• 【东pol碱的内侧前额叶皮质注射可增加可卡因的仪器反应: 大鼠静脉内自我给药研究。】 复制标题 收藏 收藏
    DOI:10.1016/s0361-9230(99)00214-2 复制DOI
    作者列表:Ikemoto S,Goeders NE
    BACKGROUND & AIMS: :The present experiments examined the effects of muscarinic cholinergic receptor blockade in the nucleus accumbens (NAC) and medial prefrontal cortex (MPC) on intravenous cocaine self-administration. Adult male Sprague-Dawley rats were implanted with chronic indwelling jugular catheters and guide cannulae stereotaxically aimed at the NAC or MPC. The rats were then given the opportunity to intravenously self-administer cocaine (0.8 mg/kg/infusion) during daily 2-h sessions. Intra-NAC microinjections of methyl-scopolamine (2, 4, 8, 16, and 32 microg/side) or vehicle did not affect either the number of lever presses made or infusions delivered. On the other hand, intra-MPC injections of scopolamine significantly increased responding, although there was only a trend for an increase in the number of cocaine infusions. The effects of intra-MPC injections of scopolamine (8 and 16 microg/side) on locomotor activity were also evaluated. Intra-MPC injections of scopolamine (16 microg/side) produced significant increases in locomotor activity. However, these same microinjections decreased locomotor activity when the animals also received cocaine (15 mg/kg, i.p.). These results suggest that cholinergic neurotransmission at muscarinic receptors in the MPC is involved in regulating cocaine-maintained responding.
    背景与目标: : 本实验研究了伏隔核 (NAC) 和内侧前额叶皮层 (MPC) 中毒蕈碱胆碱能受体阻滞对静脉内可卡因自我给药的影响。将成年雄性Sprague-Dawley大鼠植入慢性留置的颈静脉导管,并以立体定向的方式引导套管,以NAC或MPC为目标。然后给大鼠在每天2小时的时间内静脉内自我施用可卡因 (0.8 mg/kg/输注) 的机会。NAC内部微注射甲基东莨菪碱 (2、4、8、16和32微克/侧) 或媒介物不会影响所制造的杠杆压机或输注的数量。另一方面,尽管只有可卡因输注数量增加的趋势,但MPC内注射东pol碱显着增加了反应。还评估了MPC内注射东莨菪碱 (8和16微克/侧) 对运动活性的影响。MPC内注射东pol碱 (16微克/侧) 可显着增加运动活性。但是,当动物也接受可卡因 (15 mg/kg,ip) 时,这些相同的微注射会降低运动活性。这些结果表明,MPC中毒蕈碱受体的胆碱能神经传递参与调节可卡因维持的反应。
  • 【重复服用苯丙胺和可卡因对大鼠血浆中肾上腺,性腺和甲状腺激素水平的影响。】 复制标题 收藏 收藏
    DOI:10.1055/s-0029-1211463 复制DOI
    作者列表:Budziszewska B,Jaworska-Feil L,Lasoń W
    BACKGROUND & AIMS: Effects of acute and repeated administration of cocaine and amphetamine on adrenal, gonadal and thyroid plasma hormone levels were studied in male rats. Acute and repeated cocaine (15 mg/kg i.p. one dose, or once an hour for 3 hr for 8 days) enhanced the corticosterone level at 45 min after administration. Amphetamine (5 mg/kg i.p. one dose, or twice daily for 14 days) elevated the level of corticosterone after 2 hr. Acute amphetamine increased the progesterone, testosterone and androstenedione plasma levels, whereas acute cocaine had no effect on those parameters. Repeated psycho-stimulants decreased the level of androgens. Neither acute nor repeated administration of psychostimulants had any significant effect on the level of the thyroid hormone T3. The T4 plasma level decreased following repeated amphetamine only. The above results indicate that repeated psychostimulants enhance the activity of the hypothalamo-pituitary-adrenal (HPA) axis and lead to a decrease in the hypothalamo-pituitary-gonadal (HPG) axis activity. On the other hand, the hypothalamo-pituitary-thyroid (HPT) axis seems to be more resistant to the psychostimulant action.

