RESUMO
Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Comportamento de Procura de Droga , Metanfetamina , Microglia , Autoadministração , Metanfetamina/farmacologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Animais , Masculino , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Camundongos , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Reforço Psicológico , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
One of the leading drug addiction theories states that habits and the underlying neural process of a ventral to dorsal striatal shift are the building blocks of compulsive drug-seeking behaviour and that compulsion is the maladaptive persistence of responding despite adverse consequences. Here we discuss that compulsive behaviour as defined primarily from the perspective of animal experimentation falls short of the clinical phenomena and their neurobiological correlates. Thus for the human condition, the concept of compulsive habbits should be critically addressed and potentially revised.
Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Substâncias , Animais , Humanos , Corpo Estriado , Comportamento de Procura de Droga , Hábitos , Comportamento CompulsivoRESUMO
α3ß4 Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α3ß4 nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2, for the development of an α3ß4 nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p-hydroxyl motif for ligand-receptor binding affinity. Four (R)- and (S)-quinuclidine-triazole (AK1-AK4) were synthesized and the binding affinity, together with selectivity to α3ß4 nAChR subtype, were determined by competitive radioligand binding assay using [3H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α3ß4 nAChR with a Ki value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α3ß4 nAChR in comparison to α7 nAChR. The α3ß4 nAChR selectivity of AK3 was considerably higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 was shown to be a promising α3ß4 nAChR tracer for further development as a radiotracer for drug addiction.
Assuntos
Receptores Nicotínicos , Transtornos Relacionados ao Uso de Substâncias , Receptor Nicotínico de Acetilcolina alfa7 , Humanos , Receptor Nicotínico de Acetilcolina alfa7/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Ligantes , Ensaio Radioligante , Receptores Nicotínicos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Quinuclidinas/química , Quinuclidinas/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist's efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei.
Assuntos
Cocaína , Animais , Cocaína/farmacologia , Receptores de Dopamina D3 , Proteínas Proto-Oncogênicas c-akt , Condicionamento Operante , Extinção Psicológica/fisiologia , Corticosterona/farmacologia , Estresse Fisiológico , Recidiva , Quinases de Proteína Quinase Ativadas por Mitógeno , Estresse Psicológico/psicologiaRESUMO
Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra-hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.
Assuntos
Concussão Encefálica , Oxicodona , Animais , Comportamento de Procura de Droga , Neuroimagem , Oxicodona/farmacologia , Ratos , AutoadministraçãoRESUMO
Addiction to various drugs and chemicals is a significant public health concern worldwide. Addiction to prescription medications has increased due to the psychoactive effects of these medications, their availability, low price, and the lack of legal consequences for abusers. One of such prescription medication is mirtazapine (MIRT). MIRT is an antidepressant that has recently been reported to be abused and could induce withdrawal symptoms in different case studies. No previous study has investigated its abuse potential in animal models of drug addiction. Here, we conducted a free-choice drinking paradigm to investigate voluntary drinking of MIRT at two different concentrations. Male BALB/c mice were given unlimited access to two water bottles for five days before being divided into three groups: the first group had free access to two water bottles. The second group (MIRT10) and the third group (MIRT20) was allowed unlimited choice to one bottle of water and one bottle of MIRT at concentrations of 0.03 and 0.06 mg/mL, respectively. The average daily MIRT intake in the MIRT20 group was significantly higher on all tested days than that in the MIRT10 group. Moreover, mice in the MIRT20 group preferred to self-administer MIRT over water, indicating that MIRT can induce drug-seeking behavior. To further investigate the addictive potential of MIRT and its possible deterioration of memory and recognition, as reported with several known drugs of abuse, animals underwent a novel object recognition test. Mice in the MIRT20 group demonstrated significant deterioration in memory and recognition, indicating its effects on different brain regions involved in recognition, similar to other known drugs of abuse. The forced swimming test and tail suspension test were used to test MIRT-induced withdrawal symptoms after forced abstinence. After eight days of abstinence, mice in the MIRT20 group demonstrated significant depression-like symptoms in both the TST and FST, manifested by a significant increase in immobility time. MIRT was shown to induce drug-seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has the potential to induce drug dependence and further studies are warranted to explore the neurobiological basis of MIRT-induced drug-seeking behavior.
