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The Neurobiology of Substance Addiction

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 21015

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Special Issue Editors

Prof. Dr. Robert L. Meisel

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Guest Editor

Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
Interests: synaptic plasticity; dopamine signaling; mechanisms of steroid action; social behaviors; drug addiction

Prof. Dr. Sade Spencer

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Guest Editor

Department of Pharmacology, University of Minnesota Twin Cities, Minneapolis, MN, USA
Interests: glutamate; dopamine; addiction; psychostimulants; cannabinoids; behavior; synaptic plasticity; pharmacology; reward and aversion; withdrawal

Prof. Dr. Julia Lemos

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Guest Editor

Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, MN, USA
Interests: stress; basal ganglia; dopamine; acetylcholine; serotonin; CRF; addiction; depression; anxiety; PTSD; electrophysiology; electrochemistry; behavior

Special Issue Information

Dear Colleagues,

Drugs of abuse modify synaptic transmission and synaptic plasticity mechanisms in important brain reward circuits. Different classes of abused drugs have divergent actions due to distinct mechanisms of action at the molecular level, but converge on many of the same neurotransmitter and neuromodulator systems including glutamatergic, monoaminergic, and peptidergic systems. These peptidergic systems include, but are not limited to, hypocretin/orexin, neuropeptide Y, oxytocin, neuropeptide S, galanin, corticotropin-releasing factor, dynorphin, and nociceptin/orphanin FQ. Importantly, individual differences in drug response can be observed, reflecting gene–environment interactions that also influence physiological response. Substance use disorders differentially impact communities based on additional diverse factors including race, sexual orientation, and socioeconomic status, leading to prominent health disparities. Substance abuse vulnerability, treatment, and outcomes are influenced by these ethnocultural factors. Consequently, research in the neurobiology of drug abuse is represented by a diverse group of viewpoints and investigators. Unfortunately, the influential contributions highlighted in this field typically reflect the views of only a subset of these researchers. The goal of this Special Issue is to recognize and celebrate the contributions of a diverse cross-section of individuals making substantive contributions to the field of drug abuse. There is an ongoing need to identify and better understand the cellular, molecular, and neurochemical mechanisms that contribute to the pathophysiology of substance use disorder and related neuropsychiatric conditions. Contributions to this Special Issue are by invitation of the Guest Editors.

Prof. Dr. Robert L. Meisel
Prof. Dr. Sade Spencer
Prof. Dr. Julia Lemos
Guest Editors

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Keywords

addiction
stress
neurotransmission
synaptic plasticity
neuropeptides
reward

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Published Papers (7 papers)

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Research

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21 pages, 4593 KiB

Open AccessArticle

Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit

by Rachel Aruldas, Laura Buczek Orenstein and Sade Spencer

Int. J. Mol. Sci. 2023, 24(23), 16859; https://doi.org/10.3390/ijms242316859 - 28 Nov 2023

Cited by 1 | Viewed by 1906

Abstract

Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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18 pages, 1691 KiB

Open AccessArticle

Targeting the Maladaptive Effects of Binge Drinking on Circadian Gene Expression

by Kolter Grigsby, Courtney Ledford, Tanvi Batish, Snigdha Kanadibhotla, Delaney Smith, Evan Firsick, Alexander Tran, Kayla Townsley, Kaylee-Abril Vasquez Reyes, Katherine LeBlanc and Angela Ozburn

Int. J. Mol. Sci. 2022, 23(19), 11084; https://doi.org/10.3390/ijms231911084 - 21 Sep 2022

Cited by 3 | Viewed by 1832

Abstract

Previous studies (1) support a role of circadian genes in regulating alcohol intake, and (2) reveal that harmful alcohol use alters circadian rhythms. However, there is minimal knowledge of the effects of chronic alcohol processes on rhythmic circadian gene expression across brain regions important for circadian biology and alcohol intake. Therefore, the present study sought to test the effects of chronic binge-like drinking on diurnal circadian gene expression patterns in the master circadian pacemaker (SCN), the ventral tegmental area (VTA), and the nucleus accumbens (NAc) in High Drinking in the Dark-1 (HDID-1) mice, a unique genetic risk model for drinking to intoxication. Consistent with earlier findings, we found that 8 weeks of binge-like drinking reduced the amplitude of several core circadian clock genes in the NAc and SCN, but not the VTA. To better inform the use of circadian-relevant pharmacotherapies in reducing harmful drinking and ameliorating alcohol’s effects on circadian gene expression, we tested whether the casein kinase-1 inhibitor, PF-67046, or the phosphodiesterase type-4 (an upstream regulator of circadian signalling) inhibitor, apremilast, would reduce binge-like intake and mitigate circadian gene suppression. PF-67046 did not reduce intake but did have circadian gene effects. In contrast, apremilast reduced drinking, but had no effect on circadian expression patterns. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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13 pages, 4813 KiB

Open AccessArticle

Chronic Ethanol Consumption Alters Presynaptic Regulation of Dorsal Striatal Dopamine Release in C57BL/6J Mice

by Armando G. Salinas, Jacob A. Nadel, Yolanda Mateo, Thanh Huynh, Shana M. Augustin, Karel Pacak and David M. Lovinger

Int. J. Mol. Sci. 2022, 23(19), 10994; https://doi.org/10.3390/ijms231910994 - 20 Sep 2022

