Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE212417 | GEO | 2023/08/09
REPOSITORIES: GEO
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Project description:Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala
| PRJNA875396 | ENA
Project description:The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABAA receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.
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Project description:Isolation stress is a major risk factor for neuropsychiatric disorders such as depressive and anxiety disorders. However, the molecular mechanisms underlying isolation-induced neuropsychiatric disorders remain elusive. In the present study, we investigated the subcellular mechanisms by which long-term isolation elicits depression and anxiety-related behaviors in mice. First, we found that long-term isolation induced depression-related behaviors in the forced swimming test (FST) and the sucrose preference test, as well as anxiety-related behaviors in the elevated zero maze test (EZMT) and the open field test. Next, we showed that intracentral amygdala (CeA) injection of oxytocin (OXT), but not intracerebroventricular injection, attenuated isolation-induced depression and anxiety-related behaviors via oxytocin receptor (OXTR), not vasopressin-1a receptor (V1aR), in the FST and EZMT, respectively. Quantitative real-time polymerase chain reaction analysis revealed that after 5 weeks of isolation, mRNA transcription of OXTR in the CeA, but not that of V1aR, significantly decreased, whereas OXT and vasopressin mRNA transcription in the paraventricular nucleus of hypothalamus did not change significantly. Whole-cell patch clamping of acute brain slices demonstrated that the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in CeA neurons, but not their amplitude, was lower in isolated mice than in group-housed mice. Notably, OXT treatment increased the mIPSC frequency in the CeA neurons, but to a lesser extent in the case of isolated mice than in that of group-housed mice via OXTR. Taken together, our findings suggest that long-term isolation down-regulates OXTR mRNA transcription and diminishes OXT-induced inhibitory synaptic transmission in the CeA and may contribute to the development of depression and anxiety-related behaviors in isolated mice through the enhancement of CeA activity.
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Project description:Cocaine abuse is a world-wide public health and social problem without a US Food and Drug Administration-approved medication. An ideal anticocaine medication would accelerate cocaine metabolism, producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Our recent studies have led to the discovery of the desirable, highly efficient cocaine hydrolases (CocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of the CNS. Preclinical and clinical data have demonstrated that these CocHs are safe for use in humans and are effective for accelerating cocaine metabolism. However, the actual therapeutic use of a CocH in cocaine addiction treatment is limited by its short biological half-life (e.g., 8 h or shorter in rats). Here we demonstrate a novel CocH form, a catalytic antibody analog, which is a fragment crystallizable (Fc)-fused CocH dimer (CocH-Fc) constructed by using CocH to replace the Fab region of human IgG1. The CocH-Fc not only has a high catalytic efficiency against cocaine but also, like an antibody, has a considerably longer biological half-life (e.g., ∼107 h in rats). A single dose of CocH-Fc was able to accelerate cocaine metabolism in rats even after 20 d and thus block cocaine-induced hyperactivity and toxicity for a long period. Given the general observation that the biological half-life of a protein drug is significantly longer in humans than in rodents, the CocH-Fc reported in this study could allow dosing once every 2-4 wk, or longer, for treatment of cocaine addiction in humans.
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Project description:BackgroundSocial relationships have been demonstrated as a key predictor of relapse among addicted persons and are likely to be important determinants of HIV risk behaviors also. However, the degree to which this population can reliably and consistently identify important people (IPs) in retrospect has been understudied.MethodsUsing the modified Important People and Activities questionnaire, we investigated to what degree IPs were dropped, added, or retained, and whether data about individual IPs were reported accurately on 6- and 12-month follow up periods using a sample of 50 drug or alcohol abusing participants.ResultsWe found that IPs were largely retained, and that those retained versus dropped/added differed by their reaction to participant alcohol/drug use, as well as frequency of contact. We further found that there were differences in reliability of data describing specific IPs. While both 6- and 12-month follow up periods led to reliabilities ranging from excellent to fair, we found poorer reliability on responses to recall of "frequency of contact" and "reactions to drinking", as well as "reactions to drug use".ConclusionFuture investigations of reliability of social relationships recalled retrospectively should attempt to examine possible systematic biases in addition to the reliability of specific IP data. More sophisticated studies are needed on factors associated with systematic variation in reporting of aspects of social relationships that are associated with addictions or HIV risk outcomes.
