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20 pages, 1858 KiB

Open AccessArticle

Plasma Amino Acid Concentrations in Patients with Alcohol and/or Cocaine Use Disorders and Their Association with Psychiatric Comorbidity and Sex

by Nuria García-Marchena, Alberto Marcos, María Flores-López, Mario Moreno-Fernández, Nerea Requena-Ocaña, Oscar Porras-Perales, Sandra Torres-Galván, Pedro Araos, Antonia Serrano, Roberto Muga, Juan Jesús Ruiz-Ruiz, Fernando Rodríguez de Fonseca, Emilio Ambrosio and Francisco Javier Pavón-Morón

Biomedicines 2022, 10(5), 1137; https://doi.org/10.3390/biomedicines10051137 - 14 May 2022

Viewed by 2406

Abstract

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders [...] Read more.

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders and biomarkers show sex differences, we investigated amino acids in men and women with alcohol and/or cocaine use disorders (AUD and/or CUD) and psychiatric comorbidity. (2) Methods: A cross-sectional study was conducted in 295 participants, who were divided into four groups (AUD, n = 60; CUD, n = 41; AUD + CUD, n = 64; and control, n = 130). Participants were clinically assessed, and plasma amino acid concentrations were analyzed in relation to sex, diagnosis of SUD and psychiatric comorbidity (3) Results: In the total sample, there were sex differences, and women showed lower Iso, Leu, Gln and Glu than men. While patients with CUD and AUD + CUD had higher Glu, Gly, Orn and Ser than controls, patients with AUD showed no differences. In SUD, patients with psychiatric comorbidity had lower Orn and higher Ala than non-comorbid patients in the AUD group. (4) Conclusions: There was a dysregulation of plasma amino acids in abstinent patients with SUD. However, our results suggest the importance of considering the clinical characteristics and sex in the validity of amino acids as potential biomarkers for SUD. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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19 pages, 2330 KiB

Open AccessArticle

Vascular Endothelial Growth Factor as a Potential Biomarker of Neuroinflammation and Frontal Cognitive Impairment in Patients with Alcohol Use Disorder

by Nerea Requena-Ocaña, María Flores-Lopez, Esther Papaseit, Nuria García-Marchena, Juan Jesús Ruiz, Jesús Ortega-Pinazo, Antonia Serrano, Francisco Javier Pavón-Morón, Magí Farré, Juan Suarez, Fernando Rodríguez de Fonseca and Pedro Araos

Biomedicines 2022, 10(5), 947; https://doi.org/10.3390/biomedicines10050947 - 20 Apr 2022

Cited by 9 | Viewed by 2359

Abstract

(1) Background: Alcohol Use Disorder (AUD) is associated with functional disruption of several brain structures that may trigger cognitive dysfunction. One of the mechanisms of alcohol-associated cognitive impairment has been proposed to arise from its direct impact on the immune system, which culminates [...] Read more.

(1) Background: Alcohol Use Disorder (AUD) is associated with functional disruption of several brain structures that may trigger cognitive dysfunction. One of the mechanisms of alcohol-associated cognitive impairment has been proposed to arise from its direct impact on the immune system, which culminates in the release of cytokines and chemokines which can eventually reach the brain. Alcohol can also disrupt the blood–brain barrier, facilitating the penetration of pro-inflammatory molecules throughout vascular endothelial growth factor A (VEGFA). Thus, alcohol-induced alterations in chemokines and VEGFA might contribute to the neuroinflammation and cognitive impairment associated with AUD. (2) Methods: The present cross-sectional study investigates whether patients with AUD (n = 86) present cognitive disability associated to alterations in plasma concentration of SDF-1, fractalkine, eotaxin, MCP-1, MIP-1α and VEGFA when compared to control subjects (n = 51). (3) Results: The analysis indicated that SDF-1 and MCP-1 concentrations were higher in AUD patients than in controls. Concentrations of VEGFA were higher in AUD patients with severe frontal deficits, and the score of frontal lobe functions was negatively correlated with VEGFA and fractalkine. Acute alcohol effects on VEGFA plasma levels in healthy volunteers demonstrated the induction of VEGFA release by heavy alcohol drinking. VEGFA was positively correlated with pro-inflammatory chemokines in AUD patients with frontal cognitive impairment. (4) Conclusions: we propose VEGFA/chemokine monitoring as biomarkers of potential cognitive impairment in AUD patients. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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22 pages, 3101 KiB

