Editorial

3 pages, 177 KiB

Open AccessEditorial

Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation

by Tamara J. Phillips

Brain Sci. 2022, 12(1), 51; https://doi.org/10.3390/brainsci12010051 - 30 Dec 2021

Viewed by 1073

Genetic differences play a role in the susceptibility to addictive drug use, the probability that the use of these drugs will escalate and result in a drug use disorder, and whether relapse to use will occur during or after treatment [...] Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

Research

Jump to: Editorial, Review

15 pages, 1434 KiB

Open AccessArticle

Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure

by Sean P. Farris, Gayatri R. Tiwari, Olga Ponomareva, Marcelo F. Lopez, R. Dayne Mayfield and Howard C. Becker

Brain Sci. 2020, 10(5), 275; https://doi.org/10.3390/brainsci10050275 - 02 May 2020

Cited by 11 | Viewed by 3066

Abstract

Chronic stress is a known contributing factor to the development of drug and alcohol addiction. Animal models have previously shown that repeated forced swim stress promotes escalated alcohol consumption in dependent animals. To investigate the underlying molecular adaptations associated with stress and chronic [...] Read more.

Chronic stress is a known contributing factor to the development of drug and alcohol addiction. Animal models have previously shown that repeated forced swim stress promotes escalated alcohol consumption in dependent animals. To investigate the underlying molecular adaptations associated with stress and chronic alcohol exposure, RNA-sequencing and bioinformatics analyses were conducted on the prefrontal cortex (CTX) of male C57BL/6J mice that were behaviorally tested for either non-dependent alcohol consumption (CTL), chronic intermittent ethanol (CIE) vapor dependent alcohol consumption, repeated bouts of forced swim stress alone (FSS), and chronic intermittent ethanol with forced swim stress (CIE + FSS). Brain tissue from each group was collected at 0-h, 72-h, and 168-h following the final test to determine long-lasting molecular changes associated with maladaptive behavior. Our results demonstrate unique temporal patterns and persistent changes in coordinately regulated gene expression systems with respect to the tested behavioral group. For example, increased expression of genes involved in “transmitter-gated ion channel activity” was only determined for CIE + FSS. Overall, our results provide a summary of transcriptomic adaptations across time within the CTX that are relevant to understanding the neurobiology of chronic alcohol exposure and stress. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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18 pages, 1056 KiB

Open AccessArticle

A Pathway-Based Genomic Approach to Identify Medications: Application to Alcohol Use Disorder

by Laura B. Ferguson, Shruti Patil, Bailey A. Moskowitz, Igor Ponomarev, Robert A. Harris, Roy D. Mayfield and Robert O. Messing

Brain Sci. 2019, 9(12), 381; https://doi.org/10.3390/brainsci9120381 - 16 Dec 2019

Cited by 5 | Viewed by 3282

Abstract

Chronic, excessive alcohol use alters brain gene expression patterns, which could be important for initiating, maintaining, or progressing the addicted state. It has been proposed that pharmaceuticals with opposing effects on gene expression could treat alcohol use disorder (AUD). Computational strategies comparing gene [...] Read more.

Chronic, excessive alcohol use alters brain gene expression patterns, which could be important for initiating, maintaining, or progressing the addicted state. It has been proposed that pharmaceuticals with opposing effects on gene expression could treat alcohol use disorder (AUD). Computational strategies comparing gene expression signatures of disease to those of pharmaceuticals show promise for nominating novel treatments. We reasoned that it may be sufficient for a treatment to target the biological pathway rather than lists of individual genes perturbed by AUD. We analyzed published and unpublished transcriptomic data using gene set enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to identify biological pathways disrupted in AUD brain and by compounds in the Library of Network-based Cellular Signatures (LINCS L1000) and Connectivity Map (CMap) databases. Several pathways were consistently disrupted in AUD brain, including an up-regulation of genes within the Complement and Coagulation Cascade, Focal Adhesion, Systemic Lupus Erythematosus, and MAPK signaling, and a down-regulation of genes within the Oxidative Phosphorylation pathway, strengthening evidence for their importance in AUD. Over 200 compounds targeted genes within those pathways in an opposing manner, more than twenty of which have already been shown to affect alcohol consumption, providing confidence in our approach. We created a user-friendly web-interface that researchers can use to identify drugs that target pathways of interest or nominate mechanism of action for drugs. This study demonstrates a unique systems pharmacology approach that can nominate pharmaceuticals that target pathways disrupted in disease states such as AUD and identify compounds that could be repurposed for AUD if sufficient evidence is attained in preclinical studies. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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Graphical abstract

