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1.
Eur J Neurosci ; 54(7): 6397-6405, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505325

RESUMO

The lateral preoptic area is implicated in numerous aspects of substance use disorder. In particular, the lateral preoptic area is highly sensitive to the pharmacological properties of psychomotor stimulants, and its activity promotes drug-seeking in the face of punishment and reinstatement during abstinence. Despite the lateral preoptic area's complicity in substance use disorder, how precisely lateral preoptic area neurons signal the individual components of drug self-administration has not been ascertained. To bridge this gap, we examined how the firing of single lateral preoptic area neurons correlates with three discrete elements of cocaine self-administration: (1) drug-seeking (pre-response), (2) drug-taking (response) and (3) receipt of the cocaine infusion. A significant subset of lateral preoptic area neurons responded to each component with a mix of increases and decreases in firing-rate. A majority of these neurons signal the operant response with increases in spiking, though responses during the drug-seeking, taking and reciept windows were highly correlated.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Condicionamento Operante , Comportamento de Procura de Droga , Humanos , Neurônios , Área Pré-Óptica , Autoadministração
2.
Eur J Neurosci ; 54(7): 6382-6396, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34481424

RESUMO

Overdose death rates caused by psychostimulants have increased by 22.3% annually from 2008 to 2017. Cue-evoked drug craving progressively increases and contributes to perpetual relapse. Preclinical models have determined that glutamate receptor plasticity within the nucleus accumbens (NAc) drives amplified cue-evoked drug seeking after prolonged abstinence (>40 days). Isolated condition (IC) rearing increases cocaine and amphetamine (AMP) self-administration and cue-induced reinstatement. We tested the hypothesis that housing in the IC will augment AMP seeking after short and prolonged abstinence from AMP self-administration when compared with rats reared in the enrichment condition (EC). EC and IC male rats acquired stable AMP or SAL self-administration and were tested in a cue-induced AMP-seeking test after 1 and 40 days of abstinence. After the seeking test, the whole NAc was extracted and prepared for western blot analysis. Results indicate that IC rats had more active lever presses during a brief extinction interval and during the cue-induced seeking test. After 40 days of abstinence, IC rats had more active lever presses than EC rats during the cue-induced seeking test. Western blots indicated that the expression ratio between GluA1:mGlur5 was reduced only in IC-AMP-trained rats and the ratio between GluA1:mGlur1 was positively correlated with AMP seeking after prolonged abstinence in IC-AMP rats. These results indicate that IC housing engenders a vulnerable phenotype prone to persistent AMP seeking. The behavioural momentum of this vulnerable phenotype is further revealed when AMP-associated cues are presented following prolonged abstinence.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Anfetamina , Animais , Sinais (Psicologia) , Comportamento de Procura de Droga , Extinção Psicológica , Habitação , Masculino , Núcleo Accumbens , Ratos , Autoadministração
3.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361071

RESUMO

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.


Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/toxicidade , Canabidiol/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Pirrolidinas/toxicidade , Inibidores da Captação Adrenérgica/toxicidade , Animais , Anticonvulsivantes/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/patologia , Condicionamento Clássico/efeitos dos fármacos , Masculino , Camundongos
4.
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
5.
J Osteopath Med ; 121(11): 827-833, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34432972

RESUMO

CONTEXT: Person first language (PFL) - a way of referring to individuals with medical conditions or disability that emphasizes the person over their condition or disability - is important in reducing the stigma surrounding individuals who exhibit drug-seeking behavior. Drug-seeking behavior is generally associated with a negative connotation by healthcare professionals, which may create poor provider perceptions of these individuals and potentially impact patient care. Therefore, to reduce stigmatization surrounding drug-seeking behavior and to improve patient care in these individuals, the use of PFL should be promoted. OBJECTIVES: The primary objective of this study is to investigate how frequently research articles focused on drug-seeking behavior adhere to PFL. METHODS: We performed a cross-sectional analysis systematically searching PubMed for articles published between May 1, 2011, and April 30, 2020, focused on drug-seeking behavior. To be included, the article must have met the following criteria: (1) published in a peer-reviewed journal; (2) relevant to drug-seeking behavior; and (3) must include human subjects and be retrievable in English. All articles were screened and data were extracted independently in a masked, duplicate fashion. Each article was reviewed for 19 predefined non-PFL terms with certain terms adopted from the American Medical Association Manual of Style. RESULTS: Our search returned 699 articles related to drug-seeking behavior, of which 390 articles met inclusion criteria and were analyzed for non-PFL. Our analysis found only 13.6% (53/390) of articles adhered to PFL while 86.4% (337/390) of articles contained at least some form of non-PFL. There was no association between PFL adherence and extracted study characteristics. CONCLUSIONS: PFL adherence is uncommon among research literature focused on drug-seeking behavior. The power of language can be profound, and should be understood by researchers, health care providers, and educators alike, specifically when dealing with known and exhibited characteristics of substance use disorders. This is relevant because of the high prevalence of substance use disorders, limited amount of prior research, and the impact stigma has on patients and healthcare providers.


