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The elucidation of synaptic density changes provides valuable insights into the underlying brain mechanisms of substance use. In preclinical studies, synaptic density markers, like spine density, are altered by substances of abuse (e.g., alcohol, amphetamine, cannabis, cocaine, opioids, nicotine). These changes could be linked to phenomena including behavioral sensitization and drug self-administration in rodents. However, studies have produced heterogeneous results for spine density across substances and brain regions. Identifying patterns will inform translational studies given tools that now exist to measure in vivo synaptic density in humans. We performed a meta-analysis of preclinical studies to identify consistent findings across studies. PubMed, ScienceDirect, Scopus, and EBSCO were searched between September 2022 and September 2023, based on a protocol (PROSPERO: CRD42022354006). We screened 6083 publications and included 70 for meta-analysis. The meta-analysis revealed drug-specific patterns in spine density changes. Hippocampal spine density increased after amphetamine. Amphetamine, cocaine, and nicotine increased spine density in the nucleus accumbens. Alcohol and amphetamine increased, and cannabis reduced, spine density in the prefrontal cortex. There was no convergence of findings for morphine's effects. The effects of cocaine on the prefrontal cortex presented contrasting results compared to human studies, warranting further investigation. Publication bias was small for alcohol or morphine and substantial for the other substances. Heterogeneity was moderate-to-high across all substances. Nonetheless, these findings inform current translational efforts examining spine density in humans with substance use disorders.
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Background: Individual differences in gray-matter morphometry in the limbic system and frontal cortex have been linked to clinical features of cocaine use disorder (CUD). Self-administration paradigms can provide more direct measurements of the relationship between the regulation of cocaine use and gray-matter morphometry when compared to self-report assessments.Objectives: Our goal was to investigate associations with self-administration behavior in subcortical and cortical brain regions. We hypothesized the number of cocaine infusions self-administered would be correlated with gray-matter volumes (GMVs) in the striatum, amygdala, and hippocampus. Due to scarcity in human studies, we did not hypothesize subcortical directionality. In the frontal cortex, we hypothesized thickness would be negatively correlated with self-administered cocaine.Methods: We conducted an analysis of cocaine self-administration and structural MRI data from 33 (nFemales = 10) individuals with moderate-to-severe CUD. Self-administration lasted 60-minutes and cocaine (8, 16, or 32 mg/70 kg) was delivered on an FR1 schedule (5-minute lockout). Subcortical and cortical regression analyses were performed that included combined bilateral regions and age, experimental variables and use history as confounders.Results: Self-administered cocaine infusions were positively associated with caudal GMV (b = 0.18, p = 0.030) and negatively with putamenal GMV (b = -0.10, p = 0.041). In the cortical model, infusions were positively associated with insular thickness (b = 0.39, p = 0.008) and women appeared to self-administer cocaine more frequently (b = 0.23, p = 0.019).Conclusions: Brain morphometry features in the striatum and insula may contribute to cocaine consumption in CUD. These differences in morphometry may reflect consequences of prolonged use, predisposed vulnerability, or other possibilities.Clinical Trial Numbers: NCT01978431; NCT03471182.
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Transtornos Relacionados ao Uso de Cocaína , Cocaína , Substância Cinzenta , Imageamento por Ressonância Magnética , Autoadministração , Humanos , Transtornos Relacionados ao Uso de Cocaína/patologia , Masculino , Feminino , Adulto , Cocaína/administração & dosagem , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Pessoa de Meia-Idade , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Córtex Cerebral/patologia , Córtex Cerebral/diagnóstico por imagem , Adulto Jovem , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Corpo Estriado/patologia , Corpo Estriado/diagnóstico por imagemRESUMO
The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.
