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Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 6525

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Special Issue Editor

Dr. Karen K. Szumlinski

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Guest Editor

1. Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA
2. Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA
3. Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA
Interests: addiction; affect; psychostimulants; opioids; alcohol; binge-drinking; animal models; glutamate; Homer; metabotropic glutamate receptor
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Special Issue Information

Dear Colleagues,

Substance use disorder is a serious neuropsychiatric condition, characterized by intense drug craving, compulsive drug seeking and taking, disordered emotionality and pronounced cognitive impairment. In the wake of the COVID-19 pandemic, opioid-, alcohol- and psychomotor stimulant-related deaths have risen dramatically. This rise in drug-related deaths is concerning as currently, there exists only a few pharmacotherapies for treating certain substance use disorders and the available cognitive/behavioral therapies have proven relatively ineffective at reducing drug use and preventing relapse to the addicted state. Biomedical theories of substance use disorders posit that substance use disorder is a disease of the brain, stemming from a complex interaction between genetic and environmental factors to which drug experience is key. Understanding the molecular mechanism(s) through which repeated exposure to drugs of abuse results in the constellation of symptoms that characterize a substance use disorder is critical for the design of effective treatments, disease mitigation or even prevention. This Special Issue will examine the current state of our knowledge regarding the molecular bases of substance use disorders as they relate to the discovery of a broad range of druggable targets to inform biomedical strategies for predicting disease susceptibility, carrying out early and late intervention in the disease process, and promoting recovery.

Dr. Karen K. Szumlinski
Guest Editor

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Keywords

substance use disorder
pharmacotherapy
addiction
relapse
vulnerability
drug self-administration
craving

Published Papers (6 papers)

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Research

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18 pages, 8462 KiB

Open AccessArticle

Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice

by Yixin Fu, Wenfu Li, Yunlin Mai, Junhao Guan, Ruxuan Ding, Jiawei Hou, Bingqing Chen, Guoxin Cao, Shizhu Sun, Ying Tang and Rao Fu

Int. J. Mol. Sci. 2024, 25(5), 2933; https://doi.org/10.3390/ijms25052933 - 02 Mar 2024

Viewed by 999

Abstract

Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (Pnoc, Oxt, Npy) and anti-stress (Crf, Pomc, Avp, Orx, Pdyn) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced Pnoc and Orx levels while elevating Crf levels in these neuronal populations. Notably, RMTg Pnoc and Npy levels counteracted ethanol consumption and depression severity, while Crf levels were indicative of the mice’s anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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40 pages, 8470 KiB

Open AccessArticle

Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice

by Christopher J. E. Denning, Lauren E. Madory, Jessica N. Herbert, Ryan A. Cabrera and Karen K. Szumlinski

Int. J. Mol. Sci. 2024, 25(3), 1928; https://doi.org/10.3390/ijms25031928 - 05 Feb 2024

Viewed by 836

Abstract

Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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18 pages, 2657 KiB

Open AccessArticle

Impact of miR-29c-3p in the Nucleus Accumbens on Methamphetamine-Induced Behavioral Sensitization and Neuroplasticity-Related Proteins

by Hang Su, Li Zhu, Linlan Su, Min Li, Rui Wang, Jie Zhu, Yanjiong Chen and Teng Chen

Int. J. Mol. Sci. 2024, 25(2), 942; https://doi.org/10.3390/ijms25020942 - 11 Jan 2024

Viewed by 807

Abstract

Methamphetamine (METH) abuse inflicts both physical and psychological harm. While our previous research has established the regulatory role of miR-29c-3p in behavior sensitization, the underlying mechanisms and target genes remain incompletely understood. In this study, we employed the isobaric tags for relative and absolute quantitation (iTRAQ) technique in conjunction with Ingenuity pathway analysis (IPA) to probe the putative molecular mechanisms of METH sensitization through miR-29c-3p inhibition. Through a microinjection of AAV-anti-miR-29c-3p into the nucleus accumbens (NAc) of mice, we observed the attenuation of METH-induced locomotor effects. Subsequent iTRAQ analysis identified 70 differentially expressed proteins (DEPs), with 22 up-regulated potential target proteins identified through miR-29c-3p target gene prediction and IPA analysis. Our focus extended to the number of neuronal branches, the excitatory synapse count, and locomotion-related pathways. Notably, GPR37, NPC1, and IREB2 emerged as potential target molecules for miR-29c-3p regulation, suggesting their involvement in the modulation of METH sensitization. Quantitative PCR confirmed the METH-induced aberrant expression of Gpr37, Npc1, and Ireb2 in the NAc of mice. Specifically, the over-expression of miR-29c-3p led to a significant reduction in the mRNA level of Gpr37, while the inhibition of miR-29c-3p resulted in a significant increase in the mRNA level of Gpr37, consistent with the regulatory principle of miRNAs modulating target gene expression. This suggests that miR-29c-3p potentially influences METH sensitization through its regulation of neuroplasticity. Our research indicates that miR-29c-3p plays a crucial role in regulating METH-induced sensitization, and it identified the potential molecular of miR-29c-3p in regulating METH-induced sensitization. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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18 pages, 4698 KiB

