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2.
Nat Commun ; 12(1): 4788, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373454

RESUMO

Activity in numerous brain regions drives heroin seeking, but no circuits that limit heroin seeking have been identified. Furthermore, the neural circuits controlling opioid choice are unknown. In this study, we examined the role of the infralimbic cortex (IL) to nucleus accumbens shell (NAshell) pathway during heroin choice and relapse. This model yielded subpopulations of heroin versus food preferring rats during choice, and choice was unrelated to subsequent relapse rates to heroin versus food cues, suggesting that choice and relapse are distinct behavioral constructs. Supporting this, inactivation of the IL with muscimol produced differential effects on opioid choice versus relapse. A pathway-specific chemogenetic approach revealed, however, that the IL-NAshell pathway acts as a common limiter of opioid choice and relapse. Furthermore, dendritic spines in IL-NAshell neurons encode distinct aspects of heroin versus food reinforcement. Thus, opioid choice and relapse share a common addiction-limiting circuit in the IL-NAshell pathway.


Assuntos
Analgésicos Opioides/farmacologia , Comportamento Aditivo , Comportamento de Procura de Droga/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides , Animais , Comportamento Animal , Encéfalo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Sinais (Psicologia) , Tomada de Decisões/efeitos dos fármacos , Ingestão de Alimentos/psicologia , Extinção Psicológica/fisiologia , Alimentos , Heroína/farmacologia , Dependência de Heroína , Masculino , Vias Neurais/fisiologia , Núcleo Accumbens/metabolismo , Ratos , Recidiva , Reforço Psicológico , Roedores , Autoadministração
3.
Sci Rep ; 11(1): 14026, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234188

RESUMO

Lateral flow immunoassays are low cost, rapid and highly efficacious point-of-care devices, which have been used for SARS-CoV-2 antibody testing by professionals. However, there is a lack of understanding about how self-administered tests are used by the general public for mass testing in different environmental settings. The purpose of this study was to assess the user experience (UX) (including usability) of a self-testing kit to identify COVID-19 antibodies used by a representative sample of the public in their cars, which included 1544 participants in Northern Ireland. The results based on 5-point Likert ratings from a post-test questionnaire achieved an average UX score of 96.03% [95% confidence interval (CI) 95.05-97.01%], suggesting a good degree of user experience. The results of the Wilcoxon rank sum tests suggest that UX scores were independent of the user's age and education level although the confidence in this conclusion could be strengthened by including more participants aged younger than 18 and those with only primary or secondary education. The agreement between the test result as interpreted by the participant and the researcher was 95.85% [95% CI 94.85-96.85%], Kappa score 0.75 [95% CI 0.69-0.81] (indicating substantial agreement). Text analysis via the latent Dirichlet allocation model for the free text responses in the survey suggest that the user experience could be improved for blood-sample collection, by modifying the method of sample transfer to the test device and giving clearer instructions on how to interpret the test results. The overall findings provide an insight into the opportunities for improving the design of SARS-CoV-2 antibody testing kits to be used by the general public and therefore inform protocols for future user experience studies of point-of-care tests.


Assuntos
Anticorpos Antivirais/análise , Teste para COVID-19/estatística & dados numéricos , Imunoensaio/estatística & dados numéricos , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Criança , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Sistemas Automatizados de Assistência Junto ao Leito , Autoadministração , Sensibilidade e Especificidade , Adulto Jovem
4.
Neurology ; 97(7): e720-e727, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34187862

RESUMO

OBJECTIVE: To investigate whether receiving a second-line anticonvulsant medication that is part of a patient's home regimen influences outcomes in benzodiazepine-refractory convulsive status epilepticus. METHODS: Using the Established Status Epilepticus Treatment Trial data, allocation to a study drug included in the patient's home anticonvulsant medication regimen was compared to receipt of an alternative second-line study medication. The primary outcome was cessation of clinical seizures with improved consciousness by 60 minutes after study drug initiation. Secondary outcomes were seizure cessation adjudicated from medical records and adverse events. We performed inverse probability of treatment-weighted (IPTW) logistic regressions. RESULTS: Of 462 patients, 232 (50%) were taking 1-2 of the 3 study medications at home. The primary outcome was observed in 39/89 (44%) patients allocated to their home medication vs 76/143 (53%) allocated to a nonhome medication (IPTW odds ratio [OR] 0.66, 95% confidence interval [CI] 0.39-1.14). The adjudicated outcome occurred in 37/89 (42%) patients vs 82/143 (57%), respectively (IPTW OR 0.52, 95% CI 0.30-0.89). There was no interaction between study levetiracetam and home levetiracetam and there were no differences in adverse events. CONCLUSION: There was no difference in the primary outcome for patients who received a home medication vs nonhome medication. However, the retrospective evaluation suggested an association between receiving a nonhome medication and seizure cessation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with refractory convulsive status epilepticus, use of a home second-line anticonvulsant compared to a nonhome anticonvulsant did not significantly affect the probability of stopping seizures.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Levetiracetam/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Estado Epiléptico/tratamento farmacológico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/farmacologia , Criança , Pesquisa Comparativa da Efetividade , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Levetiracetam/administração & dosagem , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenitoína/farmacologia , Autoadministração , Ácido Valproico/farmacologia , Adulto Jovem
6.
Neuropsychopharmacology ; 46(11): 1969-1980, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34162997