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Transtorno Depressivo Maior , Ketamina , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Humanos , Ketamina/metabolismo , Ketamina/farmacologia , Macaca mulatta/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND: Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self-regulatory processes. Tonic and phasic changes in stress responsivity impact an individual's relapse risk to alcohol. A further complicating factor is the pervasive coexistence of depressive symptoms in those with Alcohol Use Disorder (AUD), where the contribution of depressive symptomatology to these processes is not well understood. Individuals with AUD (AD) (21 with and 12 without sub-clinical depressive symptoms) and 37 social drinking controls (16 with and 21 without sub-clinical depressive symptoms) as part of a more extensive study (Fox et al., 2019). All participants were exposed to two 5-min personalized guided imagery conditions (stress and neutral) in a randomized and counterbalanced order across consecutive days. Alcohol craving, negative mood, Stroop performance, and plasma measures (cortisol, adrenocorticotrophic hormone, and salivary alpha-amylase) were collected before and after imagery exposure. RESULTS: Elevations in autonomic response (heart rate) to imagery (stress and neutral) were observed as a function of drinking (in both depressed and non-depressed individuals with alcohol use disorder compared with depressed and non-depressed social drinkers). Conversely, suppressed cortisol following stress was observed as a function of depressive symptomatology across both drinking groups. Individuals with comorbid AD and depressive symptoms demonstrated attenuated Adrenocorticotropic Hormone and poor Stroop performance compared with the other groups, indicating an interactive effect between drinking and depression on pituitary and inhibitory systems. CONCLUSION: Sub-clinical depressive pathophysiology may be distinct from drinking severity and may alter relapse-related stress adaptations during protracted abstinence from alcohol.
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Alcoolismo , Humanos , Alcoolismo/complicações , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Hidrocortisona , Etanol , Hormônio Adrenocorticotrópico , Estresse Psicológico/complicações , Recidiva , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-SuprarrenalRESUMO
BACKGROUND: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity and a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence. METHODS: Forty-eight image data sets were acquired with a multimodal neuroimaging battery that included resting-state functional magnetic resonance imaging (fMRI) and mGlu5 receptor positron emission tomography (PET) with the radiotracer [18 F]FPEB. Participants with AUD (n = 14) were scanned twice, at approximately 1 and 4 weeks after beginning supervised abstinence. [18 F]FPEB PET results were published previously. Primary comparisons of fMRI outcomes were performed between the AUD group and healthy controls (HCs; n = 23) and assessed changes over time within the AUD group. Relationships between resting-state connectivity measures and mGlu5 receptor availability were explored within groups. RESULTS: Compared to HCs, global functional connectivity of the orbitofrontal cortex was higher in the AUD group at 4 weeks of abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses showed that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group at 1 week of abstinence, r = 0.50 and at 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between the DMN and salience networks in HCs (r = 0.60, p = 0.003) but not in the AUD group (p > 0.3). CONCLUSIONS: These preliminary findings of altered global and network connectivity during the first month of abstinence from drinking may reflect the loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence.
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Alcoolismo , Alcoolismo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico/métodos , Ácido Glutâmico , Humanos , Imageamento por Ressonância Magnética , Neuroimagem , Receptor de Glutamato Metabotrópico 5RESUMO
INTRODUCTION: Chronic nicotine exposure desensitizes dopamine responses in animals, but it is not known if this occurs in human tobacco smokers. Deficits in dopamine function are likely to make smoking cessation difficult. We used positron emission tomography (PET) brain imaging with the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO to determine if abstinent smokers exhibit less amphetamine-induced dopamine release in the ventral striatum than nonsmokers, and whether this was associated with clinical correlates of smoking cessation. METHODS: Baseline [11C]-(+)-PHNO scans were acquired from smokers (n = 22, 7 female, abstinent 11 ± 9 days) and nonsmokers (n = 20, 7 female). A subset of thirty-seven participants (18 smokers) received oral amphetamine (0.5 mg/kg) three hours before a second [11C]-(+)-PHNO scan. Binding potential (BPND) (i.e., D2/3 receptor availability) was estimated at baseline and postamphetamine in the ventral striatum. Amphetamine-induced percent change in BPND was calculated to reflect dopamine release. Subjects also completed the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: There were no group differences in baseline BPND. Amphetamine-induced percent change in BPND in the ventral striatum was significantly lower in abstinent smokers compared to nonsmokers (p=0.019; d=0.82). Higher CES-D scores were significantly associated with lower ventral striatal percent change in BPND for abstinent smokers (rs=-0.627, p=0.025). CONCLUSIONS: In conclusion, abstinent smokers exhibited significantly less amphetamine-induced dopamine release in the ventral striatum than nonsmokers. In abstinent smokers, worse mood was significantly associated with less striatal dopamine release. Our findings highlight a potential neural mechanism that may underlie negative mood symptoms during early abstinence. IMPLICATIONS: This study combined quantitative PET imaging and an amphetamine challenge to examine striatal dopamine function during early smoking cessation attempts. The findings demonstrate that recently abstinent tobacco smokers exhibit significant, mood-associated striatal dopamine dysfunction compared to nonsmokers. This study advances our knowledge of the neurobiology underlying early quit attempts, and bridges novel neural findings with clinically relevant symptoms of smoking cessation. These results may explain the challenge of maintaining long-term abstinence from smoking, and can lend insight into the development of treatment strategies for smoking cessation.
