ABSTRACT
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Subject(s)
Astrocytes , Memory Disorders , Methamphetamine , Microglia , Minocycline , Spatial Memory , Animals , Methamphetamine/toxicity , Microglia/drug effects , Microglia/metabolism , Mice , Memory Disorders/chemically induced , Astrocytes/metabolism , Astrocytes/drug effects , Astrocytes/pathology , Spatial Memory/physiology , Spatial Memory/drug effects , Male , Minocycline/pharmacology , Mice, Inbred C57BL , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Central Nervous System Stimulants/toxicityABSTRACT
Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.
Subject(s)
Fentanyl , Receptors, Opioid, mu , Reinforcement, Psychology , Animals , Female , Male , Mice , Analgesics, Opioid/pharmacology , Analgesics, Opioid/administration & dosage , Central Amygdaloid Nucleus/cytology , Central Amygdaloid Nucleus/drug effects , Central Amygdaloid Nucleus/metabolism , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Fentanyl/pharmacology , Mice, Inbred C57BL , Nucleus Accumbens/cytology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Opioid-Related Disorders/metabolism , Opioid-Related Disorders/pathology , Optogenetics , Receptors, Opioid, mu/metabolism , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Ventral Tegmental Area/cytology , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolismABSTRACT
Higher sensitivity to reward (SR) and weaker sensitivity to punishment (SP) construct the fundamental craving characteristics of methamphetamine abuse. However, few studies have appraised relationships between SR/SP (SR or SP) and cortical morphological alterations in methamphetamine abusers and whether hereditary factors take effects on SR/SP is unclear. Based on surface-based morphometric analysis, cortical discrepancy was investigated between 38 methamphetamine abusers and 37 healthy controls. Within methamphetamine abusers, correlation profiling was performed to discover associations among aberrant neuroimaging substrates, SR, SP, and craving. According to nine single nucleotide polymorphism sites of dopamine-related genes, we conducted univariate general linear model to find different effects of genotypes on cortical alterations and SR/SP/craving (SR, SP, or craving). Ultimately, mediation analyses were conducted among single nucleotide polymorphism sites, SR/SP/craving, and cortical morphological alterations to discover their association pathways. Compared to healthy controls, thinner cortices in inferior temporal gyrus, lateral orbitofrontal cortex, medial orbitofrontal cortex, inferior parietal lobule, and lateral occipital cortex in the left hemisphere were found in methamphetamine abusers (P < 0.05, family-wise error corrected). Cortical thickness in the inferior temporal gyrus was negatively correlated with SR scores. We found that rs1800497 A-containing genotypes had lower cortical thickness in the left inferior parietal lobule than the GG genotype. The rs5751876 had effects on SR scores. This study would provide convincing biomarkers for SR in methamphetamine abusers and offer potential genetic targets for personalizing relapse prevention.
Subject(s)
Amphetamine-Related Disorders , Cerebral Cortex , Magnetic Resonance Imaging , Methamphetamine , Polymorphism, Single Nucleotide , Reward , Humans , Male , Adult , Amphetamine-Related Disorders/genetics , Amphetamine-Related Disorders/diagnostic imaging , Amphetamine-Related Disorders/pathology , Methamphetamine/adverse effects , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Female , Young Adult , Substance Withdrawal Syndrome/genetics , Substance Withdrawal Syndrome/pathology , Substance Withdrawal Syndrome/psychology , Substance Withdrawal Syndrome/diagnostic imaging , Craving/physiology , PunishmentABSTRACT
Ethanol is one of the psychoactive substances most used by young individuals, usually in an intermittent and episodic manner, also called binge drinking. In the adolescent period, brain structures undergo neuromaturation, which increases the vulnerability to psychotropic substances. Our previous studies have revealed that ethanol binge drinking during adolescence elicits neurobehavioral alterations associated with brain damage. Thus, we explored the persistence of motor function impairment and cerebellum damage in the context of ethanol withdrawal periods (emerging adulthood and adult life) in adolescent female rats. Female Wistar rats (35 days old) received orally 4 cycles of ethanol (3.0â¯g/kg/day) or distilled water in 3 days on-4 days off paradigm (35th until 58th day of life). Motor behavioral tests (open field, grip strength, beam walking, and rotarod tests) and histological assays (Purkinje's cell density and NeuN-positive cells) were assessed on the 1-, 30-, and 60-days of binge alcohol exposure withdrawal. Our findings demonstrate that the adolescent binge drinking exposure paradigm induced cerebellar cell loss in all stages evaluated, measured through the reduction of Purkinje's cell density and granular layer neurons. The cerebellar tissue alterations were accompanied by behavioral impairments. In the early withdrawal, the reduction of spontaneous movement, incoordination, and unbalance was seen. However, the grip strength reduction was found at long-term withdrawal (60 days of abstinence). The cerebellum morphological changes and the motor alterations persisted until adulthood. These data suggest that binge drinking exposure during adolescence causes motor function impairment associated with cerebellum damage, even following a prolonged withdrawal, in adult life.
