pathogenesis We intended to investigate the effects of ethanol pretreatment on the severity of ICH-induced brain injury in rats Methods At 1 hour after intraperitoneal injection of ethanol (3 g/kg), 02 U bacterial collagenase was infused into the striatum of male Sprague-Dawley rats to induce ICH Accumulative mortality rate, body weight changes, and motorsensory and neurological abnormalities were evaluated The hemorrhagic volume, hematoma expansion, and water content were measured by Drabkin's method, morphometric assay, and dry/wet method, respectively Blood–brain barrier disruption was assessed using Evans blue assay Oxidative stress was evaluated by the enzymatic activity of glutathione peroxidase, oxidation of hydroethidine, and the production of malondialdehyde Cerebral blood flow perfusion volume and hypo-/hyperperfusion neuroimaging were examined by magnetic resonance imaging Results Ethanol pretreatment aggravates the hematoma hemolysis, hemorrhagic volume, hematoma expansion, brain edema, blood–brain barrier disruption, microglial activation, elevated oxidative stress, and neuroinflammation in the hemorrhagic striatum The summation effect of these consequences is the major cause of marked neurological impairment and higher mortality rate (64%) in ethanol-pretreated rats with ICH Conclusion This is a novel model to evaluate the effects of high-dose alcohol administration on experimental ICH rats Implications The present study may provide clues for making novel strategies in the management of patients with ICH who overconsume alcoholic drinks before the attack

Acute Alcohol Intoxication Aggravates Brain Injury Caused by Intracerebral Hemorrhage in Rats.

The production of midbrain dopaminergic (mDA) neurons requires precise extrinsic inductive signals and intrinsic transcriptional cascade at a specific time point in development Urocortin (UCN) is a peptide of the corticotropin-releasing hormone family that mediates various responses to stress UCN was first cloned from adult rat midbrain However, the contribution of UCN to the development of mDA neurons is poorly understood Here, we show that UCN is endogenously expressed in the developing ventral midbrain (VM) and its receptors are exhibited in Nurr1(+) postmitotic mDA precursors and TH(+) neurons, suggesting possible roles in regulating their terminal differentiation UCN treatment increased DA cell numbers in rat VM precursor cultures by promoting the conversion of Nurr1(+) precursors into DA neurons Furthermore, neutralization of secreted UCN with anti-UCN antibody resulted in a reduction in the number of DA neurons UCN induced an abundance of acetylated histone H3 and enhanced late DA regulator Nurr1, Foxa2, and Pitx3 expressions Using pharmacological and RNA interference approaches, we further demonstrated that histone deacetylase (HDAC) inhibition and late transcriptional factors upregulation contribute to UCN-mediated DA neuron differentiation Chromatin immunoprecipitation analyses revealed that UCN promoted histone acetylation of chromatin surrounding the TH promoter by directly inhibiting HDAC and releasing of methyl CpG binding protein 2-CoREST-HDAC1 repressor complex from the promoter, ultimately leading to an increase in Nurr1/coactivators-mediated transcription of TH gene Moreover, UCN treatment in vivo also resulted in increased DA neuron differentiation These findings suggest that UCN might contribute to regulate late mDA neuron differentiation during VM development

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.1949

Hock-Kean Liew

Papers

Human adipose-derived stem cells for the treatment of intracerebral hemorrhage in rats via femoral intravenous injection

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats

Acute Alcohol Intoxication Aggravates Brain Injury Caused by Intracerebral Hemorrhage in Rats.

Epigenetic Regulation Contributes to Urocortin-Enhanced Midbrain Dopaminergic Neuron Differentiation