| S-EPMC5624203 | biostudies-literature
Project description:Methamphetamine (METH) can potentially disrupt neurotransmitters activities in the central nervous system (CNS) and cause neurotoxicity through various pathways. These pathways include increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis. In this study, we investigated the long-term effects of METH addiction on the structural changes in the amygdala of postmortem human brains and the involvement of the brain- cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF) and Akt-1/GSK3 signaling pathways. We examined ten male postmortem brains, comparing control subjects with chronic METH users, using immunohistochemistry, real-time polymerase chain reaction (to measure levels of CREB, BDNF, Akt-1, GSK3, and tumor necrosis factor-α [TNF-α]), Tunnel assay, stereology, and assays for reactive oxygen species (ROS), glutathione disulfide (GSSG), and glutathione peroxidase (GPX). The findings revealed that METH significantly reduced the expression of BDNF, CREB, Akt-1, and GPX while increasing the levels of GSSG, ROS, RIPK3, GSK3, and TNF-α. Furthermore, METH-induced inflammation and neurodegeneration in the amygdala, with ROS production mediated by the CREB/BDNF and Akt-1/GSK3 signaling pathways.
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Project description:AimsMajor depressive disorder is a severe psychiatric disorder that afflicts ~17% of the world population. Neuroimaging investigations of depressed patients have consistently reported the dysfunction of the basolateral amygdala in the pathophysiology of depression. However, how the BLA and related circuits are implicated in the pathogenesis of depression is poorly understood.MethodsHere, we combined fiber photometry, immediate early gene expression (c-fos), optogenetics, chemogenetics, behavioral analysis, and viral tracing techniques to provide multiple lines of evidence of how the BLA neurons mediate depressive-like behavior.ResultsWe demonstrated that the aversive stimuli elevated the neuronal activity of the excitatory BLA neurons (BLACAMKII neurons). Optogenetic activation of CAMKII neurons facilitates the induction of depressive-like behavior while inhibition of these neurons alleviates the depressive-like behavior. Next, we found that the chemogenetic inhibition of GABAergic neurons in the BLA (BLAGABA ) increased the firing frequency of CAMKII neurons and mediates the depressive-like phenotypes. Finally, through fiber photometry recording and chemogenetic manipulation, we proved that the activation of BLAGABA neurons inhibits BLACAMKII neuronal activity and alleviates depressive-like behavior in the mice.ConclusionThus, through evaluating BLAGABA and BLACAMKII neurons by distinct interaction, the BLA regulates depressive-like behavior.
| S-EPMC10915993 | biostudies-literature
Project description:The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLAGABA) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLAGABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLAGABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLAPV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLAPV neurons alleviated depressive behaviors, and activation of BLACCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLAPV neurons play a critical role in regulating depressive-like behaviors, and that BLACCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice.
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Project description:The central nucleus of the amygdala (CeA) is a striatum-like structure that contains mainly inhibitory circuits controlling a repertoire of (mal)adaptive behaviors related to pain, anxiety, motivation, and addiction. Neural activity in the CeA is also necessary for the expression of persistent and robust drug seeking, also termed 'incubation of drug craving.' However, neuroadaptations within this brain region supporting incubated drug craving have not been characterized. Here, we conducted a comprehensive analysis of protein expression in the CeA of male rats after prolonged (45-day) abstinence from extended-access cocaine self-administration using a quantitative proteomic approach. The proteomic analysis identified 228 unique proteins altered in cocaine rats relative to animals that received saline. Out of the identified proteins, 160 were downregulated, while 68 upregulated. Upregulation of tyrosine hydroxylase and downregulation of neural cell-adhesion protein contactin-1 were validated by immunoblotting. Follow-up analysis by the Ingenuity Pathway Analysis tool revealed alterations in protein networks associated with several neurobehavioral disorders, cellular function and morphology, as well as axogenesis, long-term potentiation, and receptor signaling pathways. This study suggests that chronic cocaine self-administration, followed by a prolonged abstinence results in reorganization of specific protein signaling networks within the CeA that may underlie incubated cocaine craving and identifies potential novel 'druggable' targets for the treatment of cocaine use disorder (CUD).
| S-EPMC7483535 | biostudies-literature
Project description:BackgroundDrug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction.MethodsFour independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European).ResultsA total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes.ConclusionsThe study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction.
| S-EPMC4564302 | biostudies-literature