Subject(s)
Alcoholism , Binge Drinking , Substance Withdrawal Syndrome , Rats , Animals , Female , Rats, Wistar , Ethanol/toxicity , Alcohol Drinking , Cerebellum/pathology , Alcoholism/pathology , Substance Withdrawal Syndrome/pathology , Age FactorsABSTRACT
The association of focal motor seizures with cerebral hemiatrophy is a recognised rare paediatric syndrome known as 'hemiconvulsion, hemiatrophy and epilepsy' (HHE). To date, HHE has not been reported in adults. We present four adult patients with striking similarities to HHE, following alcohol withdrawal in chronic alcoholics. We document the imaging findings in the acute and subacute phases, discuss the underlying mechanisms and present a hypothesis regarding the pathophysiology.
Subject(s)
Alcoholism , Epilepsy , Substance Withdrawal Syndrome , Humans , Adult , Child , Brain/diagnostic imaging , Brain/pathology , Hemiplegia/complications , Hemiplegia/pathology , Substance Withdrawal Syndrome/complications , Substance Withdrawal Syndrome/pathology , Atrophy , Magnetic Resonance ImagingABSTRACT
INTRODUCTION: Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. METHODS: In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. RESULTS: Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. DISCUSSION: Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention.
Subject(s)
Alcoholism , Neuralgia , Substance Withdrawal Syndrome , Adult , Humans , Alcoholism/complications , Alcoholism/pathology , Substance Withdrawal Syndrome/complications , Substance Withdrawal Syndrome/pathology , Neuralgia/etiology , Pain Measurement/adverse effects , Pain Measurement/methods , Skin/pathologyABSTRACT
BACKGROUND AND AIMS: The diagnosis of alcoholic steatohepatitis (ASH) is based on liver biopsy, which is costly and invasive with non-negligible morbidity. The aim of this study was to evaluate the accuracy of circulating cytokeratin 18 M65 fragment (K18-M65) alone or in association with other markers for the non-invasive diagnosis of ASH in patients ongoing alcohol withdrawal. METHODS: This study examined the serum level of K18-M65 in a test cohort of 196 patients. All patients underwent liver biopsy, transient elastography (TE) and serum collection. The diagnostic accuracy of K18-M65 alone or combined with clinico-biological data was assessed and the best defined cut-offs were validated in an independent validation cohort of 58 patients. RESULTS: K18-M65 had an area under the curve (AUC) of 0.82 (test cohort) and 0.90 (validation cohort). Using two cut-off decision points, K18-M65 was able to classify 46.9% (test cohort) and 34.5% (validation cohort) of patients with 95% sensitivity or specificity. Combining K18-M65, alpha-2-macroglobulin, TE, body mass index, and age, we created a score allowing accurate diagnosis of ASH with an AUC of 0.93 (test cohort) and 0.94 (validation cohort). This new score was able to rule out or rule in the diagnosis of steatohepatitis for probability ≤0.135 or ≥0.667 respectively in more than two-thirds of patients. CONCLUSIONS: We propose a new validated non-invasive score for the diagnosis of ASH in patients ongoing alcohol withdrawal. This score can help to identify patients that may benefit from potential therapeutics or motivate them to reduce alcohol consumption.