    背景与目标: 在雄性大鼠中研究了可卡因和苯丙胺的急性和反复给药对肾上腺,性腺和甲状腺血浆激素水平的影响。急性和重复可卡因 (15 mg/kg i.p.一剂,或每小时一次,持续3小时,持续8天) 在给药后45分钟提高了皮质酮水平。苯丙胺 (5 mg/kg i.p.一剂,或每天两次,持续14天) 在2小时后升高皮质酮水平。急性苯丙胺增加了孕酮,睾丸激素和雄烯二酮的血浆水平,而急性可卡因对这些参数没有影响。反复的心理兴奋剂降低了雄激素的水平。急性或反复给药精神刺激剂对甲状腺激素t3水平没有任何显着影响。仅重复苯丙胺后,T4血浆水平降低。以上结果表明,反复的精神刺激剂会增强下丘脑-垂体-肾上腺 (HPA) 轴的活性,并导致下丘脑-垂体-性腺 (HPG) 轴的活性降低。另一方面,下丘脑-垂体-甲状腺 (HPT) 轴似乎对精神刺激作用更具抵抗力。
  • 【雌二醇增强对可卡因和苯丙胺刺激的纹状体 [3H] 多巴胺释放的行为敏感性。】 复制标题 收藏 收藏
    DOI:10.1016/0006-8993(91)91706-7 复制DOI
    作者列表:Peris J,Decambre N,Coleman-Hardee ML,Simpkins JW
    BACKGROUND & AIMS: :Locomotor activity and stereotypy induced by cocaine is increased or 'sensitized' after repeated cocaine administration. This behavioral sensitization may be mediated by a persistent increase in dopamine (DA) transmission in mesolimbic and nigrostriatal pathways. Since the female estrous cycle and ovarian steroid hormones appear to affect both cocaine sensitization and DA transmission, studies were undertaken to determine the effects of ovarian steroids on sensitization of the behavioral responses to repeated cocaine injections and any concomitant effects on striatal DA release. Young female adult rats were ovariectomized and 2 weeks later were implanted with chronic release forms of estradiol (E), progesterone (P), both (EP) or vehicle (V). Locomotor and stereotypic behavior were rated after an initial injection of either saline or cocaine (10 mg/kg, i.p.) and after the 8th daily injection of saline or cocaine. A significant increase in both locomotor and stereotypic behaviors was seen after the first cocaine injection relative to saline-injected animals and this response was not affected by steroid treatment. Repeated injections of cocaine caused sensitization of the initial behavioral response to cocaine (i.e. an increase in stereotypic and locomotor behavior) and the degree of cocaine sensitization was greatest in group E. Steroid treatment did not affect behavior in saline-treated rats. When striatal [3H]DA release was measured in vitro 1 or 7 days after the last injection, amphetamine-stimulated release was greater in vehicle-treated rats 7 days after cocaine injections but not 1 day after injections. In contrast, release was enhanced in group E both 1 and 7 days after cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
    背景与目标: : 可卡因诱导的运动活性和刻板印象在反复服用可卡因后增加或 “敏感”。这种行为敏化可能是由中脑边缘和黑质纹状体途径中多巴胺 (DA) 传递的持续增加介导的。由于女性发情周期和卵巢类固醇激素似乎同时影响可卡因致敏和DA传递,因此进行了研究以确定卵巢类固醇对反复注射可卡因的行为反应的致敏作用以及对纹状体DA释放的任何伴随影响。将年轻的成年雌性大鼠卵巢切除,并在2周后植入雌二醇 (E),孕酮 (P),两者 (EP) 或赋形剂 (V) 的慢性释放形式。在初次注射盐水或可卡因 (10 mg/kg,i.p.) 和第8次每日注射盐水或可卡因后,对运动和定型行为进行了评估。相对于注射盐水的动物,第一次注射可卡因后,运动和刻板行为均显着增加,并且这种反应不受类固醇治疗的影响。反复注射可卡因会导致对可卡因的初始行为反应敏感 (即刻板印象和运动行为的增加),而e组的可卡因敏感程度最大。类固醇治疗不会影响盐水治疗大鼠的行为。当在最后一次注射后1或7天体外测量纹状体 [3H]DA释放时,可卡因注射后7天,但注射后1天,在媒介物治疗的大鼠中,苯丙胺刺激的释放更大。相反,E组在可卡因后1天和7天释放均增强。(摘要截短于250个单词)
  • 【[35岁男性静脉注射可卡因后出现腰痛发热]。】 复制标题 收藏 收藏
    DOI:10.1157/13093476 复制DOI
    作者列表:Fernández Jiménez P,Sáez Méndez L,Solera Santos J
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【1990-2000年纽约市可卡因和鸦片相关的致命过量。】 复制标题 收藏 收藏
    DOI:10.1186/1471-2458-7-31 复制DOI
    作者列表:Bernstein KT,Bucciarelli A,Piper TM,Gross C,Tardiff K,Galea S
