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1.
bioRxiv ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39026700

RESUMO

Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted withdrawal is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTAMOR neurons in mediating protracted withdrawal-induced negative affect is not fully understood. In our study, we elucidate the role of VTAMOR neurons in mediating negative affect and altered brain-wide neuronal activities following opioid exposure and withdrawal in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted withdrawal. VTAMOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted withdrawal is facilitated by this neural population, without affecting other protracted withdrawal behaviors. Lastly, VTAMORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTAMOR neurons as critical modulators of low sociability during protracted withdrawal and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid withdrawal.

2.
Trends Neurosci ; 47(5): 367-382, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38614891

RESUMO

Neonatal opioid withdrawal syndrome (NOWS) is a growing public health concern. The complexity of in utero opioid exposure in clinical studies makes it difficult to investigate underlying mechanisms that could ultimately inform early diagnosis and treatments. Clinical studies are unable to dissociate the influence of maternal polypharmacy or the environment from direct effects of in utero opioid exposure, highlighting the need for effective animal models. Early animal models of prenatal opioid exposure primarily used the prototypical opioid, morphine, and opioid exposure that was often limited to a narrow period during gestation. In recent years, the number of preclinical studies has grown rapidly. Newer models utilize both prescription and nonprescription opioids and vary the onset and duration of opioid exposure. In this review, we summarize novel prenatal opioid exposure models developed in recent years and attempt to reconcile results between studies while critically identifying gaps within the current literature.


Assuntos
Analgésicos Opioides , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal , Animais , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gravidez , Feminino , Analgésicos Opioides/efeitos adversos , Humanos , Síndrome de Abstinência Neonatal , Transtornos Relacionados ao Uso de Opioides
3.
eNeuro ; 11(2)2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38351131

RESUMO

The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse), are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, we show that bath perfusion of morphine (10 µM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability in PVT neurons that project to the NAcSh. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath-perfused morphine (10 µM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1 and D2 receptor-expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP.


Assuntos
Núcleos da Linha Média do Tálamo , Neurônios , Camundongos , Animais , Neurônios/fisiologia , Morfina/farmacologia , Núcleo Accumbens/metabolismo , Recompensa
4.
Neuroscience ; 539: 76-85, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38211933

RESUMO

The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. RATIONALE: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. OBJECTIVES: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. METHODS: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1-10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11-20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. RESULTS: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. CONCLUSIONS: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.


Assuntos
Cocaína , Oxicodona , Adulto , Masculino , Feminino , Humanos , Camundongos , Animais , Oxicodona/farmacologia , Analgésicos Opioides , Polimorfismo de Nucleotídeo Único , Cocaína/farmacologia , Receptores Opioides , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo
5.
J Neurosci ; 44(6)2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38124015

RESUMO

Opioid use disorder is a chronic, relapsing disease associated with persistent changes in brain plasticity. A common single nucleotide polymorphism (SNP) in the µ-opioid receptor gene, OPRM1 A118G, is associated with altered vulnerability to opioid addiction. Reconfiguration of neuronal connectivity may explain dependence risk in individuals with this SNP. Mice with the equivalent Oprm1 variant, A112G, demonstrate sex-specific alterations in the rewarding properties of morphine and heroin. To determine whether this SNP influences network-level changes in neuronal activity, we compared FOS expression in male and female mice that were opioid-naive or opioid-dependent. Network analyses identified significant differences between the AA and GG Oprm1 genotypes. Based on several graph theory metrics, including small-world analysis and degree centrality, we show that GG females in the opioid-dependent state exhibit distinct patterns of connectivity compared to other groups of the same genotype. Using a network control theory approach, we identified key cortical brain regions that drive the transition between opioid-naive and opioid-dependent brain states; however, these regions are less influential in GG females leading to sixfold higher average minimum energy needed to transition from the acute to the dependent state. In addition, we found that the opioid-dependent brain state is significantly less stable in GG females compared to other groups. Collectively, our findings demonstrate sex- and genotype-specific modifications in local, mesoscale, and global properties of functional brain networks following opioid exposure and provide a framework for identifying genotype differences in specific brain regions that play a role in opioid dependence.


Assuntos
Analgésicos Opioides , Transtornos Relacionados ao Uso de Opioides , Masculino , Camundongos , Feminino , Animais , Receptores Opioides , Receptores Opioides mu/metabolismo , Genótipo , Transtornos Relacionados ao Uso de Opioides/genética , Polimorfismo de Nucleotídeo Único/genética
6.
Nat Commun ; 14(1): 5632, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37704594

RESUMO

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.