Assuntos
Comportamento de Procura de Droga , Idioma , Estudos Transversais , Pessoal de Saúde , Humanos , Estigma Social , Estados Unidos
6.
J Neurosci ; 41(39): 8262-8277, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34413203

RESUMO

Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca2+-permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. However, the delay in their accumulation (∼1 month after drug self-administration ceases) suggests earlier waves of plasticity. This prompted us to conduct the first study of NMDAR transmission in NAc core during incubation, focusing on the GluN3 subunit, which confers atypical properties when incorporated into NMDARs, including insensitivity to Mg2+ block and Ca2+ impermeability. Whole-cell patch-clamp recordings were conducted in MSNs of adult male rats 1-68 d after discontinuing extended-access saline or cocaine self-administration. NMDAR transmission was enhanced after 5 d of cocaine withdrawal, and this persisted for at least 68 d of withdrawal. The earliest functional alterations were mediated through increased contributions of GluN2B-containing NMDARs, followed by increased contributions of GluN3-containing NMDARs. As predicted by GluN3-NMDAR incorporation, fewer MSN spines exhibited NMDAR-mediated Ca2+ entry. GluN3A knockdown in NAc core was sufficient to prevent incubation of craving, consistent with biotinylation studies showing increased GluN3A surface expression, although array tomography studies suggested that adaptations involving GluN3B also occur. Collectively, our data show that a complex cascade of NMDAR and AMPAR plasticity occurs in NAc core, potentially through a homeostatic mechanism, leading to persistent increases in cocaine cue reactivity and relapse vulnerability. This is a remarkable example of experience-dependent glutamatergic plasticity evolving over a protracted window in the adult brain.SIGNIFICANCE STATEMENT "Incubation of craving" is an animal model for the persistence of vulnerability to cue-induced relapse after prolonged drug abstinence. Incubation also occurs in human drug users. AMPAR plasticity in medium spiny neurons (MSNs) of the NAc core is critical for incubation of cocaine craving but occurs only after a delay. Here we found that AMPAR plasticity is preceded by NMDAR plasticity that is essential for incubation and involves GluN3, an atypical NMDAR subunit that markedly alters NMDAR transmission. Together with AMPAR plasticity, this represents profound remodeling of excitatory synaptic transmission onto MSNs. Given the importance of MSNs for translating motivation into action, this plasticity may explain, at least in part, the profound shifts in motivated behavior that characterize addiction.


Assuntos
Cocaína/administração & dosagem , Fissura/efeitos dos fármacos , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Núcleo Accumbens/metabolismo , Animais , Cálcio/metabolismo , Comportamento de Procura de Droga/fisiologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Autoadministração
7.
Pharmacol Rev ; 73(3): 1050-1083, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34257149

RESUMO

Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration-approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drug's rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction. SIGNIFICANCE STATEMENT: This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.


Assuntos
Fissura , Preparações Farmacêuticas , Animais , Comportamento de Procura de Droga , Humanos , Modelos Animais , Ratos , Recidiva , Autoadministração
8.
Drug Alcohol Depend ; 226: 108852, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34225225

RESUMO

BACKGROUND: Contemporary treatments for heroin use disorder demonstrate only limited efficacy when the goals are long term abstinence and prevention of relapse. We have demonstrated that environmental enrichment (EE) reduces cue-induced heroin reinstatement in male rats. The present study is an attempt to extend the "anti-relapse" effects of EE to female rats and to periods where incubation of craving is hypothesized to occur. METHODS: This experiment implemented a 3-phase procedure. In Phase 1, male and female rats were trained to self-administer heroin for 15 days. Phase 2 consisted of a 3- or 15-day forced abstinence (FA) period. In Phase 3 half of the rats were placed into EE and the other half in non-EE housing and subsequently tested for responding in extinction (no heroin or cues) for 15 days followed by a cue-induced reinstatement test. RESULTS: We found that rats in the 15 days FA condition showed significantly enhanced drug seeking during extinction, irrespective of sex. We also found that EE significantly reduced this effect. During reinstatement, EE significantly reduced drug seeking in male and female rats and in both 3- and 15-day FA groups. CONCLUSIONS: EE, with or without prolonged FA, effectively reduced heroin seeking in male and female rats. These findings indicate that EE can reduce drug-seeking in males and females and when putative incubation of craving (i.e., prolonged abstinence period) has occurred and suggest that it may aid in the development of future long-term behavioral treatments for individuals at risk for heroin relapse.