13 pages, 1759 KiB

Open AccessArticle

Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

by Michal Bajo, Reesha R. Patel, David M. Hedges, Florence P. Varodayan, Roman Vlkolinsky, Tony D. Davis, Michael D. Burkart, Yuri A. Blednov and Marisa Roberto

Brain Sci. 2019, 9(12), 361; https://doi.org/10.3390/brainsci9120361 - 07 Dec 2019

Cited by 14 | Viewed by 3109

Abstract

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced [...] Read more.

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol’s modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β’s actions in reducing postsynaptic GABA_A receptor function. Pharmacological inhibition of MyD88 modulates IL-1β’s action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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29 pages, 3243 KiB

Open AccessArticle

Evaluation of Microglia/Macrophage Cells from Rat Striatum and Prefrontal Cortex Reveals Differential Expression of Inflammatory-Related mRNA after Methamphetamine

by Joanne S. Kays and Bryan K. Yamamoto

Brain Sci. 2019, 9(12), 340; https://doi.org/10.3390/brainsci9120340 - 25 Nov 2019

Cited by 10 | Viewed by 4001

Abstract

RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats [...] Read more.

RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats after a methamphetamine (METH) binge dosing regimen. Resident microglia and infiltrating macrophages were collected 2 h or 3 days after drug administration. Gene expression changes indicated there was an increase toward an overall pro-inflammatory state, or M1 polarization, along with what appears to be a subset of cells that differentiated toward the anti-inflammatory M2 polarization. In general, there were significantly more mRNA expression changes in the STR than the PFC and more at 2 h post-binge METH than at 3 days post-binge METH. Additionally, Ingenuity^® Pathway Analysis along with details of RNA expression changes revealed cyclo-oxygenase 2 (COX2)-driven prostaglandin (PG) E2 synthesis, glutamine uptake, and the Nuclear factor erythroid2-related factor 2 (NRF2) canonical pathway in microglia were associated with the binge administration regimen of METH. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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17 pages, 975 KiB

Open AccessArticle

Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood

by Jacquelyn L. Meyers, David B. Chorlian, Emma C. Johnson, Ashwini K. Pandey, Chella Kamarajan, Jessica E. Salvatore, Fazil Aliev, Stacey Subbie-Saenz de Viteri, Jian Zhang, Michael Chao, Manav Kapoor, Victor Hesselbrock, John Kramer, Samuel Kuperman, John Nurnberger, Jay Tischfield, Alison Goate, Tatiana Foroud, Danielle M. Dick, Howard J. Edenberg, Arpana Agrawal and Bernice Porjesz Show full author list Hide full author list

Brain Sci. 2019, 9(10), 280; https://doi.org/10.3390/brainsci9100280 - 17 Oct 2019

Cited by 12 | Viewed by 4647

Abstract

Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), [...] Read more.

Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18–31 (beta coefficients ranged from 0.02–0.06, p-values ranged from 10⁻⁶–10⁻¹²), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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18 pages, 1549 KiB

Open AccessArticle

Endocannabinoids and Fear-Related Behavior in Mice Selectively Bred for High or Low Alcohol Preference

by Aaron M. Kirchhoff, Eric L. Barker and Julia A. Chester

Brain Sci. 2019, 9(10), 254; https://doi.org/10.3390/brainsci9100254 - 26 Sep 2019

Cited by 6 | Viewed by 2878

Abstract

Alcohol use disorders (AUDs) have a high incidence of co-morbidity with stress-related psychopathologies, such as post-traumatic stress disorder (PTSD). Genetic and pharmacological studies support a prominent role for the endocannabinoid system (ECS) in modulating stress-related behaviors relevant to AUDs and PTSD. Mouse lines [...] Read more.

