VTA-NAc内orexin A在吗啡和性奖赏相关行为中作用的研究

There are a lot of differences in the neural mechanisms underlying between drug reward and natural reward despite the common neual basis. Undoubtedly, revealing the common and the different mechanisms underlying drug reward and natural reward will promote the development of research on drug addiction. Among diversified natural rewards, sex is often compared to drug because sexual reward has more similarities to drug. The mesolimbic dopamine system (VTA-NAc pathway) is a common pathway activated by natural reinforcers and addictive drugs, mediating reward, emotion and motivation under physiological conditions. The neuroadaptations taking place in the central nervous system including the mesolimbic dopamine system after repeatedly drug taking leads to persistent drug craving, Orexin, a neuropeptide produced in the lateral hypothalamus, plays an important role in reward-associated, motivated behaviors. Orexin neurons have extensive projections to the mesolimbic dopamine system. In order to further investigate the roles of orexin A in drug reward, this study examined the regulatory roles of orexin A in the VTA and NAcSh on drug reinforcement (acqusition of morphine CPP) and drug-seeking behavior (expression of morphine CPP). Moreover, the roles of orexin A on drug reward were compared with sexual reward. The main results are as follows: 1. The expression of morphine CPP was inhibited by intracerebroventricularly (i.c.v.) administered OX1R antagonist SB334867; 2. The male unconditioned sexual motivation was not affected by i.c.v. administered SB334867. However, i.c.v. given orexin A inhibited unconditioned sexual motivation in sexually high-motivated rats but did not affect sexual motivation in low-motivated rats; 3. The acquisition and expression of morphine CPP was inhibited by SB334867 microinjected into the VTA. SB334867 or orexin A injected into the NAcSh did not influence the acquisition of morphine CPP, but orexin A increased the locomotor activity in rats treated with morphine (3mg/kg); 4. SB334867 microinjected into the VTA did not affect male copulatory behavior, neither affect the acqusition of copulatory CPP; 5. The expression of copulatory CPP was associated with increased Fos protein expression in hypothalamic orexin A neurons, and SB334867 microinjected into the VTA inhibited expression of copulatory CPP. These results suggest that, (1) endogenous orexin A is not involved in male unconditioned sexual motivation, but involved in drug craving; (2) orexin A in the VTA instead of in the NAc is involved in drug reinforcement; (3) orexin A in the VTA is critical for drug-seeking behavior, but it is still unclear for the role of orexin A in the NAcSh; (4) in contrast to drug reinforcement, orexin A in the VTA is not involved in reinforcing effect of sexual reward. Orexin A plays a role both in drug-seeking behavior and in sexual reward-seeking behavior, but the different orexin A neuron populations may be responsible for the roles of orexin A in two types of reward. In a word, the differential roles of orexin A in drug and sexual reward are found in the present study, which provides some evidence for further research on the mechanisms of drug addiction.

鸡胚吗啡用药对学习记忆和成瘾易感性的影响及其受体机制

Prenatal morphine exposure affects neural development of fetus by impairing learning and memory, and increasing susceptibility to morphine abuse. Because nervous systems have different developmental characteristics during different developmental stages, administration of morphine at different stages also has different effects on learning, memory, and susceptibility to morphine. Due to the precise developmental processes of neurotransmitter systems in chick embryo’s brain, and unique superiority of chick embryo model, the purpose of the present studies was to explore critical periods correlated to the memory impairment and the increasing susceptibility to morphine, via one-trial passive avoidance and conditioned place preference as behavior models. Then the possible roles of mu and delta opioid receptors as the possible mechanism were analyzed. Experiment 1 showed that injecting low dose of morphine (1 mg/kg) during the period embryonic 5 to 8 significantly impaired the function of learning and memory, worse than any other periods of the same treatment. Experiment 2 showed that injecting low dose of morphine during the period embryonic 17 to 20 significantly increased the susceptibility to morphine in the new-born chicks. The affected chicks acquired the morphine conditioned place preference more quickly, and maintained it much longer. Experiment 3 showed that during E5-8, injecting delta receptor antagonist naltrindole reversed the learning and memory impairment caused by morphine while delta receptor agonist DPDPE impaired learning and partial memory function. On the other hand, mu opioid receptors had little effect. As for E17-20, given naloxonazine can reverse the increases of susceptibility to morphine, and the mu receptor agonist DAGO cause the increases of susceptibility to morphine. Delta receptors have no effect. The above results demonstrated that prenatal morphine expousure at different developmental periods of chick embryo caused different influences on memory and susceptibility to morphine. That is, E5-8 is the critical period correlate to memory impairment; and E17-20 is the critical period correlate to susceptibility to morphine. Delta receptors were critical in learning and memory impairment while mu receptors in susceptibility.

