Targeting the cytoskeleton as a therapeutic approach to substance use disorders.

Substance use disorders (SUD) are chronic relapsing disorders governed by continually shifting cycles of positive drug reward experiences and drug withdrawal-induced negative experiences. A large body of research points to plasticity within systems regulating emotional, motivational, and cognitive processes as drivers of continued compulsive pursuit and consumption of substances despite negative consequences. This plasticity is observed at all levels of analysis from molecules to networks, providing multiple avenues for intervention in SUD. The cytoskeleton and its regulatory proteins within neurons and glia are fundamental to the structural and functional integrity of brain processes and are potentially the major drivers of the morphological and behavioral plasticity associated with substance use. In this review, we discuss preclinical studies that provide support for targeting the brain cytoskeleton as a therapeutic approach to SUD. We focus on the interplay between actin cytoskeleton dynamics and exposure to cocaine, methamphetamine, alcohol, opioids, and nicotine and highlight preclinical studies pointing to a wide range of potential therapeutic targets, such as nonmuscle myosin II, Rac1, cofilin, prosapip 1, and drebrin. These studies broaden our understanding of substance-induced plasticity driving behaviors associated with SUD and provide new research directions for the development of SUD therapeutics.

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice.

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.

TAAR1 as an emerging target for the treatment of psychiatric disorders.

Trace amines, a group of amines expressed at the nanomolar level in the mammalian brain, can modulate monoamine transmission. The discovery of and the functional research on the trace amine-associated receptors (TAARs), especially the most well-characterized TAAR1, have largely facilitated our understanding of the function of the trace amine system in the brain. TAAR1 is expressed in the mammalian brain at a low level and widely distributed in the monoaminergic system, including the ventral tegmental area and substantial nigra, where the dopamine neurons reside in the mammalian brain. Growing in vitro and in vivo evidence has demonstrated that TAAR1 could negatively modulate monoamine transmission and play a crucial role in many psychiatric disorders, including schizophrenia, substance use disorders, sleep disorders, depression, and anxiety. Notably, in the last two decades, many studies have repeatedly confirmed the pharmacological effects of the selective TAAR1 ligands in various preclinical models of psychiatric disorders. Recent clinical trials of the dual TAAR1 and serotonin receptor agonist ulotaront also revealed a potential efficacy for treating schizophrenia. Here, we review the current understanding of the TAAR1 system and the recent advances in the elucidation of behavioral and physiological properties of TAAR1 agonists evaluated both in preclinical animal models and clinical trials. We also discuss the potential TAAR1-dependent signaling pathways and the cellular mechanisms underlying the inhibitory effects of TAAR1 activation on drug addiction. We conclude that TAAR1 is an emerging target for the treatment of psychiatric disorders.

miRNAs and Substances Abuse: Clinical and Forensic Pathological Implications: A Systematic Review.

Substance addiction is a chronic and relapsing brain disorder characterized by compulsive seeking and continued substance use, despite adverse consequences. The high prevalence and social burden of addiction are indisputable; however, the available intervention is insufficient. The modulation of gene expression and aberrant adaptation of neural networks are attributed to the changes in brain functions under repeated exposure to addictive substances. Considerable studies have demonstrated that miRNAs are strong modulators of post-transcriptional gene expression in substance addiction. The emerging role of microRNA (miRNA) provides new insights into many biological and pathological processes in the central nervous system: their variable expression in different regions of the brain and tissues may play a key role in regulating the pathophysiological events of addiction. This work provides an overview of the current literature on miRNAs involved in addiction, evaluating their impaired expression and regulatory role in neuroadaptation and synaptic plasticity. Clinical implications of such modulatory capacities will be estimated. Specifically, it will evaluate the potential diagnostic role of miRNAs in the various stages of drug and substance addiction. Future perspectives about miRNAs as potential novel therapeutic targets for substance addiction and abuse will also be provided.

Recognition of methamphetamine and other amines by trace amine receptor TAAR1.

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous ß-phenylethylamine (ß-PEA)1 as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and ß-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

Addictive drugs modify neurogenesis, synaptogenesis and synaptic plasticity to impair memory formation through neurotransmitter imbalances and signaling dysfunction.