Open AccessArticle

Repeated Restraint Stress and Binge Alcohol during Adolescence Induce Long-Term Effects on Anxiety-like Behavior and the Expression of the Endocannabinoid System in Male Rats

by Laura Sánchez-Marín, María Flores-López, Ana L. Gavito, Juan Suárez, Francisco Javier Pavón-Morón, Fernando Rodríguez de Fonseca and Antonia Serrano

Biomedicines 2022, 10(3), 593; https://doi.org/10.3390/biomedicines10030593 - 3 Mar 2022

Cited by 2 | Viewed by 2376

Abstract

(1) Background: Negative experiences during adolescence increase the vulnerability to develop mental disorders later in life. A better understanding of the mechanisms underlying these long-term alterations could help to identify better therapeutic interventions. (2) Methods: Adolescent male Wistar rats were used to explore [...] Read more.

(1) Background: Negative experiences during adolescence increase the vulnerability to develop mental disorders later in life. A better understanding of the mechanisms underlying these long-term alterations could help to identify better therapeutic interventions. (2) Methods: Adolescent male Wistar rats were used to explore the effects of repeated stress and alcohol exposure on anxiety-like behaviors, plasma corticosterone levels and the gene expression of the endocannabinoid system (ECS) and other relevant signaling systems (glutamatergic, corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY)) in the amygdala and the medial prefrontal cortex (mPFC). (3) Results: Overall, both stress and alcohol induced anxiety-like behaviors, but only the alcohol-exposed rats displayed increased plasma levels of corticosterone. In the amygdala, there was a general deficit in the gene expression of the ECS and increases in the mRNA levels of certain subunits of glutamate receptors. Interestingly, there were significant interaction effects between stress and alcohol on the expression of the NMDA receptor subunits. In addition, increased mRNA levels of the CRH receptor were observed in alcohol-exposed rats. In the mPFC, alcohol exposure was associated with an increase in the gene expression of the ECS. By contrast, the combination of stress and alcohol produced opposite effects. (4) Conclusions: In summary, early stress and alcohol exposure induced long-term anxiety-like behavior in male rats but different mechanisms are involved in these maladaptive changes in the brain. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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23 pages, 3224 KiB

Open AccessArticle

Molecular Mechanisms Underlying the Retrieval and Extinction of Morphine Withdrawal-Associated Memories in the Basolateral Amygdala and Dentate Gyrus

by Aurelio Franco-García, Francisco José Fernández-Gómez, Victoria Gómez-Murcia, Juana M. Hidalgo, M. Victoria Milanés and Cristina Núñez

Biomedicines 2022, 10(3), 588; https://doi.org/10.3390/biomedicines10030588 - 2 Mar 2022

Cited by 6 | Viewed by 2599

Abstract

Despite their indisputable efficacy for pain management, opiate prescriptions remain highly controversial partially due to their elevated addictive potential. Relapse in drug use is one of the principal problems for addiction treatment, with drug-associated memories being among its main triggers. Consequently, the extinction [...] Read more.