RESUMO

Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS-) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS- independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABAA + GABAB receptor agonists (muscimol + baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortex microinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Animais , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Sinais (Psicologia) , Comportamento de Procura de Droga , Extinção Psicológica , Córtex Pré-Frontal , Ratos , Recidiva , Autoadministração
7.
J Subst Abuse Treat ; 126: 108328, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34116819

RESUMO

This study describes use of the commercially available Medminder electronic pillbox at a community substance use disorder treatment program to safely increase the number of methadone take-home doses administered during the COVID-19 pandemic. The pillbox contains 28 cells that lock independently and can be opened only during preprogrammed time windows. This study provided patients (n = 42) deemed vulnerable to take-home mismanagement or more severe symptoms from COVID-19 infection the pillbox and observed them for 11 weeks. A telephone support line was staffed daily to manage technical issues. Overall, patients received about 14 more take-home doses per month after receiving the pillbox. Most medication was dispensed within scheduled windows. The study observed few incidents of suspected tampering, though five patients had their pillbox rescinded to allow more intensive on-site clinical monitoring. The study supports use of an electronic pillbox with a telephone support line to help vulnerable patients to better observe stay-at-home guidelines during the COVID-19 pandemic. The pillbox may offer public health and clinical benefits that extend beyond the pandemic by increasing program treatment capacity and patient satisfaction.


Assuntos
COVID-19 , Eletrônica , Metadona/administração & dosagem , Pandemias , Quarentena , COVID-19/epidemiologia , Eletrônica/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Autoadministração
8.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067897

RESUMO

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Fatores Etários , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Animais , Animais não Endogâmicos , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Quimiocina CXCL1/metabolismo , Dieta Hiperlipídica , Etanol/farmacologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Obesidade , Autoadministração/métodos
9.
Neuropsychopharmacology ; 46(10): 1724-1733, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34040157

RESUMO

Increasing evidence suggests that females are more vulnerable to the harmful effects of drugs of abuse, including opioids. Additionally, rates of heroin-related deaths substantially increased in females from 1999 to 2017 [1], underscoring the need to evaluate sex differences in heroin vulnerability. Moreover, the neurobiological substrates underlying sexually dimorphic responding to heroin are not fully defined. Thus, we evaluated male and female Long Evans rats on acquisition, dose-responsiveness, and seeking for heroin self-administration (SA) as well as using a long access model to assess escalation of intake at low and high doses of heroin, 0.025 and 0.1 mg/kg/inf, respectively. We paired this with ex vivo fast-scan cyclic voltammetry (FSCV) in the medial nucleus accumbens (NAc) shell and quantification of mu-opioid receptor (MOR) protein in the ventral tegmental area (VTA) and NAc. While males and females had similar heroin SA acquisition rates, females displayed increased responding and intake across doses, seeking for heroin, and escalation on long access. However, we found that males and females had similar expression levels of MORs in the VTA and NAc, regardless of heroin exposure. FSCV results revealed that heroin exposure did not change single-pulse elicited dopamine release, but caused an increase in dopamine transporter activity in both males and females compared to their naïve counterparts. Phasic-like stimulations elicited robust increases in dopamine release in heroin-exposed females compared to heroin-naïve females, with no differences seen in males. Together, our results suggest that differential adaptations of dopamine terminals may underlie the increased heroin SA behaviors seen in females.