Drug abuse changes neurophysiological functions at multiple cellular and molecular levels in the addicted brain. Well-supported scientific evidence suggests that drugs negatively affect memory formation, decision-making and inhibition, and emotional and cognitive behaviors. The mesocorticolimbic brain regions are involved in reward-related learning and habitual drug-seeking/taking behaviors to develop physiological and psychological dependence on the drugs. This review highlights the importance of specific drug-induced chemical imbalances resulting in memory impairment through various neurotransmitter receptor-mediated signaling pathways. The mesocorticolimbic modifications in the expression levels of brain-derived neurotrophic factor (BDNF) and the cAMP-response element binding protein (CREB) impair reward-related memory formation following drug abuse. The contributions of protein kinases and microRNAs (miRNAs), along with the transcriptional and epigenetic regulation have also been considered in memory impairment underlying drug addiction. Overall, we integrate the research on various types of drug-induced memory impairment in distinguished brain regions and provide a comprehensive review with clinical implications addressing the upcoming studies.

Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders.

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the pathogenesis of SUDs. Several neuroimmune signaling pathways, including TLR/NF-кB, reactive oxygen species, mitochondria dysfunction, as well as autophagy defection, etc., have been implicated in promoting SUDs. Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation induced by abused drugs. Among the family of inflammasomes, NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) serves the primary research target due to its abundant expression in microglia. NLRP3 has the capability of integrating multiple external and internal inputs and coordinately determining the intensity of microglia activation under various pathological conditions. Here, we summarize the effects of abused drugs on NLRP3 inflammasomes, as well as others, if any. The research on this topic is still at an infant stage; however, the readily available findings suggest that NLRP3 inflammasome could be a common downstream effector stimulated by various types of abused drugs and play critical roles in determining abused-drug-mediated biological effects through enhancing glia-neuron communications. NLRP3 inflammasome might serve as a novel target for ameliorating the development of SUDs.

Spectroscopic meta-analyses reveal novel metabolite profiles across methamphetamine and cocaine substance use disorder.

BACKGROUND: Although proton magnetic resonance spectroscopy (MRS) has been used to study metabolite alterations in stimulant (methamphetamine and cocaine) substance use disorders (SUDs) for over 25 years, data-driven consensus regarding the nature and magnitude of these alterations is lacking. METHOD: In this meta-analysis, we examined associations between SUD and regional metabolites (N-acetyl aspartate (NAA), choline, myo-inositol, creatine, glutamate, and glutamate+glutamine (glx)) in the medial prefrontal cortex (mPFC), frontal white matter (FWM), occipital cortex, and basal ganglia as measured by 1 H-MRS. We also examined moderating effects of MRS acquisition parameters (echo time (TE), field strength), data quality (coefficient of variation (COV)), and demographic/clinical variables. RESULTS: A MEDLINE search revealed 28 articles that met meta-analytic criteria. Significant effects included lower mPFC NAA, higher mPFC myo-inositol, and lower mPFC creatine in SUD relative to people without SUD. mPFC NAA effects were moderated by TE, with larger effects at longer TEs. For choline, although no group effects were observed, effect sizes in the mPFC were related to MRS technical indicators (field strength, COV). No effects of age, sex, primary drug of use (methamphetamine vs. cocaine), duration of use, or duration of abstinence were observed. Evidence for moderating effects of TE and COV may have implications for future MRS studies in SUDs. CONCLUSIONS: The observed metabolite profile in methamphetamine and cocaine SUD (lower NAA and creatine with higher myo-inositol) parallels that observed in Alzheimer's disease and mild cognitive impairment, suggesting these drugs are associated with neurometabolic differences similar to those characterizing these neurodegenerative conditions.

Untreated substance use disorder affects glycemic control: Results in patients with type 2 diabetes served within a network of community-based healthcare centers in Florida.