Despite their indisputable efficacy for pain management, opiate prescriptions remain highly controversial partially due to their elevated addictive potential. Relapse in drug use is one of the principal problems for addiction treatment, with drug-associated memories being among its main triggers. Consequently, the extinction of these memories has been proposed as a useful therapeutic tool. Hence, by using the conditioned place aversion (CPA) paradigm in rats, we investigated some of the molecular mechanisms that occurr during the retrieval and extinction of morphine withdrawal memories in the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which control emotional and episodic memories, respectively. The retrieval of aversive memories associated with the abstinence syndrome paralleled with decreased mTOR activity and increased Arc and GluN1 expressions in the DG. Additionally, Arc mRNA levels in this nucleus very strongly correlated with the CPA score exhibited by the opiate-treated rats. On the other hand, despite the unaltered mTOR phosphorylation, Arc levels augmented in the BLA. After the extinction test, Arc and GluN1 expressions were raised in both the DG and BLA of the control and morphine-treated animals. Remarkably, Homer1 expression in both areas correlated almost perfectly with the extinction showed by morphine-dependent animals. Moreover, Arc expression in the DG correlated strongly with the extinction of the CPA manifested by the group treated with the opiate. Finally, our results support the coordinated activity of some of these neuroplastic proteins for the extinction of morphine withdrawal memories in a regional-dependent manner. Present data provide evidence of differential expression and activity of synaptic molecules during the retrieval and extinction of aversive memories of opiate withdrawal in the amygdalar and hippocampal regions that will likely permit the development of therapeutic strategies able to minimize relapses induced by morphine withdrawal-associated aversive memories. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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17 pages, 1159 KiB

Open AccessArticle

The Combination of Galanin (1–15) and Escitalopram in Rats Suggests a New Strategy for Alcohol Use Disorder Comorbidity with Depression

by Noelia Cantero-García, Antonio Flores-Burgess, David Ladrón de Guevara-Miranda, Antonia Serrano, Laura García-Durán, Araceli Puigcerver, Kjell Fuxe, José Ángel Narváez, Luis Javier Santín, Zaida Díaz-Cabiale and Carmelo Millón

Biomedicines 2022, 10(2), 412; https://doi.org/10.3390/biomedicines10020412 - 9 Feb 2022

Cited by 2 | Viewed by 1871

Abstract

Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffer major depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanol drinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacological strategies that could modulate [...] Read more.

Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffer major depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanol drinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacological strategies that could modulate alcohol consumption and depression is necessary. We have analyzed the effect of Galanin (1–15) [GAL(1–15)] on escitalopram (ESC)-mediated effect in alcohol consumption using the alcohol self-administration test, the nuclei involved in the effect, and whether GAL(1–15) + ESC modulated the response in despair or anxiety tests in animals under chronic alcohol intake. GAL(1–15) + ESC combination substantially reduced alcohol intake in the alcohol self-administration test and, moreover, enhanced the reduction of reward capacity of ESC on different reinforcers such as sucrose or saccharine. GAL(1–15) + ESC coadministration significantly decreases the number of C-Fos-IR TH cell bodies in the VTA, and PCA analysis suggests that one functional network, including VTA, RMTg and DR, is involved in these effects. Significantly in rats with chronic alcohol consumption, GAL(1–15) reversed adverse ESC-mediated effects in the depression-related behavioural test and forced swimming test. The results open up the possibility of using GAL(1–15) in combination with the SSRI Escitalopram as a novel strategy in AUD comorbidity with depression. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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25 pages, 4240 KiB

Open AccessArticle

Disinhibition-Like Behavior Correlates with Frontal Cortex Damage in an Animal Model of Chronic Alcohol Consumption and Thiamine Deficiency

by Marta Moya, Leticia López-Valencia, Borja García-Bueno and Laura Orio

Biomedicines 2022, 10(2), 260; https://doi.org/10.3390/biomedicines10020260 - 25 Jan 2022

Cited by 3 | Viewed by 3095

Abstract

Wernicke–Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated with impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the [...] Read more.

Wernicke–Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated with impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, either isolated or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation (TDD)), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior which appeared to be dependent on TDD. Additionally, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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22 pages, 3821 KiB

Open AccessArticle

Alterations in the Proteome and Phosphoproteome Profiles of Rat Hippocampus after Six Months of Morphine Withdrawal: Comparison with the Forebrain Cortex

by Hana Ujcikova, Adam Eckhardt, Lucie Hejnova, Jiri Novotny and Petr Svoboda

Biomedicines 2022, 10(1), 80; https://doi.org/10.3390/biomedicines10010080 - 31 Dec 2021

Cited by 6 | Viewed by 2928

Abstract

The knowledge about proteome changes proceeding during protracted opioid withdrawal is lacking. Therefore, the aim of this work was to analyze the spectrum of altered proteins in the rat hippocampus in comparison with the forebrain cortex after 6-month morphine withdrawal. We utilized 2D [...] Read more.

