Opioid and Notch signaling pathways are reciprocally regulated through miR- 29a and miR-212 expression

Background

The abuse of opioids, such as morphine and phentanyl or other drugs as heroin is a social and health problem that affects an increasing number of people each year. The activation of the mu opioid receptor triggers several molecular changes that alter the expression of diverse genes, including miRNAs. The dysregulation of these molecules could explain some of the developmental alterations that are induced after drug intake. In addition, the Notch signaling cascade has also been related to alterations on these processes.

丙泊酚对认知的损伤及成瘾性研究进展

作为一种临床上常用的静脉麻醉药,丙泊酚主要用于诱导或维持全身麻醉,近年来随着临床实践及实验室研究发现,除了麻醉作用外,丙泊酚还有许多其他非麻醉效应。如在给药期间可导致认知功能的损伤,其机制可能涉及增强抑制性神经元的活性、抑制兴奋性神经元的活性、抑制某些神经递质如一氧化氮的产生等影响记忆的形成;同时该药一经临床使用,就有报道指出其可能存在潜在的成瘾性,而后续多数研究均提示其能够诱导奖赏效应的产生从而导致其成瘾及滥用。为更好的推动对丙泊酚认知功能损伤的机制及保护措施的研究、以及其成瘾机制及戒断方法的研究,本文就近年丙泊酚对认知功能损伤作用及潜在成瘾性的研究进展作一综述。     

Augmenting the efficacy of anti-cocaine catalytic antibodies through chimeric hapten design and combinatorial vaccination

Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy. In contrast, the resulting pool of antibodies from GNE/GNT co-administration demonstrated intermediate efficacy as compared to antibodies developed from either hapten alone. Overall, improved antibody catalytic efficiency appears necessary to achieve the synergistic benefits of combining cocaine hydrolysis with peripheral sequestration.     

Chromosomal loci that influence oral nicotine consumption in C57BL/6J x C3H/HeJ F2 intercross mice

Several studies have demonstrated that there are genetic influences on free-choice oral nicotine consumption in mice. In order to establish the genetic architecture that underlies individual differences in free-choice nicotine consumption, quantitative trait loci (QTL) mapping was used to identify chromosomal regions that influence free-choice nicotine consumption in male and female F(2) mice derived from a cross between C57BL/6J and C3H/HeJ mice. These two mouse strains were chosen not only because they differ significantly for oral nicotine consumption, but also because they are at or near phenotypic extremes for all measures of nicotine sensitivity that have been reported. A four-bottle choice paradigm was used to assess nicotine consumption over an 8-day period. The four bottles contained water or water supplemented with 25, 50 or 100 microg/ml of nicotine base. Using micrograms of nicotine consumed per milliliter of total fluid consumed per day as the nicotine consumption phenotype, four significant QTL were identified. The QTL with the largest LOD score was located on distal chromosome 1 (peak LOD score = 15.7). Other chromosomes with significant QTL include central chromosome 4 (peak LOD score = 4.1), proximal chromosome 7 (peak LOD score = 6.1) and distal chromosome 15 (peak LOD score = 4.8). These four QTL appear to be responsible for up to 62% of the phenotypic variance in oral nicotine consumption.     

多巴胺对吗啡成瘾大鼠海马区痛觉调制的研究进展

当今社会日益增长的吗啡等阿片类药物的非法滥用已经严重威胁到人类的健康。然而,迄今为止尚没有找到能够较为有效的防治阿片成瘾的方法。目前研究已知,阿片成瘾的形成所涉及的脑区及核团包括中脑腹侧被盖区(VTA)、伏隔核(NAc)、海马等,其成瘾涉及的神经递质系统包括多巴胺、5-羟色胺等。本文将就多巴胺及海马在痛觉调制及药物成瘾过程中的作用进行综述,为吗啡的成瘾与戒断的进一研究及治疗提供线索。     

Interactions among Positions in the Third and Fourth Membrane-associated Domains at the Intersubunit Interface of the N-Methyl-D-aspartate Receptor Forming Sites of Alcohol Action

The N-methyl-d-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The predicted structure of the NMDA receptor, based on that of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We tested the hypothesis that these positions interact to regulate receptor kinetics and ethanol sensitivity by using dual substitution mutants. In single-substitution mutants, we found that a position in both subunits adjacent to one previously identified, GluN1(Gly-638) and GluN2A(Phe-636), can strongly regulate ethanol sensitivity. Significant interactions affecting ethanol inhibition and receptor deactivation were observed at four pairs of positions in GluN1/GluN2A: Gly-638/Met-823, Phe-639/Leu-824, Met-818/Phe-636, and Leu-819/Phe-637; the latter pair also interacted with respect to desensitization. Two interactions involved a position in M4 of both subunits, GluN1(Met-818) and GluN2A(Leu-824), that does not by itself alter ethanol sensitivity, whereas a previously identified ethanol-sensitive position, GluN2A(Ala-825), did not unequivocally interact with any other position tested. These results also indicate a shift by one position of the predicted alignment of the GluN1 M4 domain. These findings have allowed for the refinement of the NMDA receptor M domain structure, demonstrate that this region can influence apparent agonist affinity, and support the existence of four sites of alcohol action on the NMDA receptor, each consisting of five amino acids at the M3-M4 domain intersubunit interfaces.     