Introduction: Patients with diabetes and comorbid substance use disorders (SUD) experience poor diabetes management, increased medical complications and mortality. However, research has documented that patients engaged in substance abuse treatment have better management of their comorbid conditions. The current study examines diabetes management among patients with type 2 diabetes, with and without comorbid SUD, receiving care at Florida-based Federally Qualified Health Centers (FQHC) of Health Choice Network (HCN). Methods: A retrospective analysis was conducted using deidentified electronic health records of 37,452 patients with type 2 diabetes who received care at a HCN site in Florida between 2016 and 2019. A longitudinal logistic regression analysis examined the impact of SUD diagnosis on achievement of diabetes management [HbA1c < 7.0% (53 mmol/mol)] over time. A secondary analysis evaluated, within those with an SUD diagnosis, the likelihood of HbA1c control between those with and without SUD treatment. Results: The longitudinal assessment of the relationship between SUD status and HbA1c control revealed that those with SUD (N = 6,878, 18.4%) were less likely to control HbA1c over time (OR = 0.56; 95% CI = 0.49-0.63). Among those with SUD, patients engaged in SUD treatment were more likely to control HbA1c (OR = 5.91; 95% CI = 5.05-6.91). Discussion: Findings highlight that untreated SUD could adversely affect diabetes control and sheds light on the opportunity to enhance care delivery for patients with diabetes and co-occurring SUD.

Transcriptional and epigenetic regulation of microglia in substance use disorders.

Microglia are widely known for their role in immune surveillance and for their ability to refine neurocircuitry during development, but a growing body of evidence suggests that microglia may also play a complementary role to neurons in regulating the behavioral aspects of substance use disorders. While many of these efforts have focused on changes in microglial gene expression associated with drug-taking, epigenetic regulation of these changes has yet to be fully understood. This review provides recent evidence supporting the role of microglia in various aspects of substance use disorder, with particular focus on changes to the microglial transcriptome and the potential epigenetic mechanisms driving these changes. Further, this review discusses the latest technical advances in low-input chromatin profiling and highlights the current challenges for studying these novel molecular mechanisms in microglia.

In vitro metabolite identification of acetylbenzylfentanyl, benzoylbenzylfentanyl, 3-fluoro-methoxyacetylfentanyl, and 3-phenylpropanoylfentanyl using LC-QTOF-HRMS together with synthesized references.

Acetylbenzylfentanyl, benzoylbenzylfentanyl, 3-fluoro-methoxyacetylfentanyl, and 3-phenylpropanoylfentanyl are fentanyl analogs that have been reported to the European Monitoring Centre for Drugs and Drug Addiction in recent years. The aim of this study was to identify metabolic pathways and potential biomarker metabolites of these fentanyl analogs. The compounds were incubated (5 µM) with cryopreserved hepatocytes for up to 5 h in vitro. Metabolites were analyzed with liquid chromatography-quadrupole time of flight-high-resolution mass spectrometry (LC-QTOF-HRMS). The experiments showed that acetylbenzylfentanyl, benzoylbenzylfentanyl, and 3-phenylpropanoylfentanyl were mainly metabolized through N-dealkylation (forming nor-metabolites) and 3-fluoro-methoxyacetylfentanyl mainly through demethylation. Other observed metabolites were formed by mono-/dihydroxylation, dihydrodiol formation, demethylation, dehydrogenation, amide hydrolysis, and/or glucuronidation. The experiments showed that a large number of metabolites of 3-phenylpropanoylfentanyl were formed. The exact position of hydroxy groups in formed monohydroxy metabolites could not be established solely based upon recorded MSMS spectra of hepatocyte samples. Therefore, potential monohydroxy metabolites of 3-phenylpropanoylfentanyl, with the hydroxy group in different positions, were synthesized and analyzed together with the hepatocyte samples. This approach could reveal that the ß position of the phenylpropanoyl moiety was highly favored; ß-OH-phenylpropanoylfentanyl was the most abundant metabolite after the nor-metabolite. Both metabolites have the potential to serve as biomarkers for 3-phenylpropanoylfentanyl. The nor-metabolites of acetylbenzylfentanyl, benzoylbenzylfentanyl, and 3-fluoro-methoxyacetylfentanyl do also seem to be suitable biomarker metabolites, as do the demethylated metabolite of 3-fluoro-methoxyacetylfentanyl. Identified metabolic pathways and formed metabolites were in agreement with findings in previous studies of similar fentanyl analogs.

Nucleus accumbens circuit disinhibits lateral hypothalamus glutamatergic neurons contributing to morphine withdrawal memory in male mice.