Assuntos
Analgesia , Dor Crônica , Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Camundongos , Ratos , Macaca , Receptores Opioides , Receptores Opioides mu/genética , Transgenes
7.
Front Behav Neurosci ; 17: 1202099, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37424750

RESUMO

Introduction: Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of somatic withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The heterogeneity of in utero opioid exposure, particularly exposure to polypharmacy, makes it difficult to investigate the underlying molecular mechanisms that could inform early diagnosis and treatment of NOWS, and challenging to investigate consequences later in life. Methods: To address these issues, we developed a mouse model of NOWS that includes gestational and post-natal morphine exposure that encompasses the developmental equivalent of all three human trimesters and assessed both behavior and transcriptome alterations. Results: Opioid exposure throughout all three human equivalent trimesters delayed developmental milestones and produced acute withdrawal phenotypes in mice reminiscent of those observed in infants. We also uncovered different patterns of gene expression depending on the duration and timing of opioid exposure (3-trimesters, in utero only, or the last trimester equivalent only). Opioid exposure and subsequent withdrawal affected social behavior and sleep in adulthood in a sex-dependent manner but did not affect adult behaviors related to anxiety, depression, or opioid response. Discussion: Despite marked withdrawal and delays in development, long-term deficits in behaviors typically associated with substance use disorders were modest. Remarkably, transcriptomic analysis revealed an enrichment for genes with altered expression in published datasets for Autism Spectrum Disorders, which correlate well with the deficits in social affiliation seen in our model. The number of differentially expressed genes between the NOWS and saline groups varied markedly based on exposure protocol and sex, but common pathways included synapse development, the GABAergic and myelin systems, and mitochondrial function.

8.
Transl Psychiatry ; 13(1): 78, 2023 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-36869037

RESUMO

Disrupted sleep is a symptom of many psychiatric disorders, including substance use disorders. Most drugs of abuse, including opioids, disrupt sleep. However, the extent and consequence of opioid-induced sleep disturbance, especially during chronic drug exposure, is understudied. We have previously shown that sleep disturbance alters voluntary morphine intake. Here, we examine the effects of acute and chronic morphine exposure on sleep. Using an oral self-administration paradigm, we show that morphine disrupts sleep, most significantly during the dark cycle in chronic morphine, with a concomitant sustained increase in neural activity in the Paraventricular Nucleus of the Thalamus (PVT). Morphine binds primarily to Mu Opioid Receptors (MORs), which are highly expressed in the PVT. Translating Ribosome Affinity Purification (TRAP)-Sequencing of PVT neurons that express MORs showed significant enrichment of the circadian entrainment pathway. To determine whether MOR + cells in the PVT mediate morphine-induced sleep/wake properties, we inhibited these neurons during the dark cycle while mice were self-administering morphine. This inhibition decreased morphine-induced wakefulness but not general wakefulness, indicating that MORs in the PVT contribute to opioid-specific wake alterations. Overall, our results suggest an important role for PVT neurons that express MORs in mediating morphine-induced sleep disturbance.


Assuntos
Morfina , Transtornos do Sono-Vigília , Animais , Camundongos , Analgésicos Opioides , Receptores Opioides mu , Neurônios , Tálamo
9.
PLoS One ; 17(12): e0270317, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36534642

RESUMO

Key targets of both the therapeutic and abused properties of opioids are µ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3'UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. The breadth of utility of this new tool will greatly facilitate the study of opioid biology under varying conditions.


Assuntos
Analgésicos Opioides , Integrases , Camundongos , Animais , Morfina , Receptores Opioides , Receptores Opioides mu/metabolismo
10.
Neuropharmacology ; 218: 109218, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35973602