The knowledge about proteome changes proceeding during protracted opioid withdrawal is lacking. Therefore, the aim of this work was to analyze the spectrum of altered proteins in the rat hippocampus in comparison with the forebrain cortex after 6-month morphine withdrawal. We utilized 2D electrophoretic workflow (Pro-Q^® Diamond staining and Colloidal Coomassie Blue staining) which was preceded by label-free quantification (MaxLFQ). The phosphoproteomic analysis revealed six significantly altered hippocampal (Calm1, Ywhaz, Tuba1b, Stip1, Pgk1, and Aldoa) and three cortical proteins (Tubb2a, Tuba1a, and Actb). The impact of 6-month morphine withdrawal on the changes in the proteomic profiles was higher in the hippocampus—14 proteins, only three proteins were detected in the forebrain cortex. Gene Ontology (GO) enrichment analysis of differentially expressed hippocampal proteins revealed the most enriched terms related to metabolic changes, cytoskeleton organization and response to oxidative stress. There is increasing evidence that energy metabolism plays an important role in opioid addiction. However, the way how morphine treatment and withdrawal alter energy metabolism is not fully understood. Our results indicate that the rat hippocampus is more susceptible to changes in proteome and phosphoproteome profiles induced by 6-month morphine withdrawal than is the forebrain cortex. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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10 pages, 722 KiB

Open AccessArticle

Oxytocin Attenuates the Stress-Induced Reinstatement of Alcohol-Seeking in Male Rats: Role of the Central Amygdala

by Hannah S. Ballas, Samantha M. Wilfur, Nicole A. Freker and Kah-Chung Leong

Biomedicines 2021, 9(12), 1919; https://doi.org/10.3390/biomedicines9121919 - 15 Dec 2021

Cited by 10 | Viewed by 2955

Abstract

Factors such as stress and anxiety often contribute to alcohol-dependent behavior and can trigger a relapse of alcohol addiction and use. Therefore, it is important to investigate potential pharmacological interventions that may alleviate the influence of stress on addiction-related behaviors. Previous studies have [...] Read more.

Factors such as stress and anxiety often contribute to alcohol-dependent behavior and can trigger a relapse of alcohol addiction and use. Therefore, it is important to investigate potential pharmacological interventions that may alleviate the influence of stress on addiction-related behaviors. Previous studies have demonstrated that the neuropeptide oxytocin has promising anxiolytic potential in mammals and may offer a pharmacological target to diminish the emotional impact on reinstatement of alcohol-seeking. The purpose of the present study was to investigate the effect of oxytocin on stress-induced alcohol relapse and identify a neural structure mediating this effect through the use of an ethanol self-administration and yohimbine-induced reinstatement paradigm. While yohimbine administration resulted in the reinstatement of ethanol-seeking behavior, the concurrent administration of yohimbine and oxytocin attenuated this effect, suggesting that oxytocin may disrupt stress-induced ethanol-seeking behavior. The central amygdala (CeA) is a structure that drives emotional responses and robustly expresses oxytocin receptors. Intra-CeA oxytocin similarly attenuated the yohimbine-induced reinstatement of ethanol-seeking behavior. These results demonstrate that oxytocin has the potential to attenuate stress-induced relapse into ethanol-seeking behavior, and that this mechanism occurs specifically within the central amygdala. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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15 pages, 716 KiB

Open AccessArticle

Plasma Concentrations of Lysophosphatidic Acid and Autotaxin in Abstinent Patients with Alcohol Use Disorder and Comorbid Liver Disease

by María Flores-López, Nuria García-Marchena, Francisco Javier Pavon, Estrella Lara, Oscar Porras-Perales, Pedro Araos, Nerea Requena-Ocaña, Sandra Torres-Galván, M. Carmen Mañas-Padilla, Gabriel Rubio, Juan Suárez, Luis J. Santín, Fernando Rodríguez de Fonseca, Estela Castilla-Ortega, María I. García-Fernández and Antonia Serrano

Biomedicines 2021, 9(9), 1207; https://doi.org/10.3390/biomedicines9091207 - 13 Sep 2021

Cited by 5 | Viewed by 2447

Abstract

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX–LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical [...] Read more.