    BACKGROUND & AIMS: BACKGROUND:In New York City (NYC), the annual mortality rate is higher for accidental drug overdoses than for homicides; cocaine and opiates are the drugs most frequently associated with drug overdose deaths. We assessed trends and correlates of cocaine- and opiate-related overdose deaths in NYC during 1990-2000. METHODS:Data were collected from the NYC Office of the Chief Medical Examiner (OCME) on all fatal drug overdoses involving cocaine and/or opiates that occurred between 1990-2000 (n = 8,774) and classified into three mutually exclusive groups (cocaine only; opiates-only; cocaine and opiates). Risk factors for accidental overdose were examined in the three groups and compared using multinomial logistic regression. RESULTS:Overall, among decedents ages 15-64, 2,392 (27.3%) were attributed to cocaine only and 2,825 (32.2%) were attributed to opiates-only. During the interval studied, the percentage of drug overdose deaths attributed to cocaine only fell from 29.2% to 23.6% while the percentage of overdose deaths attributed to opiates-only rose from 30.6% to 40.1%. Compared to New Yorkers who fatally overdosed from opiates-only, fatal overdose attributed to cocaine-only was associated with being male (OR = 0.71, 95% CI 0.62-0.82), Black (OR = 4.73, 95% CI 4.08-5.49) or Hispanic (OR = 1.51, 95% CI 1.29-1.76), an overdose outside of a residence or building (OR = 1.34, 95% CI 1.06-1.68), having alcohol detected at autopsy (OR = 0.50, 95% CI 0.44-0.56) and older age (55-64) (OR = 2.53 95% CI 1.70-3.75)). CONCLUSION:As interventions to prevent fatal overdose become more targeted and drug specific, understanding the different populations at risk for different drug-related overdoses will become more critical.
    背景与目标:
  • 【一种经过验证的液相色谱-大气压化学电离-串联质谱方法,用于定量人血浆中的可卡因和苯甲酰芽氨酸。】 复制标题 收藏 收藏
    DOI:10.1093/jat/25.7.497 复制DOI
    作者列表:Lin SN,Moody DE,Bigelow GE,Foltz RL
    BACKGROUND & AIMS: :In order to support studies on various medication protocols for the treatment of cocaine abuse, an accurate, precise, and sensitive (2.5 to 750 ng/mL) liquid chromatography-tandem mass spectrometry assay was developed to determine cocaine and benzoylecgonine in human plasma. Cocaine-d3 and benzoylecgonine-d3 were added as internal standards and samples were subjected to solid-phase extraction. Cocaine recovery was 94.4% and benzoylecgonine was 80.3% at 2.5 ng/mL. The selected reaction monitoring of parent ions at m/z 304 and 290 resulted in strong fragments at m/z 182 and 168 for cocaine and benzoylecgonine, respectively. The method was fully validated. The mean measured concentration at the 2.5 ng/mL, the lower limit of quantitation, was within 10.8% of the target and the precision determined at the low (5 ng/mL), medium (50 ng/mL), and high (650 ng/mL) quality controls ranged from 0.9 to 6.2 %CV. Cocaine and benzoylecgonine concentrations in plasma treated with 1% NaF showed changes of less than 10% when maintained at room temperature for up to 7 h and no significant changes when subjected to three freeze-thaw cycles. The concentrations of cocaine and benzoylecgonine remained stable in plasma samples stored at -20 degrees C for up to 11 months. Methanolic stock solutions of both analytes are stable, staying within 2% of the freshly prepared stock solutions, when stored at -20 degrees C for up to 235 days. Both extracted analytes reconstituted in methanolic solutions are stable for up to seven days whether stored at -20 degrees C or at room temperature on the autosampler. The method is rugged, rapid, and robust and has been applied to the batch analysis of more than 700 samples during pharmacokinetic profiling to assess potential interactions between intravenous (i.v.) cocaine challenge and treament medications. Results from three of these subjects receiving 40 mg (i.v.) cocaine demonstrate the utility of the method.