RESUMO

The single nucleotide polymorphism (SNP) D398N (rs16969968) in CHRNA5, the gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChR), has been associated with both nicotine and opiate dependence in human populations. Expression of this SNP on presynaptic VTA dopaminergic (DA) neurons is known to cause a reduction in calcium signaling, leading to alterations in transmitter signaling and altered responses to drugs of abuse. To examine the impact of the Chrna5 SNP on opiate reward and underlying dopaminergic mechanisms, mice harboring two copies of the risk-associated allele (Chrna5 A/A) at a location equivalent to human rs16969968 were generated via CRISPR/cas9 genome editing. We sought to determine whether Chrna5 A/A mice show differences in sensitivity to rewarding properties of morphine using the conditioned place preference paradigm. When mice were tested two weeks after conditioning, female Chrna5 A/A mice showed significantly enhanced preference for the morphine-paired chamber relative to WT females, suggesting that this genotype may enhance opioid reward specifically in females. In contrast, Chrna5 genotype had no effect on locomotor sensitization in male or female mice. Relative to WT females, peak amplitude of ACh-gated currents recorded from VTA DA neurons in Chrna5 A/A females was potentiated 1 day after conditioning with morphine. Increased FOS expression was also observed in Chrna5 A/A mice relative to WT mice following exposure to the morphine CPP chamber. We propose that impaired α5 nAChR subunit function alters DA neuron response following repeated morphine exposures, and that this early cellular response could contribute to enhanced opiate reward two weeks after conditioning.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos , Animais , Feminino , Masculino , Camundongos , Morfina/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Nicotina/farmacologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Recompensa
11.
Front Neurosci ; 16: 836693, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250468

RESUMO

The opioid epidemic remains a significant healthcare problem and is attributable to over 100,000 deaths per year. Poor sleep increases sensitivity to pain, impulsivity, inattention, and negative affect, all of which might perpetuate drug use. Opioid users have disrupted sleep during drug use and withdrawal and report poor sleep as a reason for relapse. However, preclinical studies investigating the relationship between sleep loss and substance use and the associated underlying neurobiological mechanisms of potential interactions are lacking. One of the most common forms of sleep loss in modern society is chronic short sleep (CSS) (<7 h/nightly for adults). Here, we used an established model of CSS to investigate the influence of disrupted sleep on opioid reward in male mice. The CSS paradigm did not increase corticosterone levels or depressive-like behavior after a single sleep deprivation session but did increase expression of Iba1, which typically reflects microglial activation, in the hypothalamus after 4 weeks of CSS. Rested control mice developed a morphine preference in a 2-bottle choice test, while mice exposed to CSS did not develop a morphine preference. Both groups demonstrated morphine conditioned place preference (mCPP), but there were no differences in conditioned preference between rested and CSS mice. Taken together, our results show that recovery sleep after chronic sleep disruption lessens voluntary opioid intake, without impacting conditioned reward associated with morphine.

12.
Nat Commun ; 13(1): 55, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013139

RESUMO

Although the synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood. Here, we perform complementary bulk nuclei- and single-nucleus transcriptome profiling and map locus-specific chromatin interactions in mouse neocortex to identify the cell type-specific transcriptional changes associated with stress-induced behavioral maladaptation. We find that cortical excitatory neurons, layer 2/3 neurons in particular, are vulnerable to chronic stress and acquire signatures of gene transcription and chromatin structure associated with reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in cortical excitatory neurons enhances stress sensitivity in both male and female mice and alters the expression of stress-associated genes following an abbreviated stress exposure. These findings demonstrate how chronic stress impacts transcription in cortical excitatory neurons and identify YY1 as a regulator of stress-induced maladaptive behavior in mice.


Assuntos
Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo , Animais , Comportamento Animal , Cromatina/metabolismo , Epigenômica , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Fisiológico
13.
Behav Brain Res ; 419: 113688, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34843742

RESUMO

Serotonin neurotransmission has been implicated in behavior deficits that occur during protracted withdrawal from opioids. In addition, studies have highlighted multiple pathways whereby serotonin (5-HT) modulates energy homeostasis, however the underlying metabolic effects of opioid withdrawal have not been investigated. A key metabolic regulator that senses the energy status of the cell and regulates fuel availability is Adenosine Monophosphate-activated Protein Kinase (AMPK). To investigate the interaction between cellular metabolism and serotonin in modulating protracted abstinence from morphine, we depleted AMPK in serotonin neurons. Morphine exposure via drinking water generates dependence in these mice, and both wildtype and serotonergic AMPK knockout mice consume similar amounts of morphine with no changes in body weight. Serotonergic AMPK contributes to baseline differences in open field and social interaction behaviors and blocks abstinence induced reductions in immobility following morphine withdrawal in the tail suspension test. Lastly, morphine locomotor sensitization is blunted in mice lacking AMPK in serotonin neurons. Taken together, our results suggest serotonergic AMPK mediates both baseline and protracted morphine withdrawal-induced behaviors.