The lateral hypothalamus (LH) is physiologically critical in brain functions. The LH also plays an important role in drug addiction. However, neural circuits underlying LH involvement of drug addiction remain obscure. In the present study,our results showed that in male mice, during context-induced expression of morphine withdrawal memory, LH glutamatergic neurons played an important role; dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) projecting from the core of nucleus accumbens (NAcC) to the LH were an important upstream circuit to activate LH glutamatergic neurons; D1-MSNs projecting from the NAcC to the LH activated LH glutamatergic neurons through inhibiting LH local gamma-aminobutyric acid (GABA) neurons. These results suggest that disinhibited LH glutamatergic neurons by neural circuits from the NAcC importantly contribute to context-induced the expression of morphine withdrawal memory.

L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities.

L-type calcium channels (LTCCs), including the Cav1.2 and Cav1.3 LTCC subtypes, are important regulators of calcium entry into neurons, which mediates neurotransmitter release and synaptic plasticity. Cav1.2 and Cav1.3 are encoded by the CACNA1C and CACNA1D genes, respectively. These genes are implicated in substance use disorders and depression in humans, as demonstrated by genetic-wide association studies (GWAS). Pre-clinical models have also revealed a critical role of LTCCs on drug and mood related behavior, including the co-morbidity of substance use and mood disorders. Moreover, LTCCs have been shown to regulate the neuronal firing of dopamine (DA) neurons as well as drug and stress-induced plasticity within the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway. Thus, LTCCs are interesting targets for the treatment of neuropsychiatric diseases. In this review, we provide a brief introduction to voltage-gated calcium channels, specifically focusing on the LTCCs. We place particular emphasis on the ability of LTCCs to regulate DA neuronal activity and downstream signaling in the VTA to NAc pathway, and how such processes mediate substance use and mood disorder-related behavioral responses. We also discuss the bi-directional control of VTA LTCCs on drug and mood-related behaviors in pre-clinical models, with implications for co-morbid psychiatric diagnosis. We conclude with a section on the clinical implications of LTCC blockers, many which are already FDA approved as cardiac medications. Thus, pre-clinical and clinical work should examine the potential of LTCC blockers to be repurposed for neuropsychiatric illness. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.

Effect of amoxicillin/clavulanic acid in attenuating pregabalin-induced condition place preference.

Substance abuse is a worldwide problem with serious repercussions for patients and the communities where they live. Pregabalin (Lyrica), is a medication commonly used to treat neuropathic pain. Like other analgesic medications there has been concern about pregabalin abuse and misuse. Although it was initially suggested that pregabalin, like other gabapentinoids, has limited abuse liability, questions still remain concerning this inquiry. Changes in glutamate system homeostasis are a hallmark of adaptations underlying drug dependence, including down-regulation of the glutamate transporter 1 (GLT-1; SLC1A2) and the cystine/glutamate antiporter (xCT; SLC7A11). In this study, it was found that pregabalin (90 mg/kg) produces a conditioned place preference (CPP), indicative of reinforcing effects that suggest a potential for abuse liability. Moreover, like other drugs of abuse, pregabalin also produced alterations in glutamate homeostasis, reducing the mRNA expression of Slc1a2 and Slc7a11 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Amoxicillin clavulanic acid, a ß-lactam antibiotic, blocked the reinforcing effects of pregabalin and normalized glutamate homeostasis. These results suggest that pregabalin has abuse potential that should be examined more critically, and that, moreover, the mechanisms underlying these effects are similar to those of other drugs of abuse, such as heroin and cocaine. Additionally, these results support previous findings showing normalization of glutamate homeostasis by ß-lactam drugs that provides a novel potential therapeutic approach for the treatment of drug abuse and dependence.

Neurobiological Underpinnings in Drug Addiction.