RESUMO
Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA), but not dorsal hippocampus (CA1), selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval. However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate synaptic actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMII-driven actin dynamics in synapses, leading to an extended window of vulnerability for memory disruption. We used time-lapse two-photon imaging of dendritic spine motility in acutely prepared brain slices from female and male mice following METH-associated learning as a readout of actin-myosin dynamics. Spine motility was persistently increased in the BLA, but not in CA1. Consistent with the memory disrupting effect of intra-BLA NMII inhibition, METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Intra-CA1 NMII inhibition, on the other hand, did not disrupt METH-associated memory. Thus, we report identification of a previously unknown ability for spine actin dynamics to persist days after stimulation and that this is under the control of NMII. Further, these perpetual NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories.SIGNIFICANCE STATEMENT There are no Food and Drug Administration-approved pharmacotherapies to prevent relapse to the use of stimulants, such as methamphetamine (METH). Environmental cues become associated with drug use, such that the memories can elicit strong motivation to seek the drug during abstinence. We previously reported that the storage of METH-associated memories is uniquely vulnerable to immediate, retrieval-independent, and lasting disruption by direct actin depolymerization or by inhibiting the actin driver nonmuscle myosin II (NMII) in the BLA or systemically. Here we report a potential structural mechanism responsible for the unique vulnerability of METH-associated memories and METH-seeking behavior to NMII inhibition within the BLA.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Espinhas Dendríticas/metabolismo , Metanfetamina/farmacologia , Neurônios/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Feminino , Masculino , Camundongos , Neurônios/efeitos dos fármacosRESUMO
Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.
Assuntos
Comportamento de Procura de Droga , Rede Nervosa/fisiologia , Recompensa , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Humanos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Núcleo Accumbens/fisiologia , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
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 , AutoadministraçãoRESUMO
Propofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5-10.0 ng/site), MSX-3 (A2AR antagonist, 5.0-20.0 µg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75-3.0 µg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75-3.0 µg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0-20.0 µg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.
Assuntos
Núcleo Accumbens/efeitos dos fármacos , Propofol/farmacologia , Receptor A2A de Adenosina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Sinais (Psicologia) , Masculino , Núcleo Accumbens/metabolismo , Fenetilaminas/farmacologia , Propofol/administração & dosagem , RNA Interferente Pequeno/farmacologia , Ratos Sprague-Dawley , Receptor A2A de Adenosina/deficiência , Recidiva , Autoadministração , Xantinas/farmacologiaRESUMO
BACKGROUND: Alcohol and cigarettes are commonly used together, but little is known about their joint motivational impact. Cue reactivity studies have customarily examined alcohol and smoking cues in isolation, despite the potential for cues to elicit stronger motivational responses when combined. This study used a validated cue reactivity procedure (Choice Behavior Under Cued Conditions) systematically to disentangle the separate and joint effects of alcohol and cigarette cues on substance use motivation. METHODS: Participants were 110 adults (Mage = 34.0, SD = 10.8) who consumed both cigarettes and alcohol. Participants completed 40 cue reactivity trials with four in vivo cue types: water, alcohol, cigarette, and combined cigarette and alcohol. Participants rated their craving prior to receiving opportunities to spend real money to gain access to the cues. Spending larger amounts of money increased the probability that the substance(s) would be available for consumption. When granted access, participants took one cigarette puff and/or sip of the beverage. A multimethod approach assessed three key motivational indices: craving, drug-seeking (spending, latency to access the cue), and consumption (puff duration, alcohol consumed). Effects of cue type and rates of substance use (cigarettes per day, drinks per day, relative frequency of co-use) were assessed using hierarchical linear models. RESULTS: Both alcohol and smoking cues enhanced cue-specific craving but not craving for the alternative substance. In a novel finding, combined cues elicited higher craving and greater spending than single-drug cues. All drug cues elicited greater spending than water cues, and spending was moderated by the relative frequency of co-use. CONCLUSIONS: We found that combined alcohol and cigarette cues provoke more powerful craving and drug-seeking responses and, therefore, may be more motivationally potent among individuals who use multiple substances.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Fissura , Sinais (Psicologia) , Comportamento de Procura de Droga , Fumar/psicologia , Adulto , Bebidas Alcoólicas , Alcoolismo/psicologia , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Fumantes , Produtos do Tabaco , Tabagismo , Água , Adulto JovemRESUMO
N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.
Assuntos
Acetilcisteína/uso terapêutico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Comportamento de Procura de Droga/efeitos dos fármacos , Ácido Glutâmico/efeitos dos fármacos , Glutamina/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Acetilcisteína/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética , RecompensaRESUMO
Akt is initially identified as one of the downstream targets of phosphatidylinositol-3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p-Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p-Akt in the nucleus accumbens (NAc) in cue-induced heroin-seeking behaviors after withdrawal. First, rats were trained to self-administer heroin for 14 days, after which we assessed heroin-seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p-Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS-induced heroin-seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p-Akt in the NAc. Finally, Akt1 or ß-arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS-induced heroin-seeking behavior was inhibited by downregulation of Akt1, but not ß-arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin-seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.