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Dopamina , Estriado Ventral , Animais , Radioisótopos de Carbono , Dopamina/metabolismo , Feminino , Humanos , não Fumantes , Tomografia por Emissão de Pósitrons/métodos , Fumantes , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/metabolismoRESUMO
Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.
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Cocaína , Vesículas Sinápticas , Encéfalo/metabolismo , Cocaína/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Piridinas/metabolismo , Vesículas Sinápticas/metabolismoRESUMO
BACKGROUND: Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. METHODS: Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. RESULTS: Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not. CONCLUSIONS: Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.
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Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Hormônio Adrenocorticotrópico/metabolismo , Alcoolismo/reabilitação , Fissura , Sinais (Psicologia) , Frequência Cardíaca/fisiologia , Hidrocortisona/metabolismo , Prazosina/uso terapêutico , Adulto , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Alcoolismo/psicologia , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Método Duplo-Cego , Feminino , Humanos , Imagens, Psicoterapia , Masculino , Pessoa de Meia-Idade , Estresse PsicológicoRESUMO
The dopaminergic motive system is compromised in cocaine addiction. Abundant research has examined the roles of the dopaminergic midbrain and ventral striatum (VS) in cue-induced craving and habitual drug consumption. Interconnected with the dopaminergic circuits, the hypothalamus is widely implicated in motivated behavior, including food and drug seeking. However, very few studies have investigated how the hypothalamus responds to drug cues and whether hypothalamic responses are related to clinical features such as craving and addiction severity. Here, in 23 cocaine-dependent individuals (CD) exposed to cocaine vs neutral cues during functional magnetic resonance imaging (fMRI), we examined regional responses using established routines. At a corrected threshold, CD demonstrated increased activation to cocaine vs neutral cues in bilateral visual cortex, inferior parietal and middle frontal gyri, and the hypothalamus. The extent of hypothalamus but not other regional response was correlated with craving and cocaine addiction severity, each as assessed by the Cocaine Craving Questionnaire (CCQ) and Cocaine Selective Severity Assessment (CSSA). In contrast, subjective "acute" craving as elicited by cocaine cues during fMRI involved deactivation of bilateral orbitofrontal cortex (OFC) and angular gyri (AG), and the OFC and AG responses were not related to CCQ or CSSA score. These findings distinguished tonic craving as a critical factor in capturing cocaine addiction severity and substantiated a role of the hypothalamus in motivational dysfunction in cocaine addiction.
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Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/farmacologia , Sinais (Psicologia) , Hipotálamo/fisiopatologia , Adulto , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Índice de Gravidade de DoençaRESUMO
Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression. We also examine the potential link between cytokine adaptations in response to stress and prospective alcohol relapse risk. Thirty-three, alcohol-dependent individuals (21 with and 12 without high depressive symptoms) and 37 controls (16 with and 21 without high depressive symptoms) were exposed to two 5-minute personalized guided imagery conditions (stress and neutral) across consecutive days in a randomized and counterbalanced order. Alcohol craving and serum measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were collected prior to and following imagery exposure. Following treatment discharge, follow-up interviews were conducted over 90 days to assess relapse. Dampened IL-1ra and IL-6 in response to stress was observed as a function of alcohol dependence and not moderated by depressive symptoms. Lower levels of IL-6 following stress also predicted greater drinking days following treatment. Conversely, high depressive symptomatology was associated solely with pro-inflammatory adaptations. Stress-related suppression of TNFα predicted drinking severity only in alcohol-dependent individuals with subclinical depression, and suppressed TNFR1 following stress was only seen in individuals with subclinical depression. Stress-induced suppression of pro-inflammatory TNF markers may indicate a risk factor for alcohol-dependent individuals with co-occurring depressive symptoms.