Open AccessArticle

Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use

by María Elena Quintanilla, Paola Morales, Daniela Santapau, Alba Ávila, Carolina Ponce, Pablo Berrios-Cárcamo, Belén Olivares, Javiera Gallardo, Marcelo Ezquer, Mario Herrera-Marschitz, Yedy Israel and Fernando Ezquer

Int. J. Mol. Sci. 2023, 24(23), 17081; https://doi.org/10.3390/ijms242317081 - 03 Dec 2023

Cited by 2 | Viewed by 1136

Abstract

Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal–striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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Review

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22 pages, 1995 KiB

Open AccessReview

Optical Intracranial Self-Stimulation (oICSS): A New Behavioral Model for Studying Drug Reward and Aversion in Rodents

by Rui Song, Omar Soler-Cedeño and Zheng-Xiong Xi

Int. J. Mol. Sci. 2024, 25(6), 3455; https://doi.org/10.3390/ijms25063455 - 19 Mar 2024

Viewed by 775

Abstract

Brain-stimulation reward, also known as intracranial self-stimulation (ICSS), is a commonly used procedure for studying brain reward function and drug reward. In electrical ICSS (eICSS), an electrode is surgically implanted into the medial forebrain bundle (MFB) in the lateral hypothalamus or the ventral tegmental area (VTA) in the midbrain. Operant lever responding leads to the delivery of electrical pulse stimulation. The alteration in the stimulation frequency-lever response curve is used to evaluate the impact of pharmacological agents on brain reward function. If a test drug induces a leftward or upward shift in the eICSS response curve, it implies a reward-enhancing or abuse-like effect. Conversely, if a drug causes a rightward or downward shift in the functional response curve, it suggests a reward-attenuating or aversive effect. A significant drawback of eICSS is the lack of cellular selectivity in understanding the neural substrates underlying this behavior. Excitingly, recent advancements in optical ICSS (oICSS) have facilitated the development of at least three cell type-specific oICSS models—dopamine-, glutamate-, and GABA-dependent oICSS. In these new models, a comparable stimulation frequency-lever response curve has been established and employed to study the substrate-specific mechanisms underlying brain reward function and a drug’s rewarding versus aversive effects. In this review article, we summarize recent progress in this exciting research area. The findings in oICSS have not only increased our understanding of the neural mechanisms underlying drug reward and addiction but have also introduced a novel behavioral model in preclinical medication development for treating substance use disorders. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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14 pages, 2209 KiB

Open AccessReview

Dysfunction of the Neurovascular Unit by Psychostimulant Drugs

by Tam Thuy Lu Vo, Dain Shin, Eunyoung Ha and Ji Hae Seo

Int. J. Mol. Sci. 2023, 24(20), 15154; https://doi.org/10.3390/ijms242015154 - 13 Oct 2023

Viewed by 1383

Abstract

‘Drug abuse’ has been recognized as one of the most pressing epidemics in contemporary society. Traditional research has primarily focused on understanding how drugs induce neurotoxicity or degeneration within the central nervous system (CNS) and influence systems related to reward, motivation, and cravings. However, recent investigations have increasingly shifted their attention toward the detrimental consequences of drug abuse on the blood–brain barrier (BBB). The BBB is a structural component situated in brain vessels, responsible for separating brain tissue from external substances to maintain brain homeostasis. The BBB’s function is governed by cellular interactions involving various elements of the ‘neurovascular unit (NVU),’ such as neurons, endothelial cells, astrocytes, pericytes, and microglia. Disruption of the NVU is closely linked to serious neurodegeneration. This review provides a comprehensive overview of the harmful effects of psychostimulant drugs on the BBB, highlighting the mechanisms through which drugs can damage the NVU. Additionally, the review proposes novel therapeutic targets aimed at protecting the BBB. By understanding the intricate relationships between drug abuse, BBB integrity, and NVU function, researchers and clinicians may uncover new strategies to mitigate the damaging impact of drug abuse on brain health. Full article

(This article belongs to the Special Issue Biochemical and Molecular Changes in the Brain Caused by Drug Abuse: Implications for Therapeutic Intervention)

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