Assuntos
Dopamina , Heroína , Animais , Feminino , Masculino , Núcleo Accumbens , Ratos , Ratos Long-Evans , Autoadministração
10.
Drug Alcohol Depend ; 224: 108719, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33940327

RESUMO

BACKGROUND: Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats. METHODS: Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29. RESULTS: SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults. CONCLUSION: Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age.


Assuntos
Metanfetamina , Fatores Etários , Animais , Comportamento de Procura de Droga , Extinção Psicológica , Feminino , Masculino , Antagonistas dos Receptores de Orexina , Orexinas , Ratos , Autoadministração
11.
Psychopharmacology (Berl) ; 238(7): 1857-1866, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33988725

RESUMO

RATIONALE: Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans. OBJECTIVE: To explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals. METHODS: Participants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test. RESULTS: Oxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids. CONCLUSIONS: Given that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder.


Assuntos
Analgésicos Opioides/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/administração & dosagem , Medição da Dor/efeitos dos fármacos , Receptores da Neurocinina-1 , Administração Intranasal , Adolescente , Adulto , Analgesia/métodos , Analgesia/psicologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/psicologia , Medição da Dor/métodos , Medição da Dor/psicologia , Reforço Psicológico , Autoadministração , Resultado do Tratamento , Adulto Jovem
12.
Exp Clin Psychopharmacol ; 29(2): 137-146, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34043398

RESUMO

Cannabis and synthetic cannabinoids are abused in spite of possible adverse health consequences. The current study investigated the reinforcing effects of an ecologically relevant mode of administration (inhalation) of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and three synthetic cannabinoids detected in synthetic cannabinoid products (JWH-018, JWH-073, and HU-210) in non-human primates (NHPs). Male and female (N = 4 each) rhesus macaques were trained to inhale warm air via a metal stem to receive a candy reinforcer, an alcohol aerosol vehicle was then paired with the candy. Dose-dependent responding for inhaled aerosols of THC (2.0-16.0 µg/kg/inhalation), JWH-018 (0.2-1.6 µg/kg/inhalation), JWH-073 (2.0-8.0 µg/kg/inhalation), and HU-210 (1.0-8.0 µg/kg/inhalation) was established using a fixed-ratio five schedule of reinforcement and compared to vehicle (alcohol) self-administration. Dose-dependent responding for inhaled heroin (25.0-100.0 µg/kg/inhalation), a known reinforcer in NHPs, was also established. Responding approximated vehicle levels for many drug doses tested, but at least half of the monkeys responded for ≥ one dose of each cannabinoid and heroin above vehicle, with the exception of THC. Drug deliveries calculated as percent vehicle followed a prototypical inverted-U shaped dose-response curve for cannabinoids and heroin except for THC and JWH-018 (in males). Grouped data according to sex demonstrated that peak percent of vehicle reinforcers earned for THC was greater in males than females, whereas peak percent of vehicle reinforcers earned for JWH-018, HU-210, and heroin were greater in females than males. These findings indicate minimal reinforcing effects of CB1 receptor agonists when self-administered by NHPs via aerosol inhalation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Dronabinol/análogos & derivados , Dronabinol/administração & dosagem , Indóis/administração & dosagem , Naftalenos/administração & dosagem , Animais , Canabinoides/farmacologia , Cannabis/química , Relação Dose-Resposta a Droga , Feminino , Heroína/administração & dosagem , Macaca mulatta , Masculino , Receptor CB1 de Canabinoide/agonistas , Reforço Psicológico , Autoadministração
13.
Transl Psychiatry ; 11(1): 293, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001858

RESUMO

There is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying "resilience" or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Animais , Masculino , Ratos , Ratos Long-Evans , Autoadministração , Ubiquitina-Proteína Ligases/genética
14.
Adv Ther ; 38(6): 3129-3142, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33948925

RESUMO

INTRODUCTION: Octreotide acetate subcutaneous injection is indicated to treat acromegaly and the symptoms of carcinoid tumors and vasoactive intestinal peptide tumors (VIPomas). This formative human factors study assessed the octreotide acetate pen injector and accompanying instructions for use (IFU) with self-trained participants. METHODS: The study enrolled patients with diagnoses of acromegaly, carcinoid tumors, or VIPomas and healthcare practitioners (HCPs) who treat patients with these diagnoses. The IFU provided a stepwise process with illustrations to train participants on using the pen injector. Participants familiarized themselves with the pen injector and the IFU before administering 2 unaided injections into skin-like pads; administering the full dose into the pad was considered a successful injection. The investigators evaluated each injection by performance measures-specific tasks necessary to safely and correctly administer the medication-and subjective measures, which included participant comments, feedback from questions, and suggestions for improvements. RESULTS: The study enrolled 11 participants-8 patients and 3 HCPs. Participants had a success rate of 100% for both injections. Errors included 1 participant priming the pen with the incorrect dose and 2 participants not holding the injector button for 10 s after the injection. Neither error led to a failed injection. To improve the IFU, participants suggested changing the order of wording on the priming step, clarifying illustrations of the plunger, and stronger indications to hold the injector button. CONCLUSION: The octreotide pen injector and IFU were usable by self-trained participants. Participant errors and suggestions provided a foundation for recommendations to improve the IFU.