Subject(s)
Alcoholism , Elasticity Imaging Techniques , Fatty Liver, Alcoholic , Fatty Liver , Non-alcoholic Fatty Liver Disease , Substance Withdrawal Syndrome , Humans , Alcoholism/pathology , Keratin-18 , Substance Withdrawal Syndrome/pathology , Biopsy , Liver/pathology , Biomarkers , Non-alcoholic Fatty Liver Disease/pathology , Liver Cirrhosis/diagnosisABSTRACT
Alcohol is globally the leading risk factor for cirrhosis and is subsumed under the term alcohol-related liver disease (ALD). However, only ca. 10% of people with harmful alcohol consumption (>40 gram alcohol per day) develop cirrhosis, while 15% have normal liver histology. Unfortunately, laboratory parameters and ultrasound hold little value to neither rule-in nor rule out alcohol related liver fibrosis. While several indices with combinations of liver associated markers such as FIB4 seem to be promising, non-invasive test strategies are urgently needed with cut-off's that can be applied to guide clinical decision making. The aims of this review article are to highlight novel developments for the diagnosis of ALD and to identify topics of controversy and potential future directions. In the last 15 years, elastography to measure liver stiffness (LS) has significantly improved our screening strategies for cirrhosis. LS values below 6 kPa are considered as normal and exclude ALD. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. Especially, transient elastography (TE) has been assessed in numerous studies, but similar performance can be obtained with point shear wave elastography, 2 SD shear wave elastography or MR elastography. Important confounders of elevated LS such as inflammation should also be considered and alcohol withdrawal not only improves liver inflammation but also LS. Liver stiffness measurement has signficiantly improved early diagnosis and follow-up of fibrosis in patients with ALD and patients with diagnosed manifest but clinically compensated cirrhosis should undergo further clinical examinations to rule out complications of portal hypertension. In addition, surveillance for the occurrence of hepatocellular carcinoma is recommended in all cirrhotic patients.
Subject(s)
Alcoholism , Elasticity Imaging Techniques , Hypertension, Portal , Substance Withdrawal Syndrome , Alcoholism/pathology , Humans , Liver/pathology , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/pathology , Substance Withdrawal Syndrome/pathologyABSTRACT
Smoking cessation increases body weight. The underlying mechanisms, however, have not been fully understood. We here report an establishment of a mouse model that exhibits an augmented body weight gain after nicotine withdrawal. High fat diet-fed mice were infused with nicotine for two weeks, and then with vehicle for another two weeks using osmotic minipumps. Body weight increased immediately after nicotine cessation and was significantly higher than that of mice continued on nicotine. Mice switched to vehicle consumed more food than nicotine-continued mice during the first week of cessation, while oxygen consumption was comparable. Elevated expression of orexigenic agouti-related peptide was observed in the hypothalamic appetite center. Pair-feeding experiment revealed that the accelerated weight gain after nicotine withdrawal is explained by enhanced energy intake. As a showcase of an efficacy of pharmacologic intervention, exendin-4 was administered and showed a potent suppression of energy intake and weight gain in mice withdrawn from nicotine. Our current model provides a unique platform for the investigation of the changes of energy regulation after smoking cessation.