Assuntos
Fissura , Heroína , Animais , Condicionamento Operante , Sinais (Psicologia) , Comportamento de Procura de Droga , Extinção Psicológica , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração
9.
Alcohol Clin Exp Res ; 45(7): 1468-1478, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34273113

RESUMO

BACKGROUND: Accumulating clinical evidence suggests that women with prior exposure to adverse childhood experiences are more susceptible to heavy drinking and other health-related behaviors. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to the unavailability of valid animal models and a shortage of studies that compare effects in males and females. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion, and reward sensitivity in male and female rats. METHODS: We recently developed a rat model for childhood/adolescent peer rejection that allows us to study the long-term consequences of ASEs. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or within a group of Wistar rats (control). Wistar rats housed with Fischer 344 rats do not reciprocate social play in adolescence. This reduced play across adolescence mimics peer rejection and results in chronic dysregulation of social and pain-related behaviors. We tested adult male and female rats in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption long after the termination of the peer rejection condition. RESULTS: Peer rejection induced persistent sex-dependent changes in alcohol cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. Sex differences were observed in locomotor activity or reward sensitivity to sucrose. CONCLUSIONS: Peer rejection has long-lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population in which to study relapse-like behaviors that are similar to clinical findings, while males seem to buffer the peer rejection effect and demonstrate resilience to later life alcohol-seeking behaviors, as measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Comportamento Animal , Comportamento de Procura de Droga , Etanol/administração & dosagem , Distância Psicológica , Fatores Etários , Animais , Ritmo Circadiano , Feminino , Masculino , Atividade Motora , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Fatores Sexuais , Sacarose/administração & dosagem
10.
Neuron ; 109(13): 2043-2044, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34237276

RESUMO

The ventral pallidum (VP) is a key hub within the reward system that mediates drug-seeking behaviors. However, molecular and cellular adaptations within the VP following drug use are not fully elucidated. In this issue of Neuron, Pribiag et al. (2021) demonstrate how cocaine induces circuit-specific changes within the VP via dopamine-receptor-D3-dependent processes to promote cocaine seeking.


Assuntos
Prosencéfalo Basal , Cocaína , Comportamento de Procura de Droga , Neurônios , Recompensa
11.
Neuropsychopharmacology ; 46(10): 1848-1856, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34226657

RESUMO

Exposure to acute stress can increase vulnerability to develop or express many psychiatric disorders, including post-traumatic stress disorder. We hypothesized that stress-induced psychiatric vulnerability is associated with enduring neuroplasticity in the nucleus accumbens core because stress exposure can alter drug addiction-related behaviors that are associated with accumbens synaptic plasticity. We used a single 2-h stress session and 3 weeks later exposed male and female rats to stress-conditioned odors in a modified defensive burying task, and quantified both active and avoidant coping strategies. We measured corticosterone, dendritic spine and astrocyte morphology in accumbens, and examined reward sensitivity using a sucrose two-bottle choice and operant sucrose self-administration. Exposure to stress odor increased burying (active coping) and immobility (avoidant coping) in the defensive burying task in female and male rats. Systemic corticosterone was transiently increased by both ongoing acute restraint stress and stress-conditioned odors. Three weeks after administering acute restraint stress, we observed increased dendritic spine density and head diameter, and decreased synaptic association with astroglia and the astroglial glutamate transporter, GLT-1. Exposure to conditioned stress further increased head diameter without affecting spine density or astroglial morphology, and this increase by conditioned stress was correlated with burying behavior. Finally, we found that stress-exposed females have a preference for sweet solutions and higher motivation to seek sucrose than stressed male rats. We conclude that acute stress produced enduring plasticity in accumbens postsynapses and associated astroglia. Moreover, conditioned stress odors induced active behavioral coping strategies that were correlated with dendritic spine morphology.


Assuntos
Sinais (Psicologia) , Plasticidade Neuronal , Animais , Comportamento de Procura de Droga , Feminino , Masculino , Núcleo Accumbens , Ratos , Ratos Sprague-Dawley
12.
Sci Rep ; 11(1): 14825, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290298

RESUMO

Patients with opioid use disorder experience high rates of relapse during recovery, despite successful completion of rehabilitation programs. A key factor contributing to this problem is the long-lasting nature of drug-seeking behavior associated with opioid use. We modeled this behavior in a rat drug self-administration paradigm in which drug-seeking is higher after extended abstinence than during the acute abstinence phase. The goal of this study was to determine the contribution of discrete or discriminative drug cues and drug dosage to time-dependent increases in drug-seeking. We examined heroin-seeking after 2 or 21 days of abstinence from two different self-administration cue-context environments using high or low doses of heroin and matched animals for their drug intake history. When lower dosages of heroin are used in discriminative or discrete cue protocols, drug intake history contributed to drug-seeking after abstinence, regardless of abstinence length. Incubation of opioid craving at higher dosages paired with discrete drug cues was not dependent on drug intake. Thus, interactions between drug cues and drug dosage uniquely determined conditions permissible for incubation of heroin craving. Understanding factors that contribute to long-lasting opioid-seeking can provide essential insight into environmental stimuli and drug-taking patterns that promote relapse after periods of successful abstinence.


