海洛因成瘾者决策障碍及其行为机制的研究----短视行为及冲动、强迫和药物在决策中的作用

Addiction can be investigated from the perspective of decision making. Addicts usually make incorrect decisions when facing drug-related cues or they are driven to drugs, resulting in repeated drug seeking and taking. The present study adopted temporal discounting as behavioral task and on the basis of the fact that heroin addicts discounted more steeply than health participants (addicts preferred to choose immediate but smaller reward, regarded as myopia) which was consistent with previous research, three questions was raised and being concentrated on in this study. The first question was whether the character of myopia would be revealed in a somewhat complicated task? We designed a card game in which the participants were tested whether they would play the trump card in order to win a trick but not the whole game. Addicts played the trump card significantly earlier than controls did, indicating they focused on immediate single trick but not the game. Moreover, the performance in the card game and temporal discounting correlated significantly, suggesting addicts would display myopic decision not only in simply task like temporal discounting but also in task more complicated and similar to daily-life decision. Secondly, the present study adopted various kinds of temporal discounting tasks. In previous research, temporal discounting gain task was usually adopted. In the present study, we also adopted temporal discounting loss task. In either gain or loss task, there are two delayed amounts. Results showed in each decision condition addicts made poorer performance compared with control but in larger amount condition, addicts actually improved their decision performance. Meanwhile, addicts did not show loss aversion due to their close discount rates in gain and loss task while for controls, the discount rates were much lower in loss task than those in gain task. Thus we demonstrated that addicts were insensitive to negative outcomes by the method of temporal discounting. Finally, we investigated three mechanisms which exerted impacts on decision making. We adopted Go/NoGo task to test impulsivity and found addicts commits more errors (higher impulsivity) than controls did. We also designed a behavioral task which could be used to test drug-related compulsive behavior on human participants. Results showed addicts produced stereotyped key-pressing behavior when presented with drug-related cues. Furthermore, it was found participants with higher impulsivity displayed poorer performance in decision making but addicts with higher compulsivity only made poorer performance in smaller amount decision and the correlation between compulsivity and decision making was relative weak. In order to investigate the role of susceptibility and effect of drugs, we adopted years of abusing heroin as the indictor and discovered addicts with longer history of heroin abusing made poorer performance in smaller amount condition than addicts with shorter history. Also, the earlier the addicts began to use drug, the worse they would do in the smaller amount decision. The results here indicated drug itself could exert impact on decision making in certain condition. The present study revealed three characters of heroin addicts from the aspect of decision making: (1) focusing upon current benefit due to they preferred to choose immediate gain and delayed loss; (2) showed no loss aversion compared with healthy participants (3) inability to inhibit inappropriate response particularly when facing drug-related cue. These characters contribute to the facts that addicts seek and take drugs repeatedly while ignoring the negative consequences caused by abusing drugs.

Novel roles for the GABAB receptor in anxiety and cocaine addiction

The GABAB receptor has been postulated as a possible drug target in the treatment of anxiety disorders and cocaine addiction. Indeed, a wealth of preclinical data is emerging that has shown that mice lacking functional GABAB receptors display a highly anxious behaviour across a range of behavioural models of anxiety. Additionally, novel compounds that act by altering the allosteric conformation of the GABAB receptor to a more active state; the GABAB receptor positive modulators, have been repeatedly demonstrated to have anxiolytic effects in animals. In addition to being a putative anxiolytic drug target, the GABAB receptor has been identified as a novel target for antiaddictive therapies. Indeed GABAB receptor positive modulators have been demonstrated to have anti-addictive properties across a broad variety of behavioural paradigms. Despite these findings, several gaps in our knowledge of the role played by the GABAB receptor in both anxiety and drug abuse disorder exist. The aim of this thesis was to use preclinical animal models in an effort to further probe the role played by the GABAB receptor in anxiety and addiction. Our studies initially examined the role played by the GABAB receptor in the neurodevelopmental processes underpinning of anxiety. Our studies demonstrated that treating mouse pups in early life with the GABAB receptor agonist baclofen produced an anxious phenotype in adult life, whereas treatment with the GABAB receptor antagonist CGP52432 produced no effects on adult behaviour. Further to this, we examined whether the anxious behaviour induced by early life blockade of the serotonin reuptake transporter was dependant on alterations in GABAB receptor function. Our studies however revealed no effect of early life selective serotonin reuptake inhibitor treatment on adult life baclofen sensitivity. The next issue addressed in this thesis is the characterization of the effects of a GABAB receptor positive modulator and a GABAB receptor antagonist in a behavioural model of conditioned fear behaviour. These novel classes of GABAB receptor ligands have been considerably less well characterized in this facet of preclinical anxiety behaviour than in terms of innate anxiety behaviour. Our study however revealed that the GABAB receptor positive modulator GS39783 and the GABAB receptor antagonist CGP52432 were without effect on the acquisition, expression or extinction of conditioned fear in our model. The next element of this thesis dealt with the characterization of a novel mouse model, the GABAB(2)- S892A mouse. This mouse has been engineered to express a form of the GABAB(2) receptor subunit wherein the function determining serine phosphorylation site cannot be phosphorylated. We initially tested this mouse in terms of its GABAB receptor function in adult life, followed by testing it in a battery of tests of unconditioned and learned anxiety behaviour. We also examined the behavioural and molecular responses of the GABAB(2)-S892A mouse to cocaine. All of our studies appear to show that the GABAB(2)-S892A mouse is indistinguishable from wildtype controls. The final aim of the thesis was to investigate the behavioural and molecular sensitivity of the GABAB(1) subunit isoform null mice, the GABAB(1a) -/- and GABAB(1b) -/- mice to cocaine. Our studies revealed that these mice display differing behavioural responses to cocaine, with the GABAB(1a) -/- mouse displaying a hypersensitivity to the acute locomotor effects of cocaine, while the GABAB(1b) -/- displayed blunted locomotor sensitisation to cocaine.