吗啡相关情境线索的形成及效应表达的神经基础——海马与基底外侧杏仁核在其中的作用

Drug-associated cue-induced relapse to drug seeking causes most difficulties of therapy for drug addiction. Addicts are exposed to two forms of environmental stimuli during drug-taking: contextual stimuli (e.g. a house in which the drug is consumed) and discrete stimuli (DS, e.g. a crack pipe or a syringe for drug). These stimuli become contextual cues and discrete cues, respectively. The incentive value of contextual cues plays a great role in opiates relapse. Compared with drug self-administration model, conditioned place preference (CPP) reflects the approach behavior for drug cues, not concerned with acquisition of operant behaviors. The present study aimed to investigate the role of basolateral amygdala (BLA) and hippocampus in the effect of opiates-related contextual cues using CPP model. Establishing DS-dependent or contextual cues-dependent CPP, the effect of BLA or hippocampus inactivation prior to training phase on acquisition of contextual cues-opiates association was evaluated. Inactivation prior to test phase was used to evaluate roles of BLA and hippocampus in expression of contextual cues-dependent morphine CPP. The main results were as follows: Inactivation of BLA or dorsal hippocampus selectively impaired acquisition of contextual cue-dependent CPP, but inactivation of ventral hippocampus had no impact on acquisition of either DS-dependent or contextual cue-dependent morphine CPP. Inactivation of BLA selectively inhibited expression of contextual cue-depended CPP. Inactivation of ventral hippocampus inhibited expression of both DS-dependent and contextual cue-dependent morphine CPP. These results suggest that BLA and dorsal hippocampus contribute to contextual cue association with opiates but not DS-opiates association. BLA and ventral hippocampus play important roles in incentive value of contextual cues. The present study provides more information for the neurological substrates underlying contextual cues associated with opiates.

影响吗啡动物行为效应的因素及其机制

Credible and stable animal behavioral models are necessary to research the mechanisms of addiction in vivo, especially to study the relationship between memory or stress and drug addiction, which has been one of the focuses in this field. So the object of this study was to observe the influences of several factors on the behavioral effects of morphine shown in the paradigms of conditioned place preference (CPP) and locomotor activity (LA), and to explore the effects of adrenalectomy on LA induced by morphine in rats. In addition, the cortexes of rats were examined, which were exposed to chronic administration of several doses of morphine with or without foot shock. Moreover, a new behavioral model was built to quantify the motivation of drug seeking. The results showed that CPP was more sensitive to low dose of morphine than to high dose. The period of experiment could be shortened by increasing the training times everyday, whereas in this way the dose of morphine should be low enough to avoid the impact between the near two exposures to morphine. Effects of chronic administration of morphine on LA in rats were dose- and time- dependent, which supplied evidence to choose parameters in other behavioral models. The results obtained by the simplified LA paradigm showed that hyperactivity of low dose of morphine following hypoactivity, and naloxone had no effects on LA but blocked the locomotion effects of morphine. Obvious effects of morphine on LA of rats might depend on a reasonable level of plasma corticosterone, which may determine individual vulnerability to drug addiction. Stress may also potentiate the vulnerability by aggravating damage to cortex of rats induced by drug dose-dependently, which is suggested by the results of histological examination. The result that frontal and temporal cortexes and hippocampus were injured suggests that there may be a close relationship between memory and drug addiction. It was showed that the new behavioral model on the basis of Morris water maze might be used to quantify the motivation of drug-craving.

Levantamento exploratório - reconhecimento de solos do Estado de Sergipe.