Assuntos
Comportamento de Procura de Droga/efeitos dos fármacos , Heroína/farmacologia , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Sinais (Psicologia) , Dependência de Heroína/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Recompensa , Autoadministração , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine-seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress-induced nicotine-seeking behavior. Non-treatment-seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled, randomized crossover design, participants (N = 21) completed two oral-dosing sessions: stress (yohimbine 54 mg + hydrocortisone 10 mg) vs placebo (lactose 54 mg + lactose 10 mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine-seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine-seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α-amylase levels; ps < .05). Relative to placebo levels, acute stress increased nicotine-seeking behavior (ps < .05), disrupted dlPFC glutamate modulation (p = .025), and impaired dlPFC function (working memory proficiency; ps < .05). The stress-induced increase in nicotine-seeking behavior was linearly related to the stress-induced disruption of dlPFC glutamate modulation (R2 = 0.24-0.37; ps < .05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress-induced nicotine-seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug-seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and "anti-stress" medications.
Assuntos
Fumar Cigarros/metabolismo , Comportamento de Procura de Droga/fisiologia , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Fisiológico/fisiologia , Tabagismo/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Método Duplo-Cego , Comportamento de Procura de Droga/efeitos dos fármacos , Feminino , Neuroimagem Funcional , Ácido Glutâmico/efeitos dos fármacos , Humanos , Hidrocortisona/farmacologia , Masculino , Memória de Curto Prazo , Nicotina , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Aleatória , Fumantes , Ioimbina/farmacologia , Adulto JovemRESUMO
Despite its lack of conceptual clarity and uniform definition, the term drug-seeking is used frequently by nurses from a variety of practice environments. The drugs patients are referred to as seeking are often pain medications. This is important because nursing has widely adopted a patient-centric definition of pain. Nursing also has a robust ethical code that places high value on human dignity and nurses' role in patient advocacy. A review of literature was conducted with the aims of describing whether/how the term drug-seeking has changed over time and to determine whether the use of the term in nursing literature is consistent with nursing values. Use of the term has shifted from objective counts of patient requests for medication to a confusing mixture of observable patient behavior and subjective interpretations of patient motivation. Its use is not consistent with nursing values. It is, in fact, a good illustration of stigmatization in nursing. Stigmatization is contrary to nursing values. Nurses in practice, research, education, authors, reviewers, and editors all have a role in ending this stigmatization.
Assuntos
Atitude do Pessoal de Saúde , Comportamento de Procura de Droga , Ética em Enfermagem , Papel do Profissional de Enfermagem , Estereotipagem , Humanos , Dor/tratamento farmacológicoRESUMO
Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure; however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for 3 days. Rats were trained to self-administer oxycodone during short (2 h) and long (6 h) access sessions. Following abstinence, rats underwent extinction and two cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding and cued reinstatement of drug seeking. A second group of rats were trained to self-administer oxycodone with varying reinforcement schedules (fixed ratio (FR)-2 and FR-4). Under an FR-2 schedule, rbTBI-exposed rats earned fewer reinforcers than sham-exposed rats. During 10 extinction sessions, the rbTBI-exposed rats exhibited significantly more seeking for oxycodone than the sham-injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not in rbTBI-exposed rats. Together, this suggests that rbTBI-exposed rats are more sensitive to oxycodone-associated cues during reinstatement than sham-exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Comportamento de Procura de Droga/fisiologia , Oxicodona/farmacologia , Autoadministração , Animais , Lesões Encefálicas Traumáticas/complicações , Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Esquema de ReforçoRESUMO
OBJECTIVES: We tested a conceptually grounded model linking athlete perceptions of strength and conditioning and technical coach doping confrontation efficacy (DCE) with athletes' doping self-regulatory efficacy (SRE), doping moral disengagement (MD), and susceptibility to intentional and inadvertent doping. DESIGN: Cross-sectional, correlational. METHODS: Participants were high-level athletes (nmale = 532; nfemale = 290) recruited in Australia (n = 261), the UK (n = 300), and the USA (n = 261). All participants completed questionnaires assessing the variables alongside a variant of the randomized response technique to estimate the prevalence of doping. RESULTS: The estimated prevalence of intentional doping in the sample was 13.9%. Structural equation modeling established: (a) perceptions of technical and strength and conditioning coaches' DCE positively predicted doping SRE; (b) doping SRE negatively predicted doping MD; (c) doping MD positively predicted susceptibility to intentional and inadvertent doping; and (d) the predictive effects of coach perceptions on susceptibility to doping were mediated by doping SRE and doping MD. Multisample analyses demonstrated these predictive effects were invariant between males and females and across the three countries represented. CONCLUSIONS: The findings show the conceptually grounded model to offer extended understanding of how multiple individuals within the athlete support personnel network may influence athlete doping.