Assuntos
Octreotida , Humanos , Injeções Subcutâneas , Autoadministração
15.
Neuropsychopharmacology ; 46(9): 1565-1573, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33972695

RESUMO

Although impulsive action is strongly associated with addiction, the neural underpinnings of this relationship and how they are influenced by sex have not been well characterized. Here, we used a titrating reaction time task to assess differences in impulsive action in male and female Long Evans rats both before and after short (4-6 days) or long (25-27 days) abstinence from 2 weeks of cocaine or water/saline self-administration (6 h daily access). Neural activity in the prelimbic cortex (PrL) and nucleus accumbens (NAc) core was assessed at each time point. We found that a history of cocaine self-administration increased impulsivity in all rats following short, but not long, abstinence. Furthermore, male rats with an increased ratio of excited to inhibited neurons in the PrL at the start of each trial in the task exhibited higher impulsivity in the naïve state (before self-administration). Following short abstinence from cocaine, PrL activity in males became more inhibited, and this change in activity predicted the shift in impulsivity. However, PrL activity did not track impulsivity in female rats. Additionally, although the NAc core tracked several aspects of behavior in the task, it did not track impulsivity in either sex. Together, these findings demonstrate a sex-dependent role for the PrL in impulsivity both before and after a history of cocaine.


Assuntos
Cocaína , Animais , Córtex Cerebral , Feminino , Comportamento Impulsivo , Masculino , Núcleo Accumbens , Ratos , Ratos Long-Evans , Autoadministração
16.
Psychopharmacology (Berl) ; 238(8): 2313-2324, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33932163

RESUMO

RATIONALE: Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. OBJECTIVE: This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. METHODS: MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1 day or 14 days after withdrawal from heroin self-administration. Following 14 days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. RESULTS: Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1 day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1 day, and meCP2 expression in NAc was higher after 14 days than after 1 day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. CONCLUSIONS: Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.


Assuntos
Fissura/fisiologia , Comportamento de Procura de Droga/fisiologia , Heroína/administração & dosagem , Proteína 2 de Ligação a Metil-CpG/biossíntese , MicroRNAs/biossíntese , Núcleo Accumbens/metabolismo , Animais , Fissura/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Masculino , Proteína 2 de Ligação a Metil-CpG/antagonistas & inibidores , Proteína 2 de Ligação a Metil-CpG/genética , MicroRNAs/genética , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração
17.
Psychopharmacology (Berl) ; 238(8): 2335-2346, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33950271

RESUMO

RATIONALE: In classical conditioning, sign-tracking reflects behavior directed toward a conditioned stimulus (CS) in expectation of a reward (unconditioned stimulus, US); in contrast, goal-tracking describes behavior directed toward the location of delivery of a US. As cues previously paired with drugs of abuse promote drug-seeking and drug-taking behavior in both animals and humans and thus contribute to the severity of substance abuse, sign-tracking may represent a maladaptive cue-focused behavior that may increase addiction vulnerability as compared to goal-tracking. Recent studies do, in fact, support this possibility. Previous work in this area has focused primarily on paradigms using relatively limited exposure to drug rather than extended drug intake. OBJECTIVES: Here, we used the DSM-IV-based 3-criteria (3-CRIT) model and examined whether a relationship exists between sign- or goal-tracking phenotypes and the prevalence of criteria associated with addiction-like behavior following extended cocaine self-administration as measured in this model. METHODS: Forty-six male Sprague Dawley rats underwent a Pavlovian conditioned approach (PCA) procedure and were characterized along a continuum as goal-trackers (GTs), intermediates (INTs), or sign-trackers (STs). The animals were subsequently trained to intravenous self-administer cocaine during 45 self-administration (SA) sessions and characterized for the 3 criteria outlined in the model: persistence of drug-seeking, motivation for cocaine-taking, and resistance to punishment. RESULTS: We performed correlational analyses on the traits measured, finding no relationships between PCA score and addiction-like characteristics measured using the 3-CRIT model of addiction. However, STs showed significantly greater resistance to punishment than GTs. CONCLUSIONS: Phenotyping along a continuum of PCA scores may not be a valid predictor for identifying vulnerability to the addiction-like behaviors examined using the 3-CRIT model. However, PCA phenotype may predict a single feature of the 3-CRIT model, resistance to punishment, among those rats classified as either STs or GTs.