    背景与目标: : 为了支持对治疗可卡因滥用的各种药物方案的研究,开发了一种准确,精确和灵敏 (2.5 750 ng/mL) 的液相色谱-串联质谱测定法,以测定人血浆中的可卡因和苯甲酰芽子碱。加入Cocaine-d3和benzoylecgonine-d3作为内标物,样品进行固相萃取。94.4% 可卡因回收,并以2.5 ng/mL 80.3% 苯甲酰腺嘧啶。在m/z 304和290对母体离子的选定反应监测分别导致可卡因和苯甲酰芽子碱在m/z 182和168处的强片段。该方法得到了充分验证。在2.5 ng/mL (定量下限) 下的平均测量浓度在目标的10.8% 内,并且在低 (5 ng/mL),培养基 (50 ng/mL) 下确定的精密度,高 (650 ng/mL) 质量控制范围为0.9至6.2% CV。当在室温下保持长达7小时时,用1% NaF处理的血浆中的可卡因和苯甲酰芽子碱浓度显示出小于10% 的变化,而当经历三个冻融循环时,没有显着变化。在-20摄氏度下储存的血浆样品中,可卡因和苯甲酰腺嘧啶的浓度保持稳定长达11个月。当在-20摄氏度下储存长达235天时,两种分析物的甲醇储备溶液都是稳定的,保持在新鲜制备的储备溶液的2% 内。在甲醇溶液中重构的两种提取的分析物无论在-20摄氏度下还是在自动进样器上的室温下均稳定长达7天。该方法是坚固的、快速的和稳健的,并且已经应用于在药代动力学分析期间对超过700个样品进行分批分析,以评估静脉内 (静脉内) 可卡因攻击和治疗药物之间的潜在相互作用。其中三名接受40 mg (i.v.) 可卡因的受试者的结果证明了该方法的实用性。
  • 【通过动态锰增强磁共振成像 (MEMRI) 检测可卡因诱导的脑激活。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0606983104 复制DOI
    作者列表:Lu H,Xi ZX,Gitajn L,Rea W,Yang Y,Stein EA
    BACKGROUND & AIMS: :Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity based on the passage of Mn(2+) into active neurons. Because this mechanism is independent of any hemodynamic response, it is potentially ideal for pharmacological studies and was applied to investigate the acute CNS effects of cocaine in the rat. Dose-dependent, region-specific MEMRI signals were seen mostly in cortical and subcortical mesocorticolimbic structures. To verify the spatial accuracy and physiological mechanisms of MEMRI, neuronal activation following electrical forepaw stimulation revealed somatotopic signal enhancement in the primary and secondary somatosensory cortices, which was blocked by diltiazem, a Ca2+ channel antagonist. These data suggest that MEMRI may serve as a tool for investigating the effects of pharmacological agents and opens an application of MRI to study CNS drug effects at a systems level.
    背景与目标: 动态锰增强磁共振成像 (MEMRI) 基于Mn(2) 进入活动神经元的通道来检测神经元活动。由于该机制与任何血液动力学反应无关,因此它可能是理想的药理学研究,并用于研究可卡因在大鼠中的急性CNS作用。剂量依赖性,区域特异性的MEMRI信号主要出现在皮质和皮质下中皮质边缘结构中。为了验证MEMRI的空间准确性和生理机制,前爪电刺激后的神经元激活揭示了初级和次级体感皮层的体位信号增强,该信号被Ca2通道拮抗剂地尔硫卓阻断。这些数据表明,MEMRI可以用作研究药理作用的工具,并打开了MRI在系统水平上研究CNS药物作用的应用。
  • 【共病多动症和可卡因依赖治疗期间同时使用大麻: 对结果的影响。】 复制标题 收藏 收藏
    DOI:10.1080/00952990600919005 复制DOI
    作者列表:Aharonovich E,Garawi F,Bisaga A,Brooks D,Raby WN,Rubin E,Nunes EV,Levin FR
    BACKGROUND & AIMS: :Cannabis is the most widely used illicit substance in the United States with especially high prevalence of use among those with psychiatric disorders. Few studies have examined the relationship between concurrent cannabis use and treatment outcome among patients receiving treatment for comorbid substance abuse and psychiatric disorders. This study investigated the effects of cannabis use on treatment retention and abstinence from cocaine among cocaine dependent patients with Attention Deficit Hyperactivity Disorder (ADHD). Cocaine dependent patients diagnosed with current ADHD (DSM-IV, N = 92) aged 25 to 51 participated in a randomized clinical trial of methylphenidate for treatment of ADHD and cocaine dependence in an outpatient setting. The majority of patients (69%) used cannabis during treatment. Results suggest that moderate/intermittent cannabis users had greater retention rates compared to abstainers and consistent users (p = .02). This study is the first to examine concurrent cannabis use in cocaine dependent patients diagnosed with ADHD.