Alcohol use disorders (AUDs) have a high incidence of co-morbidity with stress-related psychopathologies, such as post-traumatic stress disorder (PTSD). Genetic and pharmacological studies support a prominent role for the endocannabinoid system (ECS) in modulating stress-related behaviors relevant to AUDs and PTSD. Mouse lines selectively bred for high (HAP) and low (LAP) alcohol preference show reproducible differences in fear-potentiated startle (FPS), a model for PTSD-related behavior. The first experiment in this study assessed levels of the endocannabinoids, anandamide (AEA) and sn-2 arachidonylglycerol (2-AG), in the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP) of male and female HAP1 and LAP1 mice following the expression of FPS to determine whether ECS responses to conditioned-fear stress (FPS) were correlated with genetic propensity toward high or low alcohol preference. The second experiment examined effects of a cannabinoid receptor type 1 agonist (CP55940) and antagonist (rimonabant) on the expression of FPS in HAP1 and LAP1 male and female mice. The estrous cycle of females was monitored throughout the experiments to determine if the expression of FPS differed by stage of the cycle. FPS was greater in male and female HAP1 than LAP1 mice, as previously reported. In both experiments, LAP1 females in diestrus displayed greater FPS than LAP1 females in metestrus and estrus. In the AMG and HIP, AEA levels were greater in male fear-conditioned HAP1 mice than LAP1 mice. There were no line or sex differences in effects of CP55940 or rimonabant on the expression of FPS. However, surprisingly, evidence for anxiogenic effects of prior treatment with CP55940 were seen in all mice during the third drug-free FPS test. These findings suggest that genetic differences in ECS function in response to fear-conditioning stress may underlie differences in FPS expression in HAP1 and LAP1 selected lines. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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15 pages, 990 KiB

Open AccessArticle

C57BL/6 Substrain Differences in Pharmacological Effects after Acute and Repeated Nicotine Administration

by Lois S. Akinola, Bryan Mckiver, Wisam Toma, Andy Z. X. Zhu, Rachel F. Tyndale, Vivek Kumar and M. Imad Damaj

Brain Sci. 2019, 9(10), 244; https://doi.org/10.3390/brainsci9100244 - 21 Sep 2019

Cited by 19 | Viewed by 4014

Abstract

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially [...] Read more.

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine’s effects have not yet been described in these substrains. We examined the phenotypic differences in these substrains following the acute and repeated administration of nicotine in several pharmacological measures, including locomotion (after acute and repeated exposure), body temperature, nociception, and anxiety-like behaviors. We report substrain differences in the pharmacological effects of acute and repeated nicotine administration in the B6 substrains. Overall, we show enhanced nicotine sensitivity to locomotion, hypothermia, antinociception, and anxiety-like behaviors in the B6J mouse substrain compared to B6N. In the repeated administration paradigm, both the B6N and B6J substrains showed no sensitized locomotor responses after repeated exposure to nicotine at the two doses tested. This study thus provides evidence that the B6 mouse substrains may be useful for genetic studies to elucidate some of the genetic variants involved in tobacco dependence and addiction. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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20 pages, 2693 KiB

Open AccessArticle

Ethanol Induction of Innate Immune Signals Across BV2 Microglia and SH-SY5Y Neuroblastoma Involves Induction of IL-4 and IL-13

by Colleen J. Lawrimore, Leon G. Coleman, Jian Zou and Fulton T. Crews

Brain Sci. 2019, 9(9), 228; https://doi.org/10.3390/brainsci9090228 - 10 Sep 2019

Cited by 9 | Viewed by 4570

Abstract

Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact [...] Read more.

Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact learning and memory. To investigate mechanisms of ethanol induction of innate immune signaling within and between brain cells, we studied immortalized BV2 microglia and SH-SY5Y human neuroblastoma to model microglial and neuronal signaling. Cells were treated alone or in co-culture using a Transwell system, which allows transfer of soluble mediators. We determined immune signaling mRNA using real-time polymerase chain reaction. Ethanol induced innate immune genes in both BV2 and SH-SY5Y cultured alone, with co-culture altering gene expression at baseline and following ethanol exposure. Co-culture blunted ethanol-induced high mobility group box protein 1 (HMGB1)-TLR responses, corresponding with reduced ethanol induction of several proinflammatory NFκB target genes. In contrast, co-culture resulted in ethanol upregulation of cytokines IL-4 and IL-13 in BV2 and corresponding receptors, that is, IL-4 and IL-13 receptors, in SH-SY5Y, suggesting induction of a novel signaling pathway. Co-culture reduction in HMGB1-TLR levels occurs in parallel with reduced proinflammatory gene induction and increased IL-4 and IL-13 ligands and receptors. Findings from these immortalized and tumor-derived cell lines could provide insight into microglial-neuronal interactions via release of soluble mediators in vivo. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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20 pages, 5679 KiB

Open AccessArticle

Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains

by Christopher L. Cunningham

Brain Sci. 2019, 9(8), 209; https://doi.org/10.3390/brainsci9080209 - 20 Aug 2019

Cited by 17 | Viewed by 2733

Abstract

The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased [...] Read more.

The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol’s aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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19 pages, 2036 KiB

Open AccessArticle

Effects of Ethanol Exposure and Withdrawal on Neuronal Morphology in the Agranular Insular and Prelimbic Cortices: Relationship with Withdrawal-Related Structural Plasticity in the Nucleus Accumbens

by Madeline E. Frost, Veronica L. Peterson, Clark W. Bird, Brian McCool and Derek A. Hamilton

Brain Sci. 2019, 9(8), 180; https://doi.org/10.3390/brainsci9080180 - 27 Jul 2019

Cited by 9 | Viewed by 4854

Abstract

The present study investigated the effects of chronic intermittent ethanol exposure and withdrawal on dendritic morphology and spine density in the agranular insular and prelimbic cortices. Adult male Sprague–Dawley rats were passively exposed to vaporized ethanol (~37 mg/L; 12 h/day) or air (control) [...] Read more.

The present study investigated the effects of chronic intermittent ethanol exposure and withdrawal on dendritic morphology and spine density in the agranular insular and prelimbic cortices. Adult male Sprague–Dawley rats were passively exposed to vaporized ethanol (~37 mg/L; 12 h/day) or air (control) for ten consecutive days. Dendritic length, branching, and spine density were quantified in layer II/III pyramidal neurons 24 hours or seven days following the final ethanol exposure. Compared to unexposed control animals there were structural alterations on neurons in the prelimbic cortex, and to a lesser extent the agranular insular cortex. The most prominent ethanol-related differences were the transient increases in dendritic length and branching in prelimbic neurons at 24 h post-cessation, and increased mushroom-shaped spines at seven days post-cessation. The results obtained in the prelimbic cortex are the opposite of those previously reported in the nucleus accumbens core (Peterson, et al. 2015), suggesting that these regions undergo distinct functional adaptations following ethanol exposure and withdrawal. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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22 pages, 2782 KiB

Open AccessArticle

Regional Analysis of the Brain Transcriptome in Mice Bred for High and Low Methamphetamine Consumption

by Robert Hitzemann, Ovidiu D. Iancu, Cheryl Reed, Harue Baba, Denesa R. Lockwood and Tamara J. Phillips

Brain Sci. 2019, 9(7), 155; https://doi.org/10.3390/brainsci9070155 - 30 Jun 2019

Cited by 16 | Viewed by 4543

Abstract

Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq [...] Read more.

Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq data from selectively bred mice with high or low risk for voluntary MA intake to construct coexpression and cosplicing networks for differential risk. Three brain reward circuitry regions were explored, the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral midbrain (VMB). With respect to differential gene expression and wiring, the VMB was more strongly affected than either the PFC or NAc. Coexpression network connectivity was higher in the low MA drinking line than in the high MA drinking line in the VMB, oppositely affected in the NAc, and little impacted in the PFC. Gene modules protected from the effects of selection may help to eliminate certain mechanisms from significant involvement in risk for MA intake. One such module was enriched in genes with dopamine-associated annotations. Overall, the data suggest that mitochondrial function and glutamate-mediated synaptic plasticity have key roles in the outcomes of selective breeding for high versus low levels of MA intake. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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15 pages, 1796 KiB

Open AccessArticle

Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice

by John C. Crabbe, Pamela Metten, Antonia M. Savarese, Angela R. Ozburn, Jason P. Schlumbohm, Stephanie E. Spence and Wyatt R. Hack

Brain Sci. 2019, 9(1), 2; https://doi.org/10.3390/brainsci9010002 - 01 Jan 2019

Cited by 17 | Viewed by 4695

Abstract

Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a [...] Read more.

Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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Review

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14 pages, 1161 KiB

Open AccessReview

Involvement of Centrally Projecting Edinger–Westphal Nucleus Neuropeptides in Actions of Addictive Drugs

by Alfredo Zuniga and Andrey E Ryabinin

Brain Sci. 2020, 10(2), 67; https://doi.org/10.3390/brainsci10020067 - 26 Jan 2020

Cited by 14 | Viewed by 4345

Abstract

The centrally-projecting Edinger–Westphal nucleus (EWcp) is a brain region distinct from the preganglionic Edinger–Westphal nucleus (EWpg). In contrast to the EWpg, the EWcp does not send projections to the ciliary ganglion and appears not to regulate oculomotor function. Instead, evidence is accumulating that [...] Read more.

The centrally-projecting Edinger–Westphal nucleus (EWcp) is a brain region distinct from the preganglionic Edinger–Westphal nucleus (EWpg). In contrast to the EWpg, the EWcp does not send projections to the ciliary ganglion and appears not to regulate oculomotor function. Instead, evidence is accumulating that the EWcp is extremely sensitive to alcohol and several other drugs of abuse. Studies using surgical, genetic knockout, and shRNA approaches further implicate the EWcp in the regulation of alcohol sensitivity and self-administration. The EWcp is also known as the site of preferential expression of urocortin 1, a peptide of the corticotropin-releasing factor family. However, neuroanatomical data indicate that the EWcp is not a monotypic brain region and consists of several distinct subpopulations of neurons. It is most likely that these subpopulations of the EWcp are differentially involved in the regulation of actions of addictive drugs. This review summarizes and analyzes the current literature of the EWcp’s involvement in actions of drugs of abuse in male and female subjects in light of the accumulating evidence of complexities of this brain region. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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21 pages, 277 KiB

Open AccessReview

Metabotropic Glutamate Receptor Subtype 5 in Alcohol-Induced Negative Affect

by Chelsea R. Kasten, Eleanor B. Holmgren and Tiffany A. Wills

Brain Sci. 2019, 9(8), 183; https://doi.org/10.3390/brainsci9080183 - 30 Jul 2019

Cited by 12 | Viewed by 3369

Abstract

Allosteric modulators of metabotropic glutamate 5 receptors (mGlu₅ receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol [...] Read more.

Allosteric modulators of metabotropic glutamate 5 receptors (mGlu₅ receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol withdrawal can lead to negative affective states. In turn, these states are primary drivers of alcohol relapse, particularly among women. The current review synthesizes preclinical studies that have observed the role of mGlu₅ receptor modulation in negative affective states following ethanol exposure. The primary behavioral assays discussed are ethanol-seeking and intake, development and extinction of ethanol-associated cues and contexts, behavioral despair, and anxiety-like activity. The work done to-date supports mGlu₅ receptor modulation as a promising target for mediating negative affective states to reduce ethanol intake or prevent relapse. Limitations in interpreting these data include the lack of models that use alcohol-dependent animals, limited use of adolescent and female subjects, and a lack of comprehensive evaluations of negative affective-like behavior. Full article

(This article belongs to the Special Issue Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation)

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