Este trabalho constitui o texto explicativo do levantamento dos solos do Estado de Sergipe, que abrange uma area de 21.994km2 e situa-se na Regiao Nordeste do Brasil, localizado entre os paralelos de 9 31'54" e 11 34'12" de latitude Sul e os meridianos de 36 11'20" de longitude a Oeste de Greenwich. O levantamento foi executado em nivel intermediario entre exploratorio e de reconhecimento, utilizando-se como bases o mapa topografico do Estado na escala 1:400.000 e foto-mosaicos nao controlados nas escalas de 1:100.000 e 1:80.000. Na zona umida costeira foram utilizadas tambem fotografias aereas verticais na escala de 1:60.000. No Estado de Sergipe prevalecem na zona costeira clima quente e umido; vegetacao florestal e cerrado; relevo plano, suave ondulado nosvales; sedimentos do Grupo Barreiras-Terciario, do Holoceno e do Cretaceo. O solo mais importante desta area e o Podzolico Vermelho Amarelo e em menor proporcao sao encontradas as Areias Quartzosas Distroficas e Latosol Vermelho Amarelo Distrofico, os quais sao derivados principalmente de sedimentos do Terciario. Relacionados com o Holoceno, sao encontrados as Areias Quartzosas Marinhas, Solos Indiscriminados de Mangues, Podzol e outros Solos Hidromorficos. Na parte oeste do Estado predominam: clima semi-arido muito quente; vegetacao de caatinga; relevo plano e suave ondulado; rochas cristalinas (xistos, gnaisses, granitos) e meta-siltitos. Destacam-se: Solos Litolicos Eutroficos, Brunos nao Calcicos, Planosol Solodico Eutrofico, Regosol, Solonetz Solodizado..

Forgoing primacy: Damaging democratic policing in the West Bank

Since the Oslo Accords were signed between Israel and the Palestinian Liberation Organization (PLO) in September 1993, the international community has supported civil policing programmes. It has done so as part of its development commitments to Palestinian state-building. Such programmes were, until the outbreak of the second Intifada in 2000, largely regarded as successful in terms of supporting the establishment of a Palestinian civil police (PCP). Such programmes were essentially Western imported models which loosely mixed community and public order policing approaches. With re-engagement in the Palestinian security sector (PSS) in the West Bank in 2007, the international community has once again sought to play a major role in PSS reform. This role includes supporting rehabilitation and retraining of the PCP as a principal institution of state-building. Such activities alongside the so-called transformation efforts within the wider realm of the PSS have re-established as their goal law and order. Within the transformation agenda, there are inherent demands with respect to Israel and the Palestinian National Authority's security and counterterrorism agendas. This analysis examines these activities, and accompanying political intent to contend that such approaches are undermining principles of democratic policing including civil police primacy (CPP). CPP reinforces police universality and means supporting rule of law by putting security under governmental control with proper mechanisms of accountability. This article argues that support to the security sector in the West Bank has increasingly only paid lip service or sought to subvert normative approaches to democratic policing.

Sexual Health and Sexuality Education Needs of Young People in Care: a Survey of Service-provider Perspectives. Report No 1.

Aim: This study aims to describe the sex education and sexual health needs of young people in care, and to explore the degree to which these needs are being met by current provision.As part of the Department for Children and Youth Affairs ‘National Strategy for Data and Research on Children’s Lives, 2011-2016’, the HSE Crisis Pregnancy Programme (CPP) and HSE Children and Families Social Services Care Group have co-commissioned a team of researchers from UCD School of Nursing, Midwifery & Health Systems, Insights Health and Social Research and Queen’s University Belfast to examine the sex education and sexual health needs of young people in care in the Republic of Ireland. The project is supported by a steering group of senior personnel from both partner organisations (CPP and CFS) and external advisors. The study involves data collection with young people, care providers, birth parents and foster parents using a mixed methods approach. Findings from each stage of the study will be combined to inform recommendations for policy and practice.