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX–LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX–LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX–LPA axis and AUD or liver disease. LPA and ATX were log₁₀-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F_(1,131) = 10.677, p = 0.001) and higher ATX (F_(1,131) = 8.327, p = 0.005) concentrations than control subjects; patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, p < 0.05) than patients with AUD but not liver disease; significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, p < 0.05); and the severity of AUD with ATX (rho = −0.33, p < 0.05)); and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, p < 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX–LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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11 pages, 1762 KiB

Open AccessArticle

Cytokine (IL-10, IL-6, TNF-α and TGF-β1) Gene Polymorphisms in Chronic Hepatitis C Virus Infection among Malay Male Drug Abusers

by Ismail Che Noh, Imran Ahmad, Siti Suraiya, Nur Fadhlina Musa, Asma Abdullah Nurul and Abu Bakar Ruzilawati

Biomedicines 2021, 9(9), 1115; https://doi.org/10.3390/biomedicines9091115 - 30 Aug 2021

Cited by 3 | Viewed by 2104

Abstract

Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis [...] Read more.

Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis C virus infection susceptibility and cytokine gene polymorphism for interleukin-10 (IL-10) rs1800896 and rs1800871, interleukin 6 (IL-6) rs1800795, TNF-α rs1800629, and TGF-β1 rs1800471 in Malay male drug abusers. The study was conducted on 76 HCV-positive (HP) male drug abusers and 40 controls (HCV-negative male drug abusers). We found that there were significant differences in the frequencies of genotype for IL-10 rs1800871 (p = 0.0386) and at the allelic level for IL-10 rs1800896 A versus G allele (p = 0.0142) between the HP group and the control group. However, there were no significant differences in gene polymorphism in interleukin 6 rs1800795, TNF-α rs1800629 and TGF-β1 rs1800471. These findings suggest significant associations between gene polymorphism for IL-10 rs1800871, IL-10 rs1800896 (at the allelic level) and susceptibility to HCV infection among Malay male drug abusers. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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14 pages, 1447 KiB

Open AccessArticle

Environmental Enrichment Rescues Endocannabinoid-Dependent Synaptic Plasticity Lost in Young Adult Male Mice after Ethanol Exposure during Adolescence

by Irantzu Rico-Barrio, Sara Peñasco, Leire Lekunberri, Maitane Serrano, Jon Egaña-Huguet, Amaia Mimenza, Edgar Soria-Gomez, Almudena Ramos, Ianire Buceta, Inmaculada Gerrikagoitia, Juan Mendizabal-Zubiaga, Izaskun Elezgarai, Nagore Puente and Pedro Grandes

Biomedicines 2021, 9(7), 825; https://doi.org/10.3390/biomedicines9070825 - 16 Jul 2021

Cited by 5 | Viewed by 3652

Abstract

Binge drinking (BD) is a serious health concern in adolescents as high ethanol (EtOH) consumption can have cognitive sequelae later in life. Remarkably, an enriched environment (EE) in adulthood significantly recovers memory in mice after adolescent BD, and the endocannabinoid, 2-arachydonoyl-glycerol (2-AG), rescues [...] Read more.