Assuntos
Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Dependência de Morfina/metabolismo , Dependência de Morfina/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
14.
Transl Perioper Pain Med ; 9(4): 491-496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36935906

RESUMO

The world is in the midst of an opioid crisis. Nearly 92,000 persons in the U.S. alone died from illicit drugs and prescription opioids in 2020 [1]. This number does not include the countless other individuals who die as a result of the violent crime that accompanies the illicit drug trade. To address this crisis, we need to appreciate aspects of drug addiction. The goal of this brief review is to highlight some major facets of addiction neurobiology, focused on opioids, to provide a basic understanding of the research and terminology encountered in more detailed in-depth articles and discussions on addiction.

15.
Soc Cogn Affect Neurosci ; 17(1): 120-130, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33227131

RESUMO

Increased aggression and impulsivity represent a key component of several psychiatric disorders, including substance use disorder, which is often associated with deficient prefrontal brain activation. Thus, innovative tools to increase cognitive control are highly warranted. The current study investigates the potential of transcranial direct current stimulation (tDCS), a tool to modulate cortical activation and to increase cognitive control in individuals with a high potential for impulsive and aggressive behavior. In a double-blind, sham-controlled study, we applied anodal tDCS over the right dorsolateral prefrontal cortex in an all-male sample of alcohol-dependent patients (AD), tobacco users (TU) and healthy controls (HC), who completed the Taylor Aggression Paradigm and Stop Signal Reaction Time Task twice. While there were no observable effects of tDCS in controls, the results revealed altered aggressive behavior in AD following active stimulation. Specifically, these individuals did not show the standard increase in aggression over time seen in the other groups. Furthermore, improved response inhibition was found in AD and TU following active but not sham stimulation. Our study demonstrates that prefrontal tDCS improves our laboratory measure of impulse control in at-risk groups, illustrating the importance of sample characteristics such as nicotine intake and personality traits for understanding the effects of brain stimulation.


Assuntos
Estimulação Transcraniana por Corrente Contínua , Agressão/fisiologia , Método Duplo-Cego , Humanos , Comportamento Impulsivo/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Tempo de Reação , Estimulação Transcraniana por Corrente Contínua/métodos
16.
Allergol Int ; 71(1): 55-65, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34688555

RESUMO

BACKGROUND: Although population studies have implicated emotional burden in asthma severity, the underlying genetic risk factors are not completely understood. We aimed to evaluate the genetic influence of a functional single-nucleotide polymorphism (SNP) in the stress-related µ-opioid receptor gene (OPRM1; A118G SNP, rs1799971) on asthma severity. METHODS: We initially assessed disease severity in asthmatic outpatients carrying A118G. Using an ovalbumin-induced experimental asthma rodent model harboring the functionally equivalent SNP, we investigated the mechanism by which this SNP influences the allergic immune response. RESULTS: Among 292 outpatients, 168 underwent airway hyperresponsiveness (AHR) to methacholine testing. Compared with patients carrying the AA and AG genotypes, those carrying the GG genotype exhibited enhanced AHR. The stress levels were presumed to be moderate among patients and were comparable among genotypes. Compared with Oprm1 AA mice, GG mice demonstrated aggravated asthma-related features and increased pulmonary interleukin-4+CD4+ effector and effector memory T cells under everyday life stress conditions. Intraperitoneal naloxone methiodide injection reduced effector CD4+ T cell elevation associated with increased eosinophil numbers in bronchoalveolar lavage fluid of GG mice to the levels in AA mice, suggesting that elevated Th2 cell generation in the bronchial lymph node (BLN) of GG mice induces enhanced eosinophilic inflammation. CONCLUSIONS: Without forced stress exposure, patients with asthma carrying the OPRM1 GG genotype exhibit enhanced AHR, attributable to enhanced Th2 cell differentiation in the regional lymph node. Further research is necessary to elucidate the role of the OPRM1 A118G genotype in the Th2 cell differentiation pathway in the BLN.


Assuntos
Asma/genética , Receptores Opioides mu/genética , Índice de Gravidade de Doença , Adulto , Animais , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Células Th2/metabolismo
17.
Neuropharmacology ; 186: 108480, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33539855

RESUMO

Genetics are known to be a significant risk factor for drug abuse. In human populations, the single nucleotide polymorphism (SNP) D398N in the gene CHRNA5 has been associated with addiction to nicotine, opioids, cocaine, and alcohol. In this paper, we review findings from studies in humans, rodent models, and cell lines and provide evidence that collectively suggests that the Chrna5 SNP broadly influences the response to drugs of abuse in a manner that is not substance-specific. This finding has important implications for our understanding of the role of the cholinergic system in reward and addiction vulnerability. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'