The Cyrenaican Prehistory Project 2012: the sixth season of excavations in the Haua Fteah cave

The paper reports on the sixth season of fieldwork of the Cyrenaican Prehistory Project (CPP) undertaken in September 2012. As in the spring 2012 season, work focussed on the Haua Fteah cave and on studies of materials excavated in previous seasons, with no fieldwork undertaken elsewhere in the Gebel Akhdar. An important discovery, in a sounding excavated below the base of McBurney's 1955 Deep Sounding (Trench S), is of a rockfall or roof collapse conceivably dating to the cold climatic regime of Marine Isotope Stage (MIS) 6 (globally dated to c. 190-130 ka) but more likely the result of a seismic event within MIS 5 (globally dated to c. 130-80 ka). The sediments and associated molluscan fauna in Trench S and in Trench D, a trench being cut down the side of the Deep Sounding, indicate that this part of the cave was at least seasonally waterlogged during the accumulation, probably during MIS 5, of the -6.5 rn of sediment cut through by the Deep Sounding. Evidence for human fréquentation of the cave in this period is more or less visible depending on how close the trench area was to standing water as it fluctuated through time. Trench M, the trench being cut down the side of McBurney's Middle Trench, has now reached the depth of the latest Middle Stone Age or Middle Palaeolithic (Levalloiso-Mousterian) industries. The preliminary indications from its excavation are that the transition from the Levalloiso-Mousterian to the blade-based Upper Palaeolithic or Late Stone Age Dabban industry was complex and perhaps protracted, at a time when the climate was oscillating between warmstage stable environmental conditions and colder and more arid environments. The estimated age of the sediments, c. 50-40 ka, places these oscillations within the earlier part of MIS 3 (globally dated to 60-24 ka), when global climates experienced rapid fluctuations as part of an overall trend to increasing aridity and cold.

THE SAAF STUDY: evaluation of the Safeguarding Children Assessment and Analysis Framework (SAAF), compared with management as usual, for improving outcomes for children and young people who have experienced, or are at risk of, maltreatment: study protocol for a randomised controlled trial

Background: Serious case reviews and research studies have indicated weaknesses in risk assessments conducted by child protection social workers. Social workers are adept at gathering information but struggle with analysis and assessment of risk. The Department for Education wants to know if the use of a structured decision-making tool can improve child protection assessments of risk.

Methods/design: This multi-site, cluster-randomised trial will assess the effectiveness of the Safeguarding Children Assessment and Analysis Framework (SAAF). This structured decision-making tool aims to improve social workers' assessments of harm, of future risk and parents' capacity to change. The comparison is management as usual.

Inclusion criteria: Children's Services Departments (CSDs) in England willing to make relevant teams available to be randomised, and willing to meet the trial's training and data collection requirements.

Exclusion criteria: CSDs where there were concerns about performance; where a major organisational restructuring was planned or under way; or where other risk assessment tools were in use.

Six CSDs are participating in this study. Social workers in the experimental arm will receive 2 days training in SAAF together with a range of support materials, and access to limited telephone consultation post-training. The primary outcome is child maltreatment. This will be assessed using data collected nationally on two key performance indicators: the first is the number of children in a year who have been subject to a second Child Protection Plan (CPP); the second is the number of re-referrals of children because of related concerns about maltreatment. Secondary outcomes are: i) the quality of assessments judged against a schedule of quality criteria and ii) the relationship between the three assessments required by the structured decision-making tool (level of harm, risk of (re) abuse and prospects for successful intervention).

Discussion: This is the first study to examine the effectiveness of SAAF. It will contribute to a very limited literature on the contribution that structured decision-making tools can make to improving risk assessment and case planning in child protection and on what is involved in their effective implementation.