    背景与目标: : 大麻是美国使用最广泛的非法物质,在精神疾病患者中,大麻的使用率特别高。很少有研究检查同时使用大麻与接受共病药物滥用和精神疾病治疗的患者的治疗结果之间的关系。这项研究调查了使用大麻对可卡因依赖的注意力缺陷多动障碍 (ADHD) 患者的可卡因治疗保留和戒断的影响。25至51岁被诊断为当前ADHD (dsm-iv,N = 92) 的可卡因依赖者参加了哌醋甲酯的随机临床试验,用于在门诊环境中治疗ADHD和可卡因依赖性。大多数患者 (69%) 在治疗期间使用大麻。结果表明,与戒烟者和稳定使用者相比,中度/间歇性大麻使用者的保留率更高 (p = .02)。这项研究是第一个检查诊断为ADHD的可卡因依赖患者同时使用大麻的研究。
  • 【植物作为丁酰胆碱酯酶变体的来源,旨在增强可卡因水解酶的活性。】 复制标题 收藏 收藏
    DOI:10.1016/j.cbi.2012.09.004 复制DOI
    作者列表:Larrimore KE,Barcus M,Kannan L,Gao Y,Zhan CG,Brimijoin S,Mor T
    BACKGROUND & AIMS: :Cocaine addiction affects millions of people with disastrous personal and social consequences. Cocaine is one of the most reinforcing of all drugs of abuse, and even those who undergo rehabilitation and experience long periods of abstinence have more than 80% chance of relapse. Yet there is no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts. Recent studies, however, have demonstrated a promising potential treatment option with the help of the serum enzyme butyrylcholinesterase (BChE), which is capable of breaking down naturally occurring (-)-cocaine before the drug can influence the reward centers of the brain or affect other areas of the body. This activity of wild-type (WT) BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against (-)-cocaine. Plants are a promising means to produce large amounts of these cocaine hydrolase variants of BChE, cheaply, safely with no concerns regarding human pathogens and functionally equivalent to enzymes derived from other sources. Here, in expressing cocaine-hydrolyzing mutants of BChE in Nicotiana benthamiana using the MagnICON virus-assisted transient expression system, and in reporting their initial biochemical analysis, we provide proof-of-principle that plants can express engineered BChE proteins with desired properties.
    背景与目标: : 可卡因成瘾影响数百万人,带来灾难性的个人和社会后果。可卡因是所有滥用药物中最强化的药物之一,即使是那些接受康复治疗并经历长时间禁欲的人也有80% 以上的复发机会。然而,没有FDA批准的治疗方法来降低康复成瘾者复发的可能性。然而,最近的研究表明,在血清酶丁酰胆碱酯酶 (BChE) 的帮助下,有前途的潜在治疗选择,该酶能够在药物影响大脑的奖励中心或影响身体的其他区域之前分解天然存在的 (-)-可卡因。然而,野生型 (WT) BChE的这种活性相对较低。这促使设计了BChE变体,该变体对 (-)-可卡因的催化活性显着提高。植物是一种有前途的手段,可以廉价,安全地生产大量的BChE可卡因水解酶变体,而无需担心人类病原体,并且功能等同于其他来源的酶。在这里,在使用MagnICON病毒辅助的瞬时表达系统表达烟草中BChE的可卡因水解突变体,并报告其初始生化分析时,我们提供了植物可以表达具有所需特性的工程化BChE蛋白的原理证明。
  • 【大的加巴喷丁维持剂量不会减少人类对可卡因的自我给药。】 复制标题 收藏 收藏
    DOI:10.1016/j.drugalcdep.2006.05.028 复制DOI
    作者列表:Hart CL,Haney M,Collins ED,Rubin E,Foltin RW
    BACKGROUND & AIMS: :Previously, we reported that gabapentin, a lambda-aminobutyric acid (GABA) agonist, significantly reduced "positive" subjective effects of cocaine without reducing cocaine self-administration. We speculated that the gabapentin doses used in that study were too low to detect subtle shifts in the reinforcing effects of cocaine. Thus, the present study examined the effects of larger gabapentin maintenance doses on cocaine-related effects, including self-administration. During this 48-day double-blind, crossover design study, the effects of gabapentin maintenance (0, 2400, 3200 mg/day) on response to cocaine (0, 12, 25, 50 mg) were investigated in six cocaine-dependent individuals not seeking treatment for their cocaine use. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood pressure, and heart rate. Gabapentin did not decrease cocaine self-administration, cardiovascular measures, or most subjective effects of cocaine. These data agree with findings from a clinical trial examining the effects of similar gabapentin doses on cocaine use by treatment-seeking cocaine-dependent individuals and suggest that gabapentin does not show promise as a treatment medication for cocaine dependence.