Cited by 1 | Viewed by 2225

Abstract

Alcohol use disorder (AUD) is characterized by escalating alcohol consumption, preoccupation with alcohol, and continued alcohol consumption despite adverse consequences. Dopamine has been implicated in neural and behavioral processes involved in reward and reinforcement and is a critical neurotransmitter in AUD. Clinical and preclinical research has shown that long-term ethanol exposure can alter dopamine release, though most of this work has focused on nucleus accumbens (NAc). Like the NAc, the dorsal striatum (DS) is implicated in neural and behavioral processes in AUD. However, little work has examined chronic ethanol effects on DS dopamine dynamics. Therefore, we examined the effect of ethanol consumption and withdrawal on dopamine release and its presynaptic regulation with fast-scan cyclic voltammetry in C57BL/6J mice. We found that one month of ethanol consumption did not alter maximal dopamine release or dopamine tissue content. However, we did find that D2 dopamine autoreceptors were sensitized. We also found a decrease in cholinergic control of dopamine release via β2-containing nAChRs on dopamine axons. Interestingly, both effects were reversed following withdrawal, raising the possibility that some of the neuroadaptations in AUD might be reversible in abstinence. Altogether, this work elucidates some of the chronic alcohol-induced neurobiological dysfunctions in the dopamine system. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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17 pages, 2377 KiB

Open AccessArticle

Altered Accumbal Dopamine Terminal Dynamics Following Chronic Heroin Self-Administration

by Brianna E. George, Monica H. Dawes, Emily G. Peck and Sara R. Jones

Int. J. Mol. Sci. 2022, 23(15), 8106; https://doi.org/10.3390/ijms23158106 - 23 Jul 2022

Cited by 5 | Viewed by 3089

Abstract

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-h, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats exhibited reduced stimulated dopamine release during tonic-like, single-pulse stimulations, but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5–100 Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor agonist responsivity were increased following heroin self-administration. These results reveal a marked low dopamine state following heroin exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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17 pages, 3013 KiB

Open AccessArticle

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

by Larry Rodriguez, Dean Kirson, Sarah A. Wolfe, Reesha R. Patel, Florence P. Varodayan, Angela E. Snyder, Pauravi J. Gandhi, Sophia Khom, Roman Vlkolinsky, Michal Bajo and Marisa Roberto

Int. J. Mol. Sci. 2022, 23(14), 7842; https://doi.org/10.3390/ijms23147842 - 16 Jul 2022

Cited by 7 | Viewed by 3441

Abstract

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by the recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin-releasing factor (CRF)-CRF₁ receptor and Gamma-Aminobutyric Acid (GABA)-ergic signaling dysregulation occurring in alcohol-dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch-clamp electrophysiology to examine the effects of alcohol dependence on the CRF modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared to males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had fewer CeA neurons containing mRNA for the CRF₁ receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike in males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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16 pages, 2400 KiB

Open AccessArticle

Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adolescent Rats with a Human Polymorphism (rs2304297) in the 3′-UTR of the CHRNA6 Gene

by Anjelica Cardenas, Yu Bai, Yasamin Hajy Heydary, Jiaqi Li, Frances M. Leslie and Shahrdad Lotfipour

Int. J. Mol. Sci. 2022, 23(6), 3145; https://doi.org/10.3390/ijms23063145 - 15 Mar 2022

Cited by 7 | Viewed by 3779

Abstract

In human adolescents, a single nucleotide polymorphism (SNP), rs2304297, in the 3′-UTR of the nicotinic receptor subunit gene, CHRNA6, has been associated with increased smoking. To study the effects of the human CHRNA6 3′-UTR SNP, our lab generated knock-in rodent lines with either C or G SNP alleles. The objective of this study was to determine if the CHRNA6 3′-UTR SNP is functional in the knock-in rat lines. We hypothesized that the human CHRNA6 3′-UTR SNP knock-in does not impact baseline but enhances nicotine-induced behaviors. For baseline behaviors, rats underwent food self-administration at escalating schedules of reinforcement followed by a locomotor assay and a series of anxiety tests (postnatal day (PN) 25-39). In separate cohorts, adolescent rats underwent 1- or 4-day nicotine pretreatment (2×, 30 μg/kg/0.1 mL, i.v.). After the last nicotine injection (PN 31), animals were assessed behaviorally in an open-field chamber, and brain tissue was collected. We show the human CHRNA6 3′-UTR SNP knock-in does not affect food reinforcement, locomotor activity, or anxiety. Further, 4-day, but not 1-day, nicotine exposure enhances locomotion and anxiolytic behavior in a genotype- and sex-specific manner. These findings demonstrate that the human CHRNA6 3′-UTR SNP is functional in our in vivo model. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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Review

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22 pages, 929 KiB

Open AccessReview

Connecting Circuits with Networks in Addiction Neuroscience: A Salience Network Perspective

by Adriana K. Cushnie, Wei Tang and Sarah R. Heilbronner

Int. J. Mol. Sci. 2023, 24(10), 9083; https://doi.org/10.3390/ijms24109083 - 22 May 2023

Cited by 6 | Viewed by 3627

Abstract

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional network that is disrupted in addiction. Individuals with addiction display dysfunctional structural and functional connectivity of the SN. Furthermore, while there is a growing body of evidence regarding the SN, addiction, and the relationship between the two, there are still many unknowns, and there are fundamental limitations to human neuroimaging studies. At the same time, advances in molecular and systems neuroscience techniques allow researchers to manipulate neural circuits in nonhuman animals with increasing precision. Here, we describe attempts to translate human functional networks to nonhuman animals to uncover circuit-level mechanisms. To do this, we review the structural and functional connections of the salience network and its homology across species. We then describe the existing literature in which circuit-specific perturbation of the SN sheds light on how functional cortical networks operate, both within and outside the context of addiction. Finally, we highlight key outstanding opportunities for mechanistic studies of the SN. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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