BACKGROUND: Drug addiction is a chronic biochemical drug use disorder that affects the human brain and behaviour, and leads to an uncontrollable use of a licit or illicit drug. Drug addiction can commence, usually in the young, with the use of a non-medical or a recreational drug in social gatherings, which becomes more frequent over a period of time. It is associated with incremental doses of the drug in order to achieve a state of euphoria. Addiction to drugs has been identified as a relevant social and health problem presenting a risk to public health, especially with regards to communicable diseases (e.g., HIV and AIDS, hepatitis B or C, tuberculosis, and sexually transmitted infections). OBJECTIVE: The objectives of the study were to discuss the neural mechanisms and circuitry responsible for the development and maintenance of addiction. It also examined the cycle of drug addiction and the associated encephalic regions and pathways. METHOD: The search strategy used for the review employed electronic databases in the search for relevant research articles, and they included Scopus, PubMed, Science Direct, Google Scholar, Springer, and the Directory of Open Access Journals. Articles on drug addiction were identified and reviewed for selection. The keywords used in the search were: Neurobiology and [Drug Abuse], Neurobiology and [Drug Addiction], Neurobiology and [Drug Misuse], Neurobiology and [Substance Abuse], Neurobiology and [Substance Misuse], Neural Mechanisms and [Drug Abuse], Neural Mechanisms and [Drug Addiction], and Neural Mechanisms and [Drug Use Disorders]. The search was also aided by scanning the references of identified journal articles. Works identified (86 in number) were those written in English and published between 1996 and 2020. RESULT: One hundred and fifty journal articles and other materials were identified. Eighty-six (86) articles and other works were extracted and reviewed after screening of the titles. abstracts and keywords, and in tandem with the selection criteria. Findings show that addiction is a complex neurobiochemical disorder that is learnt and stored in the brain as memory. The disorder alters the cyto-architecture of the brain and its functions. Relapse from drug addiction is a common occurrence. It is preventable and can be treated, although no single modality of treatment fits all forms of drug addiction. CONCLUSION: Addiction to drugs is the most severe form of drug use disorder. The abuse of drugs and psychoactive substances can harm the security of all societies, including the rule-of-law. It inflicts pain and suffering to individuals and families alike, and may eventuate in deaths. Repetitive use of an addictive drug alters the way and manner the brain perceives pleasure. Drugs of abuse induce structural changes in the neurones in the brain, and in turn, alter the neurotransmitter function, and thereby, create moods and other sensations. These anatomical and physiological changes in the brain may progress even after the stoppage of drugs.

CONTEXTE: La toxicomanie est un trouble biochimique chronique de la consommation de drogues qui affecte le cerveau et le comportement humain et conduit à une consommation incontrôlable d'une drogue licite ou illicite. La toxicomanie peut commencer, généralement chez les jeunes, par la consommation d'une drogue à usage non médical ou récréatif lors de rencontres sociales, qui devient plus fréquente au fil du temps. Elle est associée à des doses progressives de la drogue afin d'atteindre un état d'euphorie. La dépendance aux drogues a été identifiée comme un problème social et sanitaire important, présentant un risque pour la santé publique, notamment en matière des maladies transmissibles (par exemple, le VIH et le sida, l'hépatite B ou C) la tuberculose et les infections sexuellement transmissibles). OBJECTIF: Les objectifs de l'étude étaient de discuter des mécanismes et circuits neuronaux responsables du développement du entretien de la dépendance. Elle a également examiné le cycle de la toxicomanie et les régions et voies encéphaliques associées. MÉTHODE: La stratégie de recherche utilisée pour l'examen a fait appel à des bases de données électroniques pour la recherche d'articles pertinent et ils consistent Scopus, PubMed, Science Direct, Google Scholar, Springer et le Directory of Open Access Journals. Les articles sur la toxicomanie ont été identifiés et examinés pour être sélectionnés. Les mots-clés utilisés dans la recherche étaient : Neurobiologie et [Abus de drogues], Neurobiologie et [Toxicomanie], neurobiologie et [abus de drogues], neurobiologie et [abus de substances], neurobiologie et [abus de substances], Mécanismes neuraux et [abus de drogues], Mécanismes neuraux et [toxicomanie]. Mécanismes neuraux et [troubles liés à la consommation de drogues]. La recherche a également été facilitée par l'analyse des références des articles de revues identifiés. Les ouvrages identifiés (au nombre de 86) étaient ceux rédigés en anglais et publiés entre 1996 et 2020. RÉSULTAT: Cent cinquante articles de journaux et autres matériaux ont été identifiés. Quatre-vingt-six (86) articles et autres travaux ont été extraits et examinés après avoir passé en revue les titres, les résumés et les mots-clés, et en tandem avec les critères de sélection.Les résultats montrent que l'addiction est un trouble neurobiochimique complexe qui est appris et stocké dans le cerveau en tant que mémoire. Ce trouble modifie la cyto-architecture du cerveau et ses fonctions. La rechute de la toxicomanie est un phénomène courant. Elle est évitable et peut être traitée, bien qu'il n'existe pas de modalité unique de traitement pour toutes les formes de toxicomanie. CONCLUSION: La toxicomanie est la forme la plus grave de trouble lié à l'usage de drogues. L'abus de drogues et de substances psychoactives peut nuire à la sécurité de toutes les sociétés, y compris à l'État de droit. Il inflige de la douleur et de la souffrance aux individus et aux familles, et peut entraîner la mort. L'usage répétitif d'une drogue addictive modifie la manière dont le cerveau perçoit le plaisir. Les drogues d'abus induisent des changements structurels dans les neurones du cerveau et modifient à leur tour la fonction des neurotransmetteurs et créent ainsi des humeurs et d'autres sensations. Ces changements anatomiques et physiologiques dans le cerveau peuvent progresser même après l'arrêt de la drogue. MOTS CLÉS: Neurone, Compulsivité, Impulsivité, Récompense, Renforcement, Dépendance, Tolerance.