Subject(s)
Nicotine/adverse effects , Substance Withdrawal Syndrome/pathology , Weight Gain , Agouti-Related Protein/metabolism , Animals , Calorimetry , Cell Respiration/drug effects , Disease Models, Animal , Energy Intake/drug effects , Exenatide/pharmacology , Feeding Behavior/drug effects , Gene Expression Regulation/drug effects , Hypothalamus/metabolism , Male , Mice, Inbred C57BL , RNA, Messenger/genetics , RNA, Messenger/metabolism , Substance Withdrawal Syndrome/genetics , Weight Gain/drug effects , Weight Gain/geneticsABSTRACT
BACKGROUND & AIMS: Liver stiffness measurement by transient elastography (TE) is a promising method for staging fibrosis in alcohol-related liver disease, but uncertainties remain regarding the influence of alcohol consumption and thus the ideal timing for TE performance. We evaluated the performance of TE compared with liver biopsy to exclude compensated advanced chronic liver disease (cACLD) in patients hospitalized for alcohol detoxification. METHODS: Patients were recruited prospectively at 6 in-patient addiction centers in France. Eligible patients had increased aspartate aminotransferase levels, and no history or signs of overt cirrhosis. TE, histology, and biochemistry measurements were obtained within a median of 6 days after alcohol withdrawal. TE and biochemistry were repeated 1 and 2 months later. RESULTS: The study included 259 patients for per-protocol analysis, of whom 45 (17%) had cACLD. TE identified patients with high accuracy at inclusion and at the 1- and 2-month follow-up evaluation, with area under the curve values of 0.96 (95% CIs, 0.94-0.99), 0.96 (95% CIs, 0.92-0.99), and 0.93 (95% CIs, 0.85-1.00), respectively. In 84% of patients, cACLD was ruled out when liver stiffness was less than 10 kPa (negative predictive value, 99% (95% CIs, 98%-100%)) or ruled in when greater than 25 kPa (positive predictive value, 93% (95% CI, 83%-102%)). Algorithms based on aminotransferase levels and/or bilirubin did not add to the diagnostic performance of TE in this period. Among patients with initial liver stiffness of 10 to 25 kPa, more than half of those with no cACLD showed liver stiffness of less than 10 at 1- and 2-month follow-up testing. CONCLUSIONS: TE performed during the first 2 months after alcohol cessation is an excellent method for excluding alcohol-related cACLD. CLINICAL TRIAL NUMBER: NCT01789008.
Subject(s)
Alcoholism , Elasticity Imaging Techniques , Liver Diseases , Substance Withdrawal Syndrome , Alcoholism/complications , Elasticity Imaging Techniques/methods , Humans , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/pathology , Liver Diseases/pathology , Substance Withdrawal Syndrome/pathologyABSTRACT
BACKGROUND: Alcohol withdrawal syndrome (AWS) is a common condition in hospitalized patients, yet its epidemiology in the ICU remains poorly characterized. METHODS: Retrospective cohort of patients admitted to the Nantes University Hospital ICU between January 1, 2017, and December 31, 2019, and coded for AWS using ICD-10 criteria. The objective of the study was to identify factors associated with complicated hospital stay defined as ICU length of stay ≥7 days or hospital mortality. RESULTS: Among 5,641 patients admitted to the ICU during the study period, 246 (4.4%) were coded as having AWS. Among them, 42 had exclusion criteria and 204 were included in the study. The three main reasons for ICU admission were sepsis (29.9%), altered consciousness (29.4%), and seizures (24%). At ICU admission, median Cushman's score was 6 [4-9] and median SOFA score was 3 [2-6]. Delirium tremens occurred in half the patients, seizures in one fifth and pneumonia in one third. Overall, 48% of patients developed complicated hospital stay, of whom 92.8% stayed in the ICU for ≥7 days, 36.7% received MV for ≥7 days, and 16.3% died during hospital stay. By multivariable analysis, two factors were associated with complicated hospital stay: a higher number of organ dysfunctions at ICU admission was associated with a higher risk of complicated hospital stay (OR, 1.18; 95CI, 1.05-1.32, P = 0.005), whereas ICU admission for seizures was associated with a lower risk of complicated hospital stay (OR, 0.14; 95%CI, 0.026-0.80; P = 0.026). CONCLUSIONS: AWS in ICU patients chiefly affects young adults and is often associated with additional factors such as sepsis, trauma, or surgery. Half the patients experienced an extended ICU stay or death during the hospital stay. The likelihood of developing complicated hospital stay relied on the reason for ICU admission and the number of organ dysfunctions at ICU admission.