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Alcoolismo/imunologia , Alcoolismo/terapia , Fissura , Citocinas/sangue , Depressão/terapia , Imagens, Psicoterapia , Estresse Psicológico/terapia , Adulto , Alcoolismo/complicações , Depressão/complicações , Feminino , Humanos , Masculino , Estresse Psicológico/complicaçõesRESUMO
BACKGROUND AND OBJECTIVES: Neuroactive steroids (NAS) may play a role in addiction, with observed increases in response to acute stress and drug use, but decreases with chronic substance use, suggesting that NAS neuroadaptations may occur with chronic substance use. However, levels of NAS in addicted individuals have not been systematically examined. Here, we evaluated a panel of NAS in men and women with cocaine use disorder (CUD) who participated in a clinical laboratory study of progesterone. METHODS: Forty six CUD individuals were enrolled in a randomized placebo-controlled laboratory study to evaluate progesterone effects on levels of various NAS. On day 5 of a 7-day inpatient treatment regimen of 400 mg/day progesterone (15M/8F) or placebo (14M/9F), plasma levels of NAS known to be downstream of progesterone (allopregnanolone, pregnanolone), and NAS not in the progesterone synthesis pathway (androstanediol, testosterone, dehydroepiandrosterone [DHEA] and the NAS precursor, pregnenolone) were analyzed using highly sensitive gas chromatography/mass spectrometry (GC/MS). The relationship between each of the NAS and chronicity of cocaine use was also assessed. RESULTS: Progesterone versus placebo significantly increased the GABAergic NAS allopregnanolone and pregnanolone in both CUD men and women. Levels of pregnenolone, testosterone, its GABAergic metabolite androstanediol, and the non-GABAergic DHEA were unaffected by progesterone treatment, and testosterone and androstanediol levels were significantly higher in men than women. Importantly, lower pregnenolone and androstanediol levels were associated with greater years of cocaine use. SCIENTIFIC SIGNIFICANCE: GABAergic NAS that are upstream from the progesterone synthesis pathway appear susceptible to chronic effects of cocaine use. (Am J Addict 2019;28:16-21).
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Transtornos Relacionados ao Uso de Cocaína/sangue , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Neuroesteroides/sangue , Progesterona/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Fatores Sexuais , Fatores de TempoRESUMO
Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.
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Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Dopaminérgicos/metabolismo , Oxazinas/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mapeamento Encefálico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Progressão da Doença , Dopaminérgicos/farmacologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Oxazinas/farmacologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacosRESUMO
Rates of opioid-related deaths and overdoses in the United States are at record-high levels. Thus, novel neurobiological targets for the treatment of OUD are greatly needed. Given the close interaction between the endogenous opioid system and the endocannabinoid system (ECS), targeting the ECS may have therapeutic potential in OUD. The various components of the ECS, including cannabinoid receptors, their lipid-derived endogenous ligands (endocannabinoids [eCBs]), and the related enzymes, present potential targets for developing new medications in OUD treatment. The purpose of this paper is to review the clinical and preclinical literature on the dysregulation of the ECS after exposure to opioids. We review the evidence of ECS dysregulation across various study types, exposure protocols, and measurement protocols and summarize the evidence for dysregulation of ECS components at specific brain regions. Preclinical research has shown that opioids disrupt various ECS components that are region-specific. However, the results in the literature are highly heterogenous and sometimes contradictory, possibly due to variety of different methods used. Further research is needed before a confident conclusion could be made on how exposure to opioids can affect ECS components in various brain regions.
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Canabinoides , Endocanabinoides , Humanos , Analgésicos Opioides/farmacologia , Receptores de Canabinoides , Encéfalo/metabolismo , Canabinoides/farmacologiaRESUMO
OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common condition that often persists into adulthood, although data suggest that the current diagnostic criteria may not represent how the condition presents in adults. We aimed to use qualitative methods to better understand ADHD symptomatology in young adults, especially regarding attentional and emotional dysregulation. METHODS: Nine focus groups involving young adults (aged 18-35 years; N = 43; 84% female; 86% US and Canada) with diagnoses of ADHD were conducted. Participants were asked about their perceptions of the current diagnostic criteria and how their symptoms have presented and changed over time. Data were analyzed using an interpretive phenomenological analysis framework. RESULTS: Most participants reported that the diagnostic criteria did not accurately capture their experiences with ADHD. They reported struggling with attention dysregulation, including hyperfocusing, and emotional dysregulation, including rejection-sensitive dysphoria. Many participants believed that their changing environments and behavioral adaptations influenced how their symptoms presented into adulthood. CONCLUSION: Current diagnostic criteria for ADHD may not capture the range of symptoms present in young adults. More research is needed to characterize attentional and emotional dysregulation in this population.