Binge drinking (BD) is a serious health concern in adolescents as high ethanol (EtOH) consumption can have cognitive sequelae later in life. Remarkably, an enriched environment (EE) in adulthood significantly recovers memory in mice after adolescent BD, and the endocannabinoid, 2-arachydonoyl-glycerol (2-AG), rescues synaptic plasticity and memory impaired in adult rodents upon adolescent EtOH intake. However, the mechanisms by which EE improves memory are unknown. We investigated this in adolescent male C57BL/6J mice exposed to a drinking in the dark (DID) procedure four days per week for a duration of 4 weeks. After DID, the mice were nurtured under an EE for 2 weeks and were subjected to the Barnes Maze Test performed the last 5 days of withdrawal. The EE rescued memory and restored the EtOH-disrupted endocannabinoid (eCB)-dependent excitatory long-term depression at the dentate medial perforant path synapses (MPP-LTD). This recovery was dependent on both the cannabinoid CB1 receptor and group I metabotropic glutamate receptors (mGluRs) and required 2-AG. Also, the EE had a positive effect on mice exposed to water through the transient receptor potential vanilloid 1 (TRPV1) and anandamide (AEA)-dependent MPP long-term potentiation (MPP-LTP). Taken together, EE positively impacts different forms of excitatory synaptic plasticity in water- and EtOH-exposed brains. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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25 pages, 980 KiB

Open AccessReview

Alcohol Use Disorder: Neurobiology and Therapeutics

by Waisley Yang, Rohit Singla, Oshin Maheshwari, Christine J. Fontaine and Joana Gil-Mohapel

Biomedicines 2022, 10(5), 1192; https://doi.org/10.3390/biomedicines10051192 - 21 May 2022

Cited by 19 | Viewed by 16188

Abstract

Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes [...] Read more.

Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response. Despite serious health and psychosocial consequences, this disorder still remains one of the leading causes of death globally. Treatment options include both psychological and pharmacological interventions, which are aimed at reducing alcohol consumption and/or promoting abstinence while also addressing dysfunctional behaviours and impaired functioning. However, stigma and social barriers to accessing care continue to impact many individuals. AUD treatment should focus not only on restoring the physiological and neurological impairment directly caused by alcohol toxicity but also on addressing psychosocial factors associated with AUD that often prevent access to treatment. This review summarizes the impact of alcohol toxicity on brain neurocircuitry in the context of AUD and discusses pharmacological and non-pharmacological therapies currently available to treat this addiction disorder. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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34 pages, 2311 KiB

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The Use of Drosophila to Understand Psychostimulant Responses

by Travis James Philyaw, Adrian Rothenfluh and Iris Titos

Biomedicines 2022, 10(1), 119; https://doi.org/10.3390/biomedicines10010119 - 6 Jan 2022

Cited by 8 | Viewed by 4363

Abstract

The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat [...] Read more.

The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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13 pages, 4297 KiB

Open AccessReview

Is It Possible to Shift from Down to Top Rank? A Focus on the Mesolimbic Dopaminergic System and Cocaine Abuse

by Inês M. Amaral, Alex Hofer and Rana El Rawas

Biomedicines 2021, 9(8), 877; https://doi.org/10.3390/biomedicines9080877 - 23 Jul 2021

Cited by 4 | Viewed by 2341

Abstract

Impaired social behavior is a common feature of many psychiatric disorders, in particular with substance abuse disorders. Switching the preference of the substance-dependent individual toward social interaction activities remains one of the major challenges in drug dependence therapy. However, social interactions yield to [...] Read more.

Impaired social behavior is a common feature of many psychiatric disorders, in particular with substance abuse disorders. Switching the preference of the substance-dependent individual toward social interaction activities remains one of the major challenges in drug dependence therapy. However, social interactions yield to the emergence of social ranking. In this review, we provide an overview of the studies that examined how social status can influence the dopaminergic mesolimbic system and how drug-seeking behavior is affected. Generally, social dominance is associated with an increase in dopamine D_2/3 receptor binding in the striatum and a reduced behavioral response to drugs of abuse. However, it is not clear whether higher D₂ receptor availability is a result of increased D₂ receptor density and/or reduced dopamine release in the striatum. Here, we discuss the possibility of a potential shift from down to top rank via manipulation of the mesolimbic system. Identifying the neurobiology underlying a potential rank switch to a resilient phenotype is of particular interest in order to promote a positive coping behavior toward long-term abstinence from drugs of abuse and a protection against relapse to drugs. Such a shift may contribute to a more successful therapeutic approach to cocaine addiction. Full article

(This article belongs to the Special Issue Biological Aspects of Drug Addiction)

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