海洛因成瘾模型建立及中脑腹侧被盖区Bax的表达

目的探索海洛因对中脑腹侧被盖区细胞Bax表达的影响。方法肌肉注射海洛因,建立成瘾大鼠模型,用免疫组化方法检测中脑腹侧被盖区细胞Bax的表达。结果连续给大鼠注射海洛因7d后,大鼠出现明显的戒断症状;中脑腹侧被盖区细胞Bax表达阳性细胞比对照组明显增多,与对照组相比差异有显著性（P〈0.01）。结论海洛因具有诱导Bax基因表达、损伤脑组织细胞的作用。     

Methamphetamine enhances paced mating behaviors and neuroplasticity in the medial amygdala of female rats

Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and behavior in women and men. Even though men and women are equally as likely to be addicted to or use METH, studies of sexual behavior often focus on male users. The paucity in studies examining the effect of METH in women is of great concern, when one considers the high correlation with sexually transmitted diseases such as HIV/AIDS and unplanned pregnancies. In fact, why METH so profoundly increases sexual drive is unknown. We have demonstrated that repeated exposure to METH enhances both receptivity and proceptivity in hormonally primed female rats. The current study examined whether a repeated exposure to METH enhanced female-initiated sexual behaviors in hormonally primed rats. In a paced mating paradigm, METH treatment significantly decreased the female's return latency following a mount (57%) and an ejaculation (44%), and the likelihood to leave the male following an intromission (37%) compared to controls. The METH-induced changes in paced mating behavior were accompanied by a 60% increase in spinophilin levels in the medial amygdala following hormonal priming and METH treatment. Taken together, these findings suggest that METH increases female sexual motivation and behavior in the rat potentially via changes in the neural substrate that require repeated exposure to the drug.     

药物成瘾及成瘾记忆的研究现状

本文在介绍药物成瘾与学习和记忆密切相关的神经回路及共同分子机制的基础上,围绕学习和记忆在药物成瘾中的作用,综述了关联性学习与复吸,关联性学习与敏化,异常关联性学习与强迫性用药行为,关联性学习及成瘾记忆与成瘾,多重记忆系统与成瘾的发生发展等方面的研究进展,并强调了突触可塑性及成瘾记忆在药物成瘾中的重要性。在此基础上提出：作为慢性脑病的药物成瘾的形成过程的重要特征是它包含着信息的特殊学习类型。药物成瘾与依赖于多巴胺的关联性学习紊乱有密切关系。海马可能在成瘾中扮演重要角色。     

Evaluation of the health status outcome among inpatients treated for Amphetamine Addiction

Amphetamine is one of the most abuser drugs in Saudi Arabia. The aim of this study was to evaluate health status outcome at baseline and after detoxification in amphetamine users through the evaluation of the body mass index, renal function tests, cardiac biomarkers, gonadal hormonal levels, and oxidative stress markers. A cross-sectional study was conducted on 90 participants. Sixty participants were hospitalized patients for treatment of addiction and 30 participants were healthy volunteers. This study was performed at a psychiatric and rehabilitation center, in Qassim region, in the Kingdom of Saudi Arabia. Participants were divided into: group I = control; group II = amphetamine users and group III = amphetamine plus cannabis users. Socio-demographic data was collected. The urinary amphetamine level, Severity Dependence Scale (SDS), body mass index (BMI), vital signs; serum levels of troponin T (TnT), immunoglobulin M (IgM), immunoglobulin G (IgG), luteinizing Hormone (LH), testosterone Hormone (TSTS), urea, creatinine, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured on admission and after detoxification. The results showed that the BMI was significantly decreased while, vital signs such as heart rate, blood pressure and respiratory rate were significantly increased in all abusers and returned to normal values after the detoxification period. The cardiac biomarker troponin T was significantly increased and reversed after detoxification. The immune system was evaluated through assessing serum levels of immunoglobulin (Ig) M and IgG. The immune system remained immunocompromised in drug users, and IgM and IgG levels did not reach the level of control group after treatment. Luteinizing and testosterone hormones were evaluated. Both hormones were increased on admission and improved after the detoxification period. Renal function showed no significant differences between drug users and the control group. In the evaluation of the antioxidant system, there was a significant increase in serum MDA, SOD, GPx, and CAT levels compared to healthy controls. After the detoxification phase, these oxidative stress biomarkers still remained elevated. The current results have shown the addiction of amphetamine and cannabis exert detrimental effects on different body organs and the exert major consequences on the health status of drug users. The present study showed that, there was no improvement in the levels of oxidative stress biomarkers, although an improvement was observed in the other parameters after the detoxification phase.