Subject(s)
Ethanol/adverse effects , Intensive Care Units , Substance Withdrawal Syndrome/pathology , Female , Hospital Mortality , Humans , Length of Stay , Male , Middle Aged , Retrospective Studies , Substance Withdrawal Syndrome/mortality , Substance Withdrawal Syndrome/therapyABSTRACT
Prenatal opioid exposure might disturb epigenetic programming in the brain of neonatal offspring with various consequences for gene expressions and behaviors. This study determined whether altered trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter of the tumor necrosis factor-α (tnf-α) gene with neural cell apoptosis was involved in the ventral-medial striatum, an important brain region for withdrawal symptoms, of neonatal rat offspring from morphine-addicted mothers. Female adult rats were injected with morphine before gestation and until 14 days after giving birth. On postnatal day 14 (P14), rat offspring from morphine-addicted mothers were subjected to an opioid-withdrawal protocol and were analyzed 2 or 8 h after administration of that protocol. Expressions of the TNF-α protein, H3K4me3 in the tnf-α promoter gene, and neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring were evaluated. In the absence of significant opioid withdrawal (2 h after initiation of the opioid-withdrawal protocol on P14), prenatal morphine exposure led to increased levels of H3K4me3 in the tnf-α promoter gene, of the TNF-α protein, and of neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring. Following opioid withdrawal (8 h after initiation of the opioid-withdrawal protocol on P14), differential expression of H3K4me3 in the tnf-α promoter gene locus and upregulation of the level of TNF-α protein expression were further enhanced in these offspring. In addition, increased levels of caspase-3 and neural cell apoptosis were also observed. Taken together, this study revealed that prenatal opioid exposure can activate an epigenetic histone mechanism which regulates proinflammatory factor generation, which hence, led to cell apoptotic damage within the ventral-medial striatum of neonatal rat offspring from morphine-addicted mothers. More importantly, the opioid-withdrawal episode may provide augmented effects for the abovementioned alterations and could lead to deleterious effects in the neonatal brain of such offspring.
Subject(s)
Apoptosis , Histones/metabolism , Morphine Dependence/metabolism , Morphine , Pregnancy, Animal , Promoter Regions, Genetic , Tumor Necrosis Factor-alpha/genetics , Analgesics, Opioid , Animals , Animals, Newborn , Brain/pathology , Caspase 3/metabolism , Corpus Striatum , Epigenesis, Genetic , Female , Maternal Exposure , Methylation , Pregnancy , Rats , Rats, Sprague-Dawley , Substance Withdrawal Syndrome/pathologyABSTRACT
In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal.
Subject(s)
Nicotine/adverse effects , Raphe Nuclei/pathology , Serotonergic Neurons/pathology , Substance Withdrawal Syndrome/pathology , Animals , Female , Male , Mecamylamine , Mice , Mice, Inbred C57BL , Mice, Transgenic , Optogenetics , Receptors, Nicotinic/metabolism , Serotonin/metabolismABSTRACT
Cannabis effects are predominantly mediated by pharmacological actions on cannabinoid type 1 (CB1 ) receptors. Prior positron emission tomography (PET) studies in individuals who use cannabis included almost exclusively males. PET studies in females are needed because there are sex differences in cannabis effects, progression to cannabis use disorder (CUD), and withdrawal symptom severity. Females with CUD (N = 10) completed two double-blind cannabis smoking sessions (Session 1: placebo; Session 2: active), and acute cannabis effects were assessed. After Session 2, participants underwent 3 days of monitored cannabis abstinence; mood, craving, and withdrawal symptoms were assessed and a PET scan (radiotracer: [11 C]OMAR) followed. [11 C]OMAR Distribution volume (VT ) from these participants was compared with VT of age/BMI-similar female non-users of cannabis ("healthy controls"; N = 10). VT was also compared between female and male healthy controls (N = 7). Females with CUD displayed significantly lower VT than female healthy controls in specific brain regions (hippocampus, amygdala, cingulate, and insula). Amygdala VT was negatively correlated with mood changes (anger/hostility) during abstinence, but VT was not correlated with other withdrawal symptoms or cannabis effects. Among healthy controls, females had significantly higher VT than males in all brain regions examined. Chronic cannabis use appears to foster downregulation of CB1 receptors in women, as observed previously in men, and there are inherent sex differences in CB1 availability. Future studies should elucidate the time course of CB1 downregulation among females who use cannabis and examine the relation between CB1 availability and cannabis effects among other populations (e.g., infrequent users; medicinal users).