Assuntos
Atletas/psicologia , Dopagem Esportivo/psicologia , Mentores , Adolescente , Adulto , Estudos Transversais , Dopagem Esportivo/ética , Feminino , Humanos , Masculino , Princípios Morais , Autoeficácia , Inquéritos e Questionários , Adulto JovemRESUMO
Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995 and has been widely studied since. The role of the N/OFQ system in drug abuse has attracted researchers' attention since its initial discovery. The first two scientific papers describing the effect of intracranial injection of N/OFQ appeared 20 years ago and reported efficacy of the peptide in attenuating alcohol intake, whereas heroin self-administration was insensitive. Since then more than 100 scientific articles investigating the role of the N/OFQ and N/OFQ receptor (NOP) system in drug abuse have been published. The present article provides an historical overview of the advances in the field with focus on three major elements. First, the most robust data supportive of the efficacy of NOP agonists in treating drug abuse come from studies in the field of alcohol research, followed by psychostimulant and opioid research. In contrast, activation of NOP appears to facilitate nicotine consumption. Second, emerging data challenge the assumption that activation of NOP is the most appropriate strategy to attenuate consumption of substances of abuse. This assumption is based first on the observation that animals carrying an overexpression of NOP system components are more prone to consume substances of abuse, whereas NOP knockout rats are less motivated to self-administer heroin, alcohol, and cocaine. Third, administration of NOP antagonists also reduces alcohol consumption. In addition, NOP blockade reduces nicotine self-administration. Hypothetical mechanisms explaining this apparent paradox are discussed. Finally, we focus on the possibility that co-activation of NOP and mu opioid (MOP) receptors is an alternative strategy, readily testable in the clinic, to reduce the consumption of psychostimulants, opiates, and, possibly, alcohol.
Assuntos
Analgésicos Opioides/farmacologia , Peptídeos Opioides/metabolismo , Receptores Opioides , Transtornos Relacionados ao Uso de Substâncias , Analgésicos Opioides/química , Animais , Etanol/química , Peptídeos Opioides/química , Ratos , Receptores Opioides/química , Autoadministração , NociceptinaRESUMO
All nurses have a responsibility for monitoring their patients for signs of substance misuse or substance use disorder. Adolescents and young adults are at risk for substance use. Prescription medications may be used by adolescents for non-medical reasons such as to feel high, to assist with sleep, to avoid negative feelings or thoughts or to avoid withdrawal symptoms after chronic use. Some adolescents with legally prescribed medications have been asked to divert those medications by giving them to someone else. Drug diversion by employees is often reported in healthcare settings, but diversion of medications done by patients is far less commonly reported. This paper is a report of two patients with complex medical issues and chronic pain who diverted opioid medications while hospitalized. Hiring clinical staff, such as nurses, working in Drug Diversion Prevention positions will provide knowledge and expertise to facilitate investigations and to help reduce risks for diversion in healthcare settings. In addition, nurses with concerns about patient diversion should discuss these concerns with the care team. Organizational leaders need to support their teams by providing education and resources so staff feel comfortable addressing these challenging situations.
Assuntos
Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Comportamento de Procura de Droga , Papel do Profissional de Enfermagem , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Adolescente , Analgésicos Opioides/administração & dosagem , Criança Hospitalizada/estatística & dados numéricos , Dor Crônica/diagnóstico , Relação Dose-Resposta a Droga , Feminino , Humanos , Tempo de Internação , Masculino , Monitorização Fisiológica/métodos , Transtornos Relacionados ao Uso de Opioides/enfermagem , Enfermagem Pediátrica , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Estados UnidosRESUMO
Propofol has been proven to be potentially abused by humans and laboratory animals; however, studies that have examined propofol relapse behavior are limited, and its underlying mechanism remains unclear. In this study, we examined whether basolateral amygdala-specific or systematic administration of the dopamine receptor antagonist alters cue-induced propofol-seeking behaviors in a rat model. Male Sprague-Dawley rats first received 14 days of propofol self-administration training, where active nose poke resulted in the delivery of propofol infusion paired with a tone and light cues. After 1-30 days of forced abstinence, the cue-induced propofol-seeking behaviors were tested in the operant chamber. We demonstrated, for the first time, after a few days of withdrawal from intravenous bolus administration of propofol, propofol-related cues could induce robust reinstatement of drug-seeking behavior. Systematic administration of dopamine D1 receptor antagonist (SCH-23390) or dopamine D2 receptor antagonist (spiperone) inhibited propofol relapse behavior induced by drug-related cues. Furthermore, we show that microinfusion of SCH-23390 into basolateral amygdala dose-dependently attenuated cue-induced propofol drug-seeking behavior, whereas infusion of spiperone had no effect on the propofol relapse behavior. Our results reveal the involvement of dopamine receptors within the basolateral amygdala in the cue-induced propofol relapse behavior in rats.