Molecular determinants of the cellular internalization of crotamine-derived peptides

Tese de doutoramento, Ciências Biomédicas (Bioquímica Médica), Universidade de Lisboa, Faculdade de Medicina, 2014

Expert Insight into the Assessment of Competence in Cognitive–behavioural Therapy: a Qualitative Exploration of Experts' Experiences, Opinions and Recommendations

To offer insight into how cognitive–behavioural therapy (CBT) competence is defined, measured and evaluated and to highlight ways in which the assessment of CBT competence could be further improved, the current study utilizes a qualitative methodology to examine CBT experts’ (N = 19) experiences of conceptualizing and assessing the competence of CBT therapists. Semi-structured interviews were used to explore participants’ experiences of assessing the competence of CBT therapists. Interview transcripts were then analysed using interpretative phenomenological analysis in order to identify commonalities and differences in the way CBT competence is evaluated. Four superordinate themes were identified: (i) what to assess, the complex and fuzzy concept of CBT competence; (ii) how to assess CBT competence, selecting from the toolbox of assessment methods; (iii) who is best placed to assess CBT competence, expertise and independence; and (iv) pitfalls, identifying and overcoming assessment biases. Priorities for future research and ways in which the assessment of CBT competence could be further improved are discussed in light of these findings.

Structural proteins of enveloped virus : from biochemistry to molecular medicine : a focus on dengue virus

Tese de doutoramento, Ciências Biomédicas (Bioquímica Médica), Universidade de Lisboa, Faculdade de Medicina, 2016

"A testemunha-vítima e o dieito de recusa de depoimento, no Código de Processo Penal

Study of the problems involved in the application of the right of refusal to testify (Article 134. º CPP) to criminal charges of domestic violence, namely in situations of violence between spouses. Drawing attention, to some of the contingencies of the exercise of the right of refusal in such proceedings, a matter never before examined under Portuguese law, and also to the need to reconsider, based on the North American experience, the application of the law in these cases.

A WXW Motif Is Required for the Anticancer Activity of the TAT-RasGAP317-326 Peptide.

TAT-RasGAP317-326, a cell-permeable 10-amino acid-long peptide derived from the N2 fragment of p120 Ras GTPase-activating protein (RasGAP), sensitizes tumor cells to apoptosis induced by various anticancer therapies. This RasGAP-derived peptide, by targeting the deleted in liver cancer-1 (DLC1) tumor suppressor, also hampers cell migration and invasion by promoting cell adherence and by inhibiting cell movement. Here, we systematically investigated the role of each amino acid within the RasGAP317-326 sequence for the anticancer activities of TAT-RasGAP317-326. We report here that the first three amino acids of this sequence, tryptophan, methionine, and tryptophan (WMW), are necessary and sufficient to sensitize cancer cells to cisplatin-induced apoptosis and to reduce cell migration. The WMW motif was found to be critical for the binding of fragment N2 to DLC1. These results define the interaction mode between the active anticancer sequence of RasGAP and DLC1. This knowledge will facilitate the design of small molecules bearing the tumor-sensitizing and antimetastatic activities of TAT-RasGAP317-326.

The association between body composition and arterial stiffness in peri-pubescent children

The objective of this study was to examine the association between body composition and arterial stiffuess in peri-pubescent boys and girls. Differences in arterial distensibility were measured in 68 children (45 normal weight, 12 overweight, and 11 obese) between the ages of9 to 12 years. Weight classification was based on age and gender-specific body mass index cut-offs, while pubertal maturation was self-reported using Tanner staging. Distensibility was determined using two-dimensional, B-Mode echo Doppler ultrasound to measure changes at the right common carotid artery (CCA) diameter changes, while carotid pulse pressure (cPP) was measured at the left CCA by applanation tonometry. One-way ANOV A analysis revealed significant differences (p<0.001) in all anthropometric measures between the normal weight and overweight children, as well as the normal weight and obese children. Body stature was only higher in obese children compared to normal weight children (p<0.01). No significant differences were found between groups regarding age or Tanner stage. Common carotid artery distensibility showed a significant difference (p<0.01) between normal weight children (0.008 ± 0.002 mmHg-1 ) compared to obese children (0.005 ± 0.002 mmHg-1 ), with a borderline significant difference between the normal and overweight subjects (p=0.06). There was no significant effect for gender between males and females across all independent variables. The strongest determinants of distensibility in children were cPP (r= -0.52, pcPP alone explained 27% of the variance in distensibility in children. In addition, cPP, diameter difference, systolic and diastolic diameter, as well as waist-to-hip ratio explained 94% of the variance among peri-pubescent children. This study greatly underscores the need for weight management for long-term prevention of cardiovascular disease in overweight and obese children.