Subject(s)
Brain/drug effects , Marijuana Abuse/pathology , Receptor, Cannabinoid, CB1/drug effects , Substance Withdrawal Syndrome/pathology , Adult , Affect/drug effects , Age Factors , Body Mass Index , Brain/diagnostic imaging , Craving/drug effects , Double-Blind Method , Female , Hippocampus/drug effects , Humans , Male , Marijuana Abuse/diagnostic imaging , Patient Acuity , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Self Administration , Young AdultABSTRACT
Morphine withdrawal evokes neuronal apoptosis through mechanisms that are still under investigation. We have previously shown that morphine withdrawal increases the levels of pro-brain-derived neurotrophic factor (BDNF), a proneurotrophin that promotes neuronal apoptosis through the binding and activation of the pan-neurotrophin receptor p75 (p75NTR). In this work, we sought to examine whether morphine withdrawal increases p75NTR-driven signaling events. We employed a repeated morphine treatment-withdrawal paradigm in order to investigate biochemical and histological indicators of p75NTR-mediated neuronal apoptosis in mice. We found that repeated cycles of spontaneous morphine withdrawal promote an accumulation of p75NTR in hippocampal synapses. At the same time, TrkB, the receptor that is crucial for BDNF-mediated synaptic plasticity in the hippocampus, was decreased, suggesting that withdrawal alters the neurotrophin receptor environment to favor synaptic remodeling and apoptosis. Indeed, we observed evidence of neuronal apoptosis in the hippocampus, including activation of c-Jun N-terminal kinase (JNK) and increased active caspase-3. These effects were not seen in saline or morphine-treated mice which had not undergone withdrawal. To determine whether p75NTR was necessary in promoting these outcomes, we repeated these experiments in p75NTR heterozygous mice. The lack of one p75NTR allele was sufficient to prevent the increases in phosphorylated JNK and active caspase-3. Our results suggest that p75NTR participates in the neurotoxic and proinflammatory state evoked by morphine withdrawal. Because p75NTR activation negatively influences synaptic repair and promotes cell death, preventing opioid withdrawal is crucial for reducing neurotoxic mechanisms accompanying opioid use disorders.
Subject(s)
Apoptosis , Morphine Dependence/pathology , Neurons/pathology , Receptors, Nerve Growth Factor/metabolism , Substance Withdrawal Syndrome/pathology , Alleles , Animals , Apoptosis/physiology , Brain-Derived Neurotrophic Factor/physiology , Caspase 3/metabolism , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Receptor, trkB/metabolism , Receptors, Nerve Growth Factor/genetics , Signal TransductionABSTRACT
OBJECTIVE: To investigate the effect of minocycline on morphine withdrawal symptoms. METHODS: We established a rat model of morphine dependence, then injected the animals with naloxone to induce withdrawal symptoms. Minocycline was injected into the midbrain periaqueductal gray and its effect on withdrawal symptoms and Ca2+-dependent protein kinase (CaMKII), Ras, and phospho-extracellular signal-regulated kinase (p-ERK) expression was observed. RESULTS: Minocycline inhibited withdrawal symptoms such as "wet dog" shakes, teeth chatter, and ptosis, perhaps by inhibiting the activation of microglia and the expression of CaMKII, Ras, and p-ERK. Minocycline had no effect on the behavior of control rats or on CaMKII, Ras, or p-ERK expression. CONCLUSION: Minocycline alleviates morphine withdrawal symptoms by inhibiting the activation of microglia and downregulating the expression of CaMKII, Ras, and p-ERK.