Assuntos
Encéfalo/fisiologia , Ligação Genética/fisiologia , Rede Nervosa/fisiologia , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Animais , Encéfalo/diagnóstico por imagem , Ligação Genética/genética , Humanos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroimagem/métodos , Receptores Nicotínicos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Transtornos Relacionados ao Uso de Substâncias/metabolismo
18.
Front Mol Neurosci ; 14: 790213, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35002622

RESUMO

Psychedelic compounds that target the 5-HT2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however, the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through mitogen-activated protein (MAP) kinase and calcium/calmodulin dependent kinase II (CaMKII) pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb, and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo. This DOI-evoked upregulation of neuronal plasticity-associated genes was completely blocked by the 5-HT2A receptor antagonist MDL100,907 in vitro and was also abrogated in the neocortex of 5-HT2A receptor deficient mice. Further, 5-HT2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc, Bdnf1, Cebpb, cFos, but not Egr1 and Egr2, promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc, cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient/knockout (CREBαδ KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.

19.
Addict Biol ; 26(4): e12994, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33325096

RESUMO

Prescription opioid misuse is a major public health concern among children and adolescents in the United States. Opioids are the most commonly abused drugs and are the fastest growing drug problem among adolescents. In humans and animals, adolescence is a particularly sensitive period associated with an increased response to drugs of abuse. Our previous studies indicate that oxycodone exposure during adolescence increases morphine reward in adulthood. How early drug exposure mediates long-term changes in the brain and behavior is not known, but epigenetic regulation is a likely mechanism. To address this question, we exposed mice to oxycodone or saline during adolescence and examined epigenetic modifications at genes associated with dopamine activity during adulthood at early and late withdrawal, in the ventral tegmental area (VTA). We then compared these with alterations in the VTA of adult-treated mice following an equivalent duration of exposure and withdrawal to determine if the effects of oxycodone are age dependent. We observed persistence of adolescent-like gene expression following adolescent oxycodone exposure relative to age-matched saline exposed controls, although dopamine-related gene expression was transiently activated at 1 day of withdrawal. Following prolonged withdrawal enrichment of the repressive histone mark, H3K27me3, was maintained, consistent with inhibition of gene regulation following adolescent exposure. By contrast, mice exposed to oxycodone as adults showed loss of the repressive mark and increased gene expression following 28 days of withdrawal following oxycodone exposure. Together, our findings provide evidence that adolescent oxycodone exposure has long-term epigenetic consequences in VTA of the developing brain.


Assuntos
Analgésicos Opioides/metabolismo , Dopamina/metabolismo , Expressão Gênica/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Oxicodona/metabolismo , Animais , Epigênese Genética/efeitos dos fármacos , Masculino , Camundongos , Morfina/metabolismo , Recompensa , Autoadministração , Área Tegmentar Ventral/efeitos dos fármacos
20.
Neuropharmacology ; 181: 108351, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33031806

RESUMO

The widely abused prescription opioid oxycodone is a mu-opioid receptor (MOP-r) agonist and addiction to such opioids is a relapsing disorder. The human MOP-r gene (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G, which affects risk of severe opioid use disorders. A112G (G/G) knock-in mice are models of human A118G carriers. We examined oxycodone self-administration (SA) in male and female G/G versus wild type (A/A) mice in SA sessions and in relapse-like behavior. Adult male and female G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, FR1) for 10 consecutive days. Following 10-day home cage drug free withdrawal, the mice were re-exposed to oxycodone SA for a further 10 days. MOP-r receptor mRNA in various brain regions were examined immediately after the last re-exposure session. We found that G/G mice had greater oxycodone SA than A/A mice in the initial and in re-exposure sessions. Mice of both genotypes had greater oxycodone intake during the re-exposure period than during the initial exposure. We also detected differences in MOP-r gene expression due to genotype, sex and oxycodone SA history in the dorsal striatum, hippocampus, and prefrontal cortex. These studies may improve our understanding of MOP-r-agonist self-exposure and relapse in human carriers of the A118G SNP.


Assuntos
Entorpecentes/farmacologia , Oxicodona/farmacologia , Receptores Opioides mu/genética , Animais , Corpo Estriado/efeitos dos fármacos , Feminino , Técnicas de Introdução de Genes , Genótipo , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Entorpecentes/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Oxicodona/administração & dosagem , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Autoadministração , Caracteres Sexuais , Abuso de Substâncias por Via Intravenosa , Síndrome de Abstinência a Substâncias/psicologia
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