MicroRNAs in drug addiction: Current status and future perspectives.

Drug addiction is a chronic and relapsing brain disorder characterized by compulsive drug seeking and continued drug use despite adverse consequences. The high prevalence and social burden of addiction is indisputable; however, the available intervention is insufficient. Abnormal gene expression is observed in reward-related brain regions in animal models of addiction. The modulation of gene expression and aberrant adaptation of neural networks attribute to the changes in brain function under repeated exposure to addictive drugs. The emerging recognition of the role of microRNA (miRNA) provides new insights into many biological and pathological processes in the central nervous system. Considerable studies have demonstrated that miRNAs are strong modulators of posttranscriptional gene expression in drug addiction. Here, we provide an overview of miRNAs, followed by evidence for aberrant miRNA expression and regulatory roles of miRNAs in drug addiction as well as neuroadaptation. We concluded by providing our perspectives that miRNAs have the potential as novel therapeutic targets for drug addiction.

Nanoparticle delivery systems for substance use disorder.

Innovative breakthroughs in nanotechnology are having a substantial impact in healthcare, especially for brain diseases where effective therapeutic delivery systems are desperately needed. Nanoparticle delivery systems offer an unmatched ability of not only conveying a diverse array of diagnostic and therapeutic agents across complex biological barriers, but also possess the ability to transport payloads to targeted cell types over a sustained period. In substance use disorder (SUD), many therapeutic targets have been identified in preclinical studies, yet few of these findings have been translated to effective clinical treatments. The lack of success is, in part, due to the significant challenge of delivering novel therapies to the brain and specific brain cells. In this review, we evaluate the potential approaches and limitations of nanotherapeutic brain delivery systems. We also highlight the examples of promising strategies and future directions of nanocarrier-based treatments for SUD.

A mathematical model of reward-mediated learning in drug addiction.

Substances of abuse are known to activate and disrupt neuronal circuits in the brain reward system. We propose a simple and easily interpretable dynamical systems model to describe the neurobiology of drug addiction that incorporates the psychiatric concepts of reward prediction error, drug-induced incentive salience, and opponent process theory. Drug-induced dopamine releases activate a biphasic reward response with pleasurable, positive "a-processes" (euphoria, rush) followed by unpleasant, negative "b-processes" (cravings, withdrawal). Neuroadaptive processes triggered by successive intakes enhance the negative component of the reward response, which the user compensates for by increasing drug dose and/or intake frequency. This positive feedback between physiological changes and drug self-administration leads to habituation, tolerance, and, eventually, to full addiction. Our model gives rise to qualitatively different pathways to addiction that can represent a diverse set of user profiles (genetics, age) and drug potencies. We find that users who have, or neuroadaptively develop, a strong b-process response to drug consumption are most at risk for addiction. Finally, we include possible mechanisms to mitigate withdrawal symptoms, such as through the use of methadone or other auxiliary drugs used in detoxification.

Early life stress and substance use disorders: The critical role of adolescent substance use.

Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain-particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control-in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS.

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions.

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.