Subject(s)
MAP Kinase Signaling System/drug effects , Minocycline/pharmacology , Morphine/adverse effects , Substance Withdrawal Syndrome/drug therapy , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Disease Models, Animal , Down-Regulation/drug effects , Humans , Male , Microglia/drug effects , Microglia/pathology , Minocycline/therapeutic use , Morphine/antagonists & inhibitors , Naloxone/administration & dosage , Periaqueductal Gray/drug effects , Periaqueductal Gray/pathology , Rats , Substance Withdrawal Syndrome/pathology , ras Proteins/metabolismABSTRACT
Protective effects of Puerariae flos extract (PFE) on ethanol (EtOH) exposure have been previously verified. This study attempts to explore the protective effects of PEF on EtOH withdrawal models. Sixty male Kunming mice were involved which were randomly divided into five groups (intact control, EtOH group (35-day EtOH exposure), EtOH withdrawal group (28-day exposure + 7-day withdrawal), EtOH withdrawal group + positive control (Deanxit) group, and EtOH withdrawal group + PFE group). The changes of neuropsychological behaviors; hippocampal BDNF expression and CA1 neuronal density; and plasma corticotropin-releasing hormone (CRH), ACTH, and CORT levels were observed. It was found that depression-like behaviors reduced by EtOH exposure and increased by withdrawal under the 28-day EtOH exposure and 7-day withdrawal conditions. In addition, anxiety-like behaviors worsened by EtOH exposure and unchanged by withdrawal. Deanxit and PEF ameliorated such behaviors (vs. withdrawal group). Hippocampal BDNF expression was significantly downregulated by EtOH exposure and upregulated by withdrawal. Deanxit and PEF significantly upregulated the BDNF expression. The hippocampal CA1 neuronal density significantly decreased by EtOH exposure but unchanged by withdrawal and treatments. The plasma CRH, ACTH, and CORT levels show a significant enhancement by EtOH exposure and reduced by withdrawal. They were further reduced by Deanxit and PEF. The protective effects of PEF on EtOH chronic withdrawal mouse models were verified. The results of this study also indicated a complicated scenario of neuropsychological behaviors, hippocampal BDNF expression, and hypothalamic-pituitary-adrenal axis which are affected by the timing of EtOH exposure and withdrawal.
Subject(s)
Alcoholism/drug therapy , Anxiety/prevention & control , CA1 Region, Hippocampal/drug effects , Depression/prevention & control , Drugs, Chinese Herbal/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Pueraria , Substance Withdrawal Syndrome/drug therapy , Adrenocorticotropic Hormone/blood , Alcoholism/metabolism , Alcoholism/pathology , Alcoholism/psychology , Animals , Anxiety/metabolism , Anxiety/pathology , Anxiety/psychology , Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/metabolism , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/pathology , Corticotropin-Releasing Hormone/blood , Depression/metabolism , Depression/pathology , Depression/psychology , Disease Models, Animal , Drugs, Chinese Herbal/isolation & purification , Hydrocortisone/blood , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/pathology , Male , Mice , Pueraria/chemistry , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Substance Withdrawal Syndrome/psychologyABSTRACT
Drug addiction is a recurrent, chronic brain disease. The existing treatment methods have limitations, such as poor adherence and inability to completely avoid relapse. Histidine triad nucleotide-binding protein 1 (HINT1) is involved in many neuropsychiatric diseases, such as schizophrenia, pain, and drug dependence. Studies have confirmed that there is a genetic link between HINT1 and addictions such as nicotine and cocaine. However, there is no research on the role of HINT1 protein in morphine addiction at home and abroad. Thus, we designed this project by constructing different types of morphine addiction animal models, including conditioned place preference and behavioral sensitization. We comprehensively examined the participation of HINT1 protein in key brain regions associated with addiction, including prefrontal cortex, nucleus accumbens, corpus striatum, and hippocampus, in different stages of different models. In addition, we used HINT1 knockout mice to establish the above models and physical dependence model to investigate the effect of HINT1 protein deletion on morphine addiction-related behaviors. We found that HINT1 has varying degrees of involvement in different stages of multiple addictive animal models. The absence of HINT1 can attenuate morphine-mediated addictive behavior to a certain extent and can alleviate the withdrawal symptoms of morphine.