Assuntos
Comportamento Aditivo/psicologia , Cocaína/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Objetivos , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Ratos , Ratos Sprague-Dawley , Recompensa , Autoadministração
18.
Contraception ; 104(3): 289-295, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33932400

RESUMO

OBJECTIVE: To explore US provider perspectives about self-sourced medication abortion and how their attitudes and clinic practices changed in the context of the COVID-19 pandemic. STUDY DESIGN: We conducted a multi-method study of survey and interview data. We performed 40 baseline interviews and surveys in spring 2019 and 36 follow-up surveys and ten interviews one year later. We compared pre- and post-Likert scale responses of provider views on the importance of different aspects of standard medication abortion assessment and evaluation (e.g., related to ultrasounds and blood-typing). We performed content analysis of the follow-up interviews using deductive-inductive analysis. RESULTS: Survey results revealed that clinics substantially changed their medication abortion protocols in response to COVID-19, with more than half increasing their gestational age limits and introducing telemedicine for follow-up of a medication abortion. Interview analysis suggested that physicians were more supportive of self-sourced medication abortion in response to changing clinic protocols that decreased in-clinic assessment and evaluation for medication abortion, and as a result of physicians' altered assessments of risk in the context of COVID-19. Having evidence already in place that supported these practice changes made the implementation of new protocols more efficient, while working in a state with restrictive abortion policies thwarted the flexibility of clinics to adapt to changes in standards of care. CONCLUSION: This exploratory study reveals that the COVID-19 pandemic has altered clinical assessment of risk and has shifted practice towards a less medicalized model. Further work to facilitate person-centered abortion information and care can build on initial modifications in response to the pandemic. IMPLICATIONS: COVID-19 has shifted clinician perception of risk and has catalyzed a change in clinical protocols for medication abortion. However, state laws and policies that regulate medication abortion limit physician ability to respond to changes in risk assessment.


Assuntos
Abortivos/uso terapêutico , Aborto Induzido/métodos , Aborto Induzido/tendências , Atitude do Pessoal de Saúde , COVID-19/prevenção & controle , Médicos/psicologia , Padrões de Prática Médica/tendências , Adulto , Assistência ao Convalescente/métodos , Assistência ao Convalescente/tendências , Protocolos Clínicos , Feminino , Política de Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Medição de Risco , Autoadministração , Inquéritos e Questionários , Estados Unidos
19.
MMWR Morb Mortal Wkly Rep ; 70(20): 739-743, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34014910

RESUMO

U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR), adapted by CDC from global guidance developed by the World Health Organization (WHO), provides evidence-based guidance on contraceptive use for U.S. health care providers (1). During January-February, 2021, CDC evaluated the 2019 WHO recommendation on self-administered subcutaneous depot medroxyprogesterone acetate (DMPA-SC) (2). CDC adopted the WHO recommendation on the basis of moderate-certainty evidence that self-administered DMPA-SC is safe and effective, and has higher continuation rates compared with provider-administered DMPA. The new U.S. SPR recommendation states that self-administered DMPA-SC should be made available as an additional approach to deliver injectable contraception. Provider-administered DMPA should remain available. Self-administered DMPA-SC is a user-controlled method that has the potential to improve contraceptive access and increase reproductive autonomy. Self-administered DMPA-SC should be offered in a noncoercive manner through a shared decision-making process between patients and their health care providers, with a focus on patient preferences and equitable access to the full range of contraceptive methods.


Assuntos
Anticoncepcionais Femininos/administração & dosagem , Acetato de Medroxiprogesterona/administração & dosagem , Centers for Disease Control and Prevention, U.S. , Feminino , Humanos , Injeções Subcutâneas , Autoadministração , Estados Unidos
20.
eNeuro ; 8(3)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33875455

RESUMO

The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.


Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Animais , Bancos de Espécimes Biológicos , Oxicodona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Autoadministração
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