Assuntos
Sinais (Psicologia) , Comportamento de Procura de Droga , Heroína/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/psicologia , Síndrome de Abstinência a Substâncias/psicologia , Animais , Fissura , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Heroína/administração & dosagem , Masculino , Transtornos Relacionados ao Uso de Opioides/reabilitação , Ratos Sprague-Dawley , Recidiva , Autoadministração/psicologia
13.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074751

RESUMO

A relapse in addiction is often precipitated by heightened attention bias to drug-related cues, underpinned by a subcortically mediated transition to habitual/automatized responding and reduced prefrontal control. Modification of such automatized attention bias is a fundamental, albeit elusive, target for relapse reduction. Here, on a trial-by-trial basis, we used electroencephalography and eye tracking with a task that assessed, in this order, drug cue reactivity, its instructed self-regulation via reappraisal, and the immediate aftereffects on spontaneous (i.e., not instructed and automatized) attention bias. The results show that cognitive reappraisal, a facet of prefrontal control, decreased spontaneous attention bias to drug-related cues in cocaine-addicted individuals, more so in those with less frequent recent use. The results point to the mechanisms underlying the disruption of automatized maladaptive drug-related attention bias in cocaine addiction. These results pave the way for future studies to examine the role of such habit disruption in reducing compulsive drug seeking outside the controlled laboratory environment, with the ultimate goal of developing a readily deployable cognitive-behavioral and personalized intervention for drug addiction.


Assuntos
Viés de Atenção , Comportamento Aditivo/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Comportamento de Procura de Droga , Eletroencefalografia , Adulto , Feminino , Humanos , Masculino
14.
Neuropsychopharmacology ; 46(12): 2090-2100, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34188183

RESUMO

Cue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30-46 days) withdrawal. Rats were gavage-infused with everolimus (0-1.0 mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24 h. No everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. In addition, everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. everolimus' "anti-incubation" effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Preparações Farmacêuticas , Síndrome de Abstinência a Substâncias , Animais , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Fissura , Sinais (Psicologia) , Reposicionamento de Medicamentos , Comportamento de Procura de Droga , Everolimo , Extinção Psicológica , Fosfatidilinositol 3-Quinases , Ratos , Autoadministração , Síndrome de Abstinência a Substâncias/tratamento farmacológico
15.
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
16.
Psychopharmacology (Berl) ; 238(9): 2439-2447, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34008048

RESUMO

RATIONALE: Opioid use disorder (OUD) is highly comorbid with stress-related disorders, and stress can serve as a trigger for reinstatement of drug seeking. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) may be effective against stress-induced drug seeking. In the current study, PT150 (formerly ORG-34517), a more selective GR antagonist, was tested using two models of stress-induced drug seeking, namely footshock and yohimbine. METHODS: Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl (2.5 µg/kg/infusion, i.v.) in a model of escalation. Rats then received 7 days of abstinence, followed by extinction; PT150 (0, 50 or 100 mg/kg in Nutella®; p.o.) treatment started on the first day of extinction training and continued daily until the end of the study. Following 14 days of extinction, rats were tested for reinstatement following footshock and yohimbine (0, 1, or 2 mg/kg; i.p.), tested in counterbalanced order; PT150 or placebo treatment occurred prior to each extinction and reinstatement session. RESULTS: Prior to initiation of PT150 treatment, females self-administered greater levels of fentanyl during 1-h sessions compared to males; however, when switched to 6-h sessions, males and females self-administered similar levels of fentanyl and showed a similar escalation of intake over time. PT150 had no effect on extinction of self-administration. While both footshock and yohimbine reinstated fentanyl seeking, only footshock-induced reinstatement was decreased by PT150 (50 and 100 mg/kg). The effect of PT150 on footshock-induced reinstatement was driven primarily by males. CONCLUSION: The glucocorticoid antagonist PT150 reduces shock-induced fentanyl seeking, suggesting it may be effective against stress-induced relapse, although the sex difference in response may need further exploration.


Assuntos
Fentanila/farmacologia , Receptores de Glucocorticoides , Animais , Comportamento de Procura de Droga , Extinção Psicológica , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração , Ioimbina/farmacologia
17.
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
18.
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
19.
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
20.
Neuron ; 109(13): 2165-2182.e10, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34048697

RESUMO

Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.


Assuntos
Prosencéfalo Basal/fisiologia , Cocaína/administração & dosagem , Dopamina/fisiologia , Comportamento de Procura de Droga/fisiologia , Habenula/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Dopamina D3/fisiologia , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Recompensa , Área Tegmentar Ventral/fisiologia
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