Subject(s)
Brain/drug effects , Morphine Dependence/pathology , Morphine/pharmacology , Narcotics/pharmacology , Nerve Tissue Proteins/drug effects , Animals , Drug Dosage Calculations , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , RNA, Messenger/biosynthesis , Real-Time Polymerase Chain Reaction , Substance Withdrawal Syndrome/pathologyABSTRACT
The current study tested the hypothesis that drug withdrawal contributes to the addiction cycle in part because of an action on memory consolidation. Hence, four experiments in male Sprague-Dawley rats compared the effects of precipitated morphine withdrawal and conditioned morphine withdrawal on the consolidation of object memory and on activation of c-Fos in the central nucleus of the amygdala (CeA). It was found that immediate, but not 6 h delayed, post sample administration of 3 mg/kg of naltrexone significantly enhanced object memory in rats maintained, or previously maintained, on 10 mg/kg/day of morphine via osmotic minipumps. To establish whether conditioned withdrawal could also alter object memory, a contextual conditioning procedure was employed whereby morphine-maintained (10 mg/kg/day) animals received naltrexone (3 mg/kg) in a distinctive context (CS+) and vehicle in a separate context (CS-) for 10 days. During conditioning in the CS+, naltrexone suppressed locomotor activity, caused a rapid body weight loss and increased frequency of wet dog shakes. Interestingly, confinement to this CS+ immediately, but not 6 h, after the sample phase, also enhanced object memory. Finally, posttraining naltrexone and exposure to the CS+ both induced significant expression of c-Fos in the CeA. Therefore, this study reports for the first time that both acute precipitated withdrawal and conditioned withdrawal can facilitate memory consolidation, possibly through a common neural pathway that involves the central amygdala.
Subject(s)
Central Amygdaloid Nucleus/diagnostic imaging , Memory Consolidation/drug effects , Morphine/pharmacology , Narcotics/pharmacology , Proto-Oncogene Proteins c-fos/drug effects , Substance Withdrawal Syndrome/pathology , Animals , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley , Weight LossABSTRACT
Accumulating evidence has linked pathological changes associated with chronic alcohol exposure to neuroimmune signaling mediated by microglia. Prior characterization of the microglial structure-function relationship demonstrates that alterations in activity states occur concomitantly with reorganization of cellular architecture. Accordingly, gaining a better understanding of microglial morphological changes associated with ethanol exposure will provide valuable insight into how neuroimmune signaling may contribute to ethanol-induced reshaping of neuronal function. Here we have used Iba1-staining combined with high-resolution confocal imaging and 3D reconstruction to examine microglial structure in the prelimbic (PL) cortex and nucleus accumbens (NAc) in male Long-Evans rats. Rats were either sacrificed at peak withdrawal following 15 days of exposure to chronic intermittent ethanol (CIE) or 24 hr after two consecutive injections of the immune activator lipopolysaccharide (LPS), each separated by 24 hr. LPS exposure resulted in dramatic structural reorganization of microglia in the PL cortex, including increased soma volume, overall cellular volume, and branching complexity. In comparison, CIE exposure was associated with a subtle increase in somatic volume and differential effects on microglia processes, which were largely absent in the NAc. These data reveal that microglial activation following a neuroimmune challenge with LPS or exposure to chronic alcohol exhibits distinct morphometric profiles and brain region-dependent specificity.