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Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Feminino , Adulto Jovem , Masculino , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Pesquisa Qualitativa , CanadáRESUMO
Background: Ketamine and psychedelics have abuse liability. They can also induce "transformative experiences" where individuals experience enhanced states of awareness. This enhanced awareness can lead to changes in preexisting behavioral patterns which could be beneficial in the treatment of substance use disorders (SUDs). Preclinical and clinical studies suggest that ketamine and psychedelics may alter markers associated with synaptic density, and that these changes may underlie effects such as sensitization, conditioned place preference, drug self-administration, and verbal memory performance. In this scoping review, we examined studies that measured synaptic markers in animals and humans after exposure to ketamine and/or psychedelics. Methods: A systematic search was conducted following PRISMA guidelines, through PubMed, EBSCO, Scopus, and Web of Science, based on a published protocol (Open Science Framework, DOI: 10.17605/OSF.IO/43FQ9). Both in vivo and in vitro studies were included. Studies on the following synaptic markers were included: dendritic structural changes, PSD-95, synapsin-1, synaptophysin-1, synaptotagmin-1, and SV2A. Results: Eighty-four studies were included in the final analyses. Seventy-one studies examined synaptic markers following ketamine treatment, nine examined psychedelics, and four examined both. Psychedelics included psilocybin/psilocin, lysergic acid diethylamide, N,N-dimethyltryptamine, 2,5-dimethoxy-4-iodoamphetamine, and ibogaine/noribogaine. Mixed findings regarding synaptic changes in the hippocampus and prefrontal cortex (PFC) have been reported when ketamine was administered in a single dose under basal conditions. Similar mixed findings were seen under basal conditions in studies that used repeated administration of ketamine. However, studies that examined animals during stressful conditions found that a single dose of ketamine counteracted stress-related reductions in synaptic markers in the hippocampus and PFC. Repeated administration of ketamine also counteracted stress effects in the hippocampus. Psychedelics generally increased synaptic markers, but results were more consistently positive for certain agents. Conclusion: Ketamine and psychedelics can increase synaptic markers under certain conditions. Heterogeneous findings may relate to methodological differences, agents administered (or different formulations of the same agent), sex, and type of markers. Future studies could address seemingly mixed results by using meta-analytical approaches or study designs that more fully consider individual differences.
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The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the ß2-subunit containing nicotinic acetylcholine receptor (ß2*-nAChR) partial agonist radioligand (-)-[18F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[18F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (VT) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[18F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[18F]flubatine VT, consistent with increased cortical acetylcholine levels reducing the number of ß2*-nAChR sites available for (-)-[18F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[18F]flubatine VT was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Assuntos
Acetilcolina , Receptores Nicotínicos , Animais , Masculino , Feminino , Acetilcolina/metabolismo , Acetilcolinesterase , Fisostigmina , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Receptores Nicotínicos/metabolismo , Cognição , Colinérgicos , Fumar/efeitos adversosRESUMO
BACKGROUND: Centanafadine is an inhibitor of reuptake transporters for norepinephrine (NET), dopamine (DAT) and serotonin (SERT). AIMS: This phase 1, adaptive-design positron emission tomography study investigated the occupancy time course of NET, DAT, and SERT and the relationship to centanafadine plasma concentrations. METHODS: Healthy adult males received centanafadine sustained-release 400 mg/day for 4 days (N = 6) or 800 mg in a single day (N = 4). Assessments included safety monitoring; time course of occupancy of NET, DAT, and SERT; and centanafadine plasma concentrations. RESULTS: Transporter occupancy was numerically higher for NET versus DAT or SERT. For NET, estimated (mean ± standard error [SE]) maximal observable target occupancy (TOmax) and concentration at half maximal occupancy (IC50) were 64 ± 7% and 132 ± 65 ng/mL, respectively, for all regions and 82 ± 13% and 135 ± 97 ng/mL after excluding the thalamus, which showed high nonspecific binding. For DAT and SERT, TOmax could not be established and was assumed to be 100%; estimated IC50 (mean ± SE) values were 1580 ± 186 ng/mL and 1,760 ± 309 ng/mL, respectively. For centanafadine, the estimated in vivo affinity ratio was 11.9 ± 6.0 (mean ± SE) for NET/DAT, 13.3 ± 7.0 for NET/SERT, and 1.1 ± 0.2 for DAT/SERT. DAT and SERT occupancies at a plasma concentration of 1400 ng/mL were estimated to be 47 and 44%, respectively. CONCLUSIONS: High occupancy at NET and moderate occupancy at DAT and SERT was observed at peak concentrations achieved following 400 mg total daily doses of centanafadine.