    背景与目标: : 以前,我们报道了加巴喷丁,一种 λ-氨基丁酸 (GABA) 激动剂,在不减少可卡因自我给药的情况下显着降低了可卡因的 “积极” 主观作用。我们推测该研究中使用的加巴喷丁剂量太低,无法检测可卡因增强作用的细微变化。因此,本研究检查了较大的加巴喷丁维持剂量对可卡因相关作用 (包括自我给药) 的影响。在这项为期48天的双盲,交叉设计研究中,在六个可卡因依赖者中研究了加巴喷丁维持 (0、2400、3200 mg/天) 对可卡因 (0、12、25、50 mg) 的反应的影响。不寻求可卡因使用治疗的个体。活性可卡因显着增加了自我管理可卡因的选择,主观效果等级 (例如 “良好的药物效果”),血压和心率。加巴喷丁没有减少可卡因的自我给药,心血管措施或可卡因的最主观影响。这些数据与一项临床试验的结果一致,该试验研究了类似加巴喷丁剂量对寻求可卡因依赖的个体使用可卡因的影响,并表明加巴喷丁没有显示出可卡因依赖的治疗药物的希望。
  • 【可卡因滥用者与海洛因使用相关的死亡风险: 一项后续研究。】 复制标题 收藏 收藏
    DOI:10.3109/10826084.2013.786731 复制DOI
    作者列表:Pavarin RM
    BACKGROUND & AIMS: :Cohort study on 471 subjects resident in the metropolitan area of Bologna who had visited a public treatment center for problems due to the abuse of cocaine from January 1, 1988 to December 31, 2009. Two user typologies were created: cocaine users (no heroin) and heroin and cocaine users. Crude mortality rates and standardized mortality ratios were calculated. We performed a regression analysis using the Poisson method. The study results show a higher mortality risk for those injecting substances and for subjects who took both heroin and cocaine. They appear to have different characteristics from their counterparts who do not use heroin. Future studies should be oriented to this aspect.
    背景与目标: : 对居住在博洛尼亚都会区的471名受试者的队列研究,他们因从1988年1月1日到2009年12月31日滥用可卡因而去公共治疗中心就诊。创建了两种用户类型: 可卡因使用者 (无海洛因) 和海洛因和可卡因使用者。计算了粗死亡率和标准化死亡率。我们使用泊松方法进行了回归分析。研究结果表明,注射毒品的人以及同时服用海洛因和可卡因的受试者的死亡风险更高。他们似乎与不使用海洛因的同行具有不同的特征。未来的研究应该面向这方面。
  • 【病毒介导的腹侧被盖区细胞外信号调节激酶2的表达调节对可卡因的行为反应。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbr.2010.05.040 复制DOI
    作者列表:Iñiguez SD,Warren BL,Neve RL,Russo SJ,Nestler EJ,Bolaños-Guzmán CA
    BACKGROUND & AIMS: :Chronic exposure to cocaine increases the activity of extracellular signal-regulated kinase (ERK1/2) in the ventral tegmental area (VTA), a neural substrate for drugs of abuse. However, the functional significance of changes in ERK1/2 activity in this brain region is unknown. Using herpes simplex virus-mediated gene transfer to regulate ERK2 activity within the VTA in male rats, we show that overexpressing ERK2 increases preference for environments previously paired with low doses of cocaine and enhances cocaine-induced locomotion, whereas blocking ERK2 activity blocks cocaine-induced place conditioning and locomotor activity. These results demonstrate that ERK2-signaling within the VTA is a key modulator of functional responses to cocaine.