Gender and racial/ethnic differences in addiction severity, HIV risk, and quality of life among adults in opioid detoxification: results from the National Drug Abuse Treatment Clinical Trials Network.

PURPOSE: Detoxification often serves as an initial contact for treatment and represents an opportunity for engaging patients in aftercare to prevent relapse. However, there is limited information concerning clinical profiles of individuals seeking detoxification, and the opportunity to engage patients in detoxification for aftercare often is missed. This study examined clinical profiles of a geographically diverse sample of opioid-dependent adults in detoxification to discern the treatment needs of a growing number of women and whites with opioid addiction and to inform interventions aimed at improving use of aftercare or rehabilitation. METHODS: The sample included 343 opioid-dependent patients enrolled in two national multi-site studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-002). Patients were recruited from 12 addiction treatment programs across the nation. Gender and racial/ethnic differences in addiction severity, human immunodeficiency virus (HIV) risk, and quality of life were examined. RESULTS: Women and whites were more likely than men and African Americans to have greater psychiatric and family/social relationship problems and report poorer health-related quality of life and functioning. Whites and Hispanics exhibited higher levels of total HIV risk scores and risky injection drug use scores than African Americans, and Hispanics showed a higher level of unprotected sexual behaviors than whites. African Americans were more likely than whites to use heroin and cocaine and to have more severe alcohol and employment problems. CONCLUSIONS: Women and whites show more psychopathology than men and African Americans. These results highlight the need to monitor an increased trend of opioid addiction among women and whites and to develop effective combined psychosocial and pharmacologic treatments to meet the diverse needs of the expanding opioid-abusing population. Elevated levels of HIV risk behaviors among Hispanics and whites also warrant more research to delineate mechanisms and to reduce their risky behaviors.

Effect of Addiction Modeling Reinforcement Schedules on Delay Discounting

Elevated delay discounting, in which delayed rewards quickly lose value as a function of time, is associated with substance use and abuse. Currently, the direction of causation is unclear: while some research indicates that elevated delay discounting leads to future substance use, it is also possible that chronic substance use and specifically the rate of reinforcement associated with drug use, leads to elevated delay discounting. This project aims to examine the latter possibility. 47 participants completed ten 30-minute daily sessions of a visual attention task, and were reinforced at a rate intended to model drug use (fixed ratio 1) or drug abstinence (fixed ratio 10). Baseline and post-training rates of delay discounting were assessed for hypothetical $50 and $1000. Area under the curve of the indifference points as a function of delay was calculated. A greater area under the curve suggests more self-control, whereas a lower value represents more impulsiveness. Results at the monetary value of both $50 and $1000 showed increased impulsivity in relation to the control for both the FR1 and FR10 groups indicating that the two schedules may both model drug use.

Myopic Rationality in a Mania

The rationality of investors during asset price bubbles has been the subject of considerable debate. An analysis of the British Railway Mania, which occurred in the 1840s, suggests that investors may have been myopic, as their expectations were only accurate in the short-term, but they remained rational, as they acted in a utility maximising manner given their expectations. Investors successfully incorporated forecasts of short-term dividend changes into their valuations, but were unable to predict longer-term changes. When short-term growth is controlled for, it appears that the railways were priced consistently with the non-railways throughout the entire episode.