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Humanos , Masculino , Encéfalo/metabolismo , Preparações de Ação Retardada , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Tomografia por Emissão de Pósitrons , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Comprimidos/metabolismo , AdultoRESUMO
BACKGROUND: Our group has established the feasibility of using on-body electrocardiographic (ECG) sensors to detect cocaine use in the human laboratory. The purpose of the current study was to test whether ECG sensors and features are capable of discriminating cocaine use from other non-cocaine sympathomimetics. METHODS: Eleven subjects with cocaine use disorder wore the Zephyr BioHarness™ 3 chest band under six experimental (drug and non-drug) conditions, including 1) laboratory, intravenous cocaine self-administration, 2) after a single oral dose of methylphenidate, 3) during aerobic exercise, 4) during tobacco use (N=7 who smoked tobacco), and 5) during routine activities of daily inpatient living (unit activity). Three ECG-derived feature sets served as primary outcome measures, including 1) the RR interval (i.e., heart rate), 2) a group of ECG interval proxies (i.e., PR, QS, QT and QTc intervals), and 3) the full ECG waveform. Discriminatory power between cocaine and non-cocaine conditions for each of the three outcomes measures was expressed as the area under the receiver operating characteristics (AUROC) curve. RESULTS: All three outcomes successfully discriminated cocaine use from unit activity, exercise, tobacco, and methylphenidate conditions with a mean AUROC values ranging from 0.66 to 0.99 and with least squares means values all statistically different/higher than 0.5 among all subjects [F(3, 99) = 3.38, p =0.02] and among those with tobacco use [F(4, 84) = 5.39, p = 0.0007]. CONCLUSIONS: These preliminary results support discriminatory power of wearable ECG sensors for detecting cocaine use.
Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Metilfenidato , Dispositivos Eletrônicos Vestíveis , Humanos , Simpatomiméticos , Eletrocardiografia , Transtornos Relacionados ao Uso de Cocaína/diagnósticoRESUMO
This case report describes a woman with no psychiatric history and previously diagnosed Hashimoto's thyroiditis who presented to the psychiatric emergency department with a first episode of psychosis. The initial workup for organic causes of psychosis revealed an astronomically high thyroid stimulating hormone (TSH) (> 1,000 µIU/mL) out of proportion to the patient's minimal physical symptoms of hypothyroidism. Additionally the patient's head imaging showed an enlarged pituitary, a rare, but reversible, presentation of chronically untreated primary hypothyroidism. The patient was transferred to a medical unit to receive IV thyroid hormone replacement as well as an adjunctive antipsychotic to assist with remission of her distressing auditory hallucinations and persecutory delusions. This case highlights the importance of a thorough medical workup for causes of new onset psychosis and the need for further consensus in the literature regarding choice of antipsychotic and duration of treatment for psychosis secondary to hypothyroidism.
RESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a common condition that frequently persists into adulthood, although research and diagnostic criteria are focused on how the condition presents in children. We aimed to review qualitative research on lived experiences of adults with ADHD to characterize potential ADHD symptomatology in adulthood and provide perspectives on how needs might be better met. We searched three databases for qualitative studies on ADHD. Studies (n = 35) in English that included data on the lived experiences of adults with ADHD were included. These studies covered experiences of receiving a diagnosis as an adult, symptomatology of adult ADHD, skills used to adapt to these symptoms, relationships between ADHD and substance use, patients' self-perceptions, and participants' experiences interacting with society. Many of the ADHD symptoms reported in these studies had overlap with other psychiatric conditions and may contribute to misdiagnosis and delays in diagnosis. Understanding symptomatology of ADHD in adults may inform future diagnostic criteria and guide interventions to improve quality of life.