    背景与目标: : 长期暴露于可卡因会增加腹侧被盖区 (VTA) (滥用药物的神经底物) 中细胞外信号调节激酶 (ERK1/2) 的活性。然而,该大脑区域中ERK1/2活性变化的功能意义尚不清楚。使用单纯疱疹病毒介导的基因转移来调节雄性大鼠VTA内的ERK2活性,我们表明,过表达ERK2会增加对先前与低剂量可卡因配对的环境的偏好,并增强可卡因诱导的运动,而阻断ERK2活性会阻止可卡因诱导的位置调节和运动活动。这些结果表明,VTA内的ERK2-signaling是对可卡因的功能性反应的关键调节剂。
  • 【事先延长每日使用可卡因的时间会提高条件场所偏好测试中的奖励阈值。】 复制标题 收藏 收藏
    DOI:10.1111/adb.12053 复制DOI
    作者列表:Su ZI,Wenzel J,Ettenberg A,Ben-Shahar O
    BACKGROUND & AIMS: :We have previously shown that extended-access subjects exhibit heightened motivation for cocaine in the runway model, as reflected by reduced number of retreats. This heightened motivation could reflect either an increase in cocaine-induced reward or a decrease in cocaine-induced aversion. The current experiment was therefore devised to assess the cocaine-induced reward and aversion in extended-access rats using a place conditioning test. Rats trained to lever press for intravenous (IV) cocaine (0.25 mg/infusion) were provided 6-hour daily access to the drug over 10 days. Lever pressing in control subjects produced IV infusions of saline. Following drug self-administration, subjects underwent place conditioning for the immediate or delayed effects of cocaine (1.0 or 2.5 mg/kg, IV). In control subjects, the immediate effects of the low dose of cocaine produced conditioned places preferences (CPPs), while the delayed effects produced conditioned place aversions (CPAs). In contrast, the animals receiving low cocaine dose for 6 hours, exhibited place aversions but not preferences; an effect that was reversed when the dose of cocaine was increased. Additionally, in the 6-hour group, delayed conditioning was associated with a reduction in zif268 immunoreactivity in the medial prefrontal cortex and nucleus accumbens shell while immediate conditioning was associated with an increase in zif268-positive cells in the central nucleus of the amygdala. Collectively, these data suggest that extended daily access to cocaine produces a shift in the subject's perceived reward threshold that is paralleled by alterations in the activity of both the reward and stress pathways.
    背景与目标: : 我们以前已经表明,扩展访问对象在跑道模型中表现出对可卡因的动机增强,这反映在撤退次数减少的情况下。这种增强的动机可能反映出可卡因引起的奖励的增加或可卡因引起的厌恶情绪的减少。因此,当前的实验旨在使用位置条件测试来评估可卡因诱导的延长访问大鼠的奖赏和厌恶。训练的大鼠在10天内每天6小时接触药物,以静脉注射 (IV) 可卡因 (0.25毫克/输注)。对照受试者的杠杆按压可静脉输注盐水。在药物自我给药后,受试者对可卡因的即时或延迟作用 (1.0或2.5  mg/kg,IV) 进行了位置调节。在对照受试者中,低剂量可卡因的直接影响产生了条件偏好 (cpp),而延迟影响产生了条件厌恶 (cpa)。相反,接受低可卡因剂量6小时的动物表现出厌恶的地方,但没有偏好; 当可卡因剂量增加时,这种效果被逆转。此外,在6小时组中,延迟调节与内侧前额叶皮层和伏隔核壳中zif268免疫反应性降低有关,而立即调节与杏仁核中央核中zif268-positive细胞的增加有关。总的来说,这些数据表明,每天延长使用可卡因的时间会导致受试者感知的奖励阈值发生变化,而奖励和压力途径的活动也发生了变化。
  • 【产前可卡因暴露严重的青少年对实验性社会挑衅的反应是逃避而不是攻击。】 复制标题 收藏 收藏
    DOI:10.1016/j.ntt.2010.06.008 复制DOI
    作者列表:Greenwald MK,Chiodo LM,Hannigan JH,Sokol RJ,Janisse J,Delaney-Black V
    BACKGROUND & AIMS: :Preclinical data show that, compared to no exposure, prenatal cocaine exposure (PCE) has age-dependent effects on social interaction and aggression. The aim of this clinical study was to determine how heavy/persistent PCE--after controlling for other prenatal drug exposures, sex and postnatal factors--predicts behavioral sensitivity to provocation (i.e., reactive aggression) using a well-validated human laboratory model of aggression. African American teens (mean=14.2 years old) with histories of heavy/persistent PCE (maternal cocaine use ≥ 2 times/week during pregnancy, or positive maternal or infant urine/meconium test at delivery; n=86) or none/some exposure (NON: maternal cocaine use < 2 times/week during pregnancy; n=330) completed the Point Subtraction Aggression Paradigm. In this task, teens competed in a computer game against a fictitious opponent. There were three possible responses: (a) earn points, to exchange for money later; or (b) "aggress" against the fictitious opponent by subtracting their points; or (c) escape temporarily from point subtraction perpetrated by the fictitious opponent. The PCE group responded significantly more frequently on the escape option than the NON group, but did not differ in aggressive or money-earning responses. These data indicate that PCE-teens provoked with a social stressor exhibit a behavioral preference for escape (negative reinforcement) than for aggressive (retaliatory) or appetitive (point- or money-reinforced) responses. These findings are consistent with preclinical data showing that social provocation of adolescent or young adult offspring after PCE is associated with greater escape behavior, inferring greater submission, social withdrawal, or anxiety, as opposed to aggressive behavior.