Cognitive biases and addiction: an evolution in theory and method

An evolution in theoretical models and methodological paradigms for investigating cognitive biases in the addictions is discussed. Anomalies in traditional cognitive perspectives, and problems with the self-report methods which underpin them, are highlighted. An emergent body of cognitive research, contextualized within the principles and paradigms of cognitive neuropsychology rather than social learning theory, is presented which, it is argued, addresses these anomalies and problems. Evidence is presented that biases in the processing of addiction-related stimuli, and in the network of propositions which motivate addictive behaviours, occur at automatic, implicit and pre-conscious levels of awareness. It is suggested that methods which assess such implicit cognitive biases (e.g. Stroop, memory, priming and reaction-time paradigms) yield findings which have better predictive utility for ongoing behaviour than those biases determined by self-report methods of introspection. The potential utility of these findings for understanding "loss of control" phenomena, and the desynchrony between reported beliefs and intentions and ongoing addictive behaviours, is discussed. Applications to the practice of cognitive therapy are considered.

Total Addiction:The Life of an Eclipse Chaser

Seeing a total solar eclipse is often described as a once-in-a-lifetime experience. However, for many who have experienced totality, once-in-a-lifetime is simply not enough. They want more, and are willing to go to great lengths often at great expense to repeat the experience. What is it like to experience totality? What is it about the experience that motivates these eclipse chasers? Is there an eclipse chaser personality? Can eclipse chasing actually be described as an addiction? This book describes the people who dedicate their lives to chasing their dream.

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.

Biometric measurements in highly myopic eyes

Purpose: To assess the repeatability and accuracy of optical biometry (Lenstar LS900 optical low-coherence reflectometry [OLCR] and IOLMaster partial coherence interferometry [PCI]) and applanation ultrasound biometry in highly myopic eyes. Setting: Division of Preventive Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China. Design: Comparative evaluation of diagnostic technology. Methods: Biometric measurements were taken in highly myopic subjects with a spherical equivalent (SE) of -6.00 diopters (D) or higher and an axial length (AL) longer than 25.0 mm. Measurements of AL and anterior chamber depth (ACD) obtained by OLCR were compared with those obtained by PCI and applanation A-scan ultrasound. Right eyes were analyzed. Repeatability was evaluated using the coefficient of variation (CoV) and agreement, using Bland-Altman analyses. Results: The mean SE was -11.20 D ± 4.65 (SD). The CoVs for repeated AL measurements using OLCR, PCI, and applanation ultrasound were 0.06%, 0.07%, and 0.20%, respectively. The limits of agreement (LoA) for AL were 0.11 mm between OLCR and PCI, 1.01 mm between OLCR and applanation ultrasound, and 1.03 mm between PCI and ultrasound. The ACD values were 0.29 mm, 0.53 mm, and 0.51 mm, respectively. These repeatability and agreement results were comparable in eyes with extreme myopia (AL ≥27.0 mm) or posterior staphyloma. The mean radius of corneal curvature was similar between OLCR and PCI (7.66 ± 0.24 mm versus 7.64 ± 0.25 mm), with an LoA of 0.12 mm. Conclusion: Optical biometry provided more repeatable and precise measurements of biometric parameters, including AL and ACD, than applanation ultrasound biometry in highly myopic eyes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2012 ASCRS and ESCRS.

Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.

Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism

Epigenetic modulation is found to get involved in multiple neurobehavioral processes. It is believed that different types of environmental stimuli could alter the epigenome of the whole brain or related neural circuits, subsequently contributing to the long-lasting neural plasticity of certain behavioral phenotypes. While the maternal influence on the health of offsprings has been long recognized, recent findings highlight an alternative way for neurobehavioral phenotypes to be passed on to the next generation, i.e., through the male germ line. In this review, we focus specifically on the transgenerational modulation induced by environmental stress, drugs of abuse, and other physical or mental changes (e.g., ageing, metabolism, fear) in fathers, and recapitulate the underlying mechanisms potentially mediating the alterations in epigenome or gene expression of offsprings. Together, these findings suggest that the inheritance of phenotypic traits through male germ-line epigenome may represent the unique manner of adaptation during evolution. Hence, more attention should be paid to the paternal health, given its equivalently important role in affecting neurobehaviors of descendants.