    背景与目标: : 临床前数据表明,与未暴露相比,产前可卡因暴露 (PCE) 对社交互动和攻击具有年龄依赖性。这项临床研究的目的是确定在控制其他产前药物暴露,性别和产后因素后,重/持续的PCE如何使用经过充分验证的人类实验室模型预测对挑衅 (即反应性侵略) 的行为敏感性攻击非裔美国青少年 (平均 = 14.2岁) 有重度/持续性PCE史 (孕妇在怀孕期间使用可卡因 ≥ 2次/周,或分娩时孕妇或婴儿尿液/胎粪试验呈阳性; n = 86) 或无/部分暴露 (非: 孕妇在怀孕期间使用可卡因 <2次/周; n = 330) 完成了点减法攻击范例。在此任务中,青少年在计算机游戏中与虚拟对手竞争。有三种可能的回应 :( a) 赚取积分,以后再换钱; 或 (b) 通过减去虚拟对手的积分来 “攻击” 虚拟对手; 或 (c) 暂时从虚拟对手进行的点减法中逃脱。与非PCE组相比,PCE组对escape选项的反应频率明显更高,但在积极或赚钱的反应上没有差异。这些数据表明,受到社会压力刺激的PCE青少年表现出对逃避 (负强化) 的行为偏好,而不是对侵略性 (报复性) 或食欲 (点或金钱强化) 反应的行为偏好。这些发现与临床前数据一致,该数据表明,PCE后青少年或年轻成年后代的社交挑衅与更大的逃避行为有关,推断出更大的屈服,社交退缩或焦虑,而不是攻击行为。
  • 【脂质递质信号作为可卡因成瘾治疗的新靶点: 酰基乙醇胺和溶血磷脂酸的新作用。】 复制标题 收藏 收藏
    DOI:10.2174/138161281940131209143421 复制DOI
    作者列表:Orio L,Pavón FJ,Blanco E,Serrano A,Araos P,Pedraz M,Rivera P,Calado M,Suárez J,de Fonseca FR
    BACKGROUND & AIMS: :This review analyzes the roles of lipid transmitters, especially those derived from the cleavage of membrane phospholipids, in cocaine-associated behaviors. These lipid signals are important modulators of information processing in the brain, affecting transmitter release, neural plasticity, synaptogenesis, neurogenesis, and cellular energetics. This broad range of actions makes them suitable targets for pharmaceutical development of cocaine addiction therapies because they participate in the main cellular processes underlying the neuroadaptations associated with chronic use of this psychostimulant. The main lipid transmitters reviewed here include a) acylethanolamides and acylglycerols acting on cannabinoid receptors, such as anandamide and 2-arachidonoylglycerol; b) acylethanolamides that do not act on cannabinoid receptors, such as oleoylethanolamide; c) eicosanoids derived from arachidonic acid, including prostaglandins; and d) lysophosphatidic acid, focusing on the role of its LPA-1 receptor. Direct experimental evidence for the significance of these lipids in cocaine-related behaviors is presented and discussed. Additionally, the roles for both their biosynthesis and degradation pathways, as well as the participation of their receptors, are examined. Overall, lipid transmitter signaling can offer new targets for the development of therapies for cocaine addiction.
    背景与目标: : 这篇综述分析了脂质递质,尤其是源自膜磷脂裂解的脂质递质在可卡因相关行为中的作用。这些脂质信号是大脑中信息处理的重要调节剂,影响递质释放,神经可塑性,突触发生,神经发生和细胞能量学。这种广泛的作用使它们成为可卡因成瘾疗法药物开发的合适目标,因为它们参与了与长期使用这种精神兴奋剂相关的神经适应的主要细胞过程。此处审查的主要脂质递质包括a) 作用于大麻素受体的酰基乙醇胺和酰基甘油,例如anandamide和2-花生四烯基甘油; b) 不作用于大麻素受体的酰基乙醇胺,例如油酰乙醇酰胺; c) 源自花生四烯酸的类花生酸,包括前列腺素; 和d) 溶血磷脂酸,重点研究其LPA-1受体的作用。提出并讨论了这些脂质在可卡因相关行为中的重要性的直接实验证据。此外,还检查了它们的生物合成和降解途径的作用以及它们受体的参与。总体而言,脂质递质信号可以为开发可卡因成瘾疗法提供新的靶标。

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