The ethics of the pharmaceutical industry and the need for a dual market system

In an era of increasing medical costs and cries for health care reform in the United States, the pharmaceutical industry has come under intense scrutiny. Ethical issues are inherent in the pharmaceutical marketplace, and there is a need to address the moral rights and responsibilities of drug manufacturers consumers, health care professionals, and governmental agents in the production, distribution, regulation, and use of these products. A dual market system protecting individual rights to access and autonomy without placing an undue strain on societal resources would provide an adequate and equitable framework for an ethical pharmaceutical industry.     

Recording puff volume in smoking

Recent research on nicotine self-administration has highlighted the need to accurately assess within-cigarette topography in order to estimate changes in puff profiles that occur in response to varying nicotine content. This paper describes equipment and techniques that may be used to record puff volume in the laboratory and discusses methods used by other researchers to study puff volume with an emphasis on methodological advantages of the present technique.     

A Defence of Pharmaceutical Paternalism

Pharmaceutical paternalism is the normative stance upheld by pharmaceutical regulatory agencies like the US Food and Drug Administration. These agencies prevent patients from accessing treatments declared safe and ineffective for the patient's good without their consent. Libertarian critics of the FDA have shown a number of significant flaws in regulatory paternalism. Against these objections, I will argue that, in order to make an informed decision about treatments, a libertarian patient should request full disclosure of the uncertainty about an experimental treatment. But pharmaceutical markets, on their own, are not a reliable source of information about such uncertainty. And companies have the power to capture any independent expert who may assess it. Therefore, the libertarian is better off deferring on an independent regulatory body the assessment of the pharmaceutical risks, constraining access to treatments until tested.     

Unit-price analysis of opioid consumption by monkeys responding under a progressive-ratio schedule of drug injection.

Several reports have indicated that drug consumption in self-administration procedures is a function of the ratio of the instrumental requirement to the dose of drug, a quantity termed unit price. We evaluated three predictions from this unit-price model in a reanalysis of data on opioid self-administration in rhesus monkeys responding under a progressive-ratio schedule (Hoffmeister, 1979). We evaluated whether consumption was inversely related to unit price, and compared the goodness of fit of an equation devised by Hursh, Raslear, Shurtleff, Bauman, and Simmons (1988) to that of a linear model predicting consumption as a function of dose. We also tested whether consumption was constant when the same unit price was comprised of different combinations of dose and instrumental requirement. Consumption declined overall as unit price increased. The equation devised by Hursh et al. and the linear model based on dose fit the data equally well. Drug consumption was not uniform at a given unit price. The analyses suggest limits on the unit-price model as a characterization of drug consumption.     

Psychological stress and blood glucose regulation in type I diabetic patients

Fifteen Type I diabetic patients self-monitored daily mean blood glucose levels (BGL), psychological stress, diet, exercise, and insulin injections for a period of 8 weeks. Separate multiple-regression analyses were conducted for each subject to assess the predictability of BGL from stress reports, independent of the effects of diet, exercise, and insulin self-administration. Considerable individual variability in findings was evident, with stress predicting BGL in a statistically significant manner in 7 of the 15 subjects. Stress had a significant effect on BGL independent of diet, exercise, and insulin administration for each of these 7 subjects. Discussion focused on the problems of measuring the key self-management behaviors influencing BGL and on the possibility that a subgroup of diabetic patients may be BGL stress responders.     

Male HIV-1 transgenic rats show reduced cocaine-maintained lever-pressing compared to F344 wildtype rats despite similar baseline locomotion

The HIV-1 transgenic (Tg) rat model is valuable for understanding HIV-associated neurocognitive disorders (HAND) and accompanying substance use and misuse. Tg and F344/NHsd wildtype (WT) rats were allowed to self-administer intrajugular cocaine. For the first 7 sessions, neither genotype self-administered cocaine (0.1 mg/kg/infusion) on a fixed ratio 1 schedule. We thus implemented a lever–cocaine “autoshaping” session followed by a series of manipulations changing dose and reinforcement schedule. Tg rats self-administered much less cocaine than WT rats throughout the study. Of 8 Tg rats, 5 modestly increased self-administration from sessions 36–50. Of those, only 3 showed a lever discrimination. Of 10 WT rats, 8 acquired robust self-administration by session 19; all WT rats self-administered cocaine by the end of the study. WT and Tg rats had similar baseline locomotor activity in the self-administration chamber suggesting that the low levels of cocaine intake in the Tg rats did not reflect a nonspecific motor impairment in this rat strain. Concomitant measurement of activity with self-administration revealed activity increases that followed increased cocaine intake. That relation held in Tg rats. Therefore, the present study provides evidence that HIV-1 Tg rats are less sensitive to the reinforcing effects of cocaine than their F344 WT counterparts.     

The “pill popper”: A device for drug capsule self-administration by primates

An apparatus for establishing self-administration of drugs in capsule preparation form by nonhuman primates is described. The system includes a capsule loading unit combined with a pressurized liquid dispenser and mouth-operated drinking tube lever. Operation of the mouth lever results in forced ingestion of a capsule or other solid substance and a measured quantity of liquid. The components of the system are separately programmable and adjustable to permit shaping of pressurized liquid and capsule ingestion through successive approximations. Examination of absorption factors and temporal variables associated with delay of drug reinforcement onset, as well as precision in oral dosage, are thus possible in a model which approximates the most common method and features of drug self-administration in humans.     

Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems

Repeated cycles of ethanol intoxication and withdrawal associated with dependence induce neuroadaptations in a variety of brain systems. Withdrawal-induced negative emotional states can be ameliorated by ethanol consumption; a learned process termed negative reinforcement. Accordingly, a dependence-induced phenotype is escalated ethanol self-administration. Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade the extracellular matrix to allow for synaptic reorganization and plasticity. To test the hypothesis that an intact MMP system is required for animals to learn about the negative reinforcing effects of ethanol and display escalated self-administration during acute withdrawal when ethanol-dependent, male Wistar rats were trained to self-administer ethanol and then assigned to either acute or chronic MMP inhibition treatment groups. The chronic treatment group received intracerebroventricular (ICV) infusions of the broad spectrum MMP inhibitor FN-439 or artificial cerebrospinal fluid (aCSF) via osmotic minipumps during a 1 month ethanol dependence induction period and subsequent post-dependence induction self-administration sessions that occurred during acute withdrawal. The acute treatment group only received ICV FN-439 or aCSF on the day of self-administration sessions following dependence induction during acute withdrawal. The results showed that inhibition of MMPs attenuated escalated ethanol self-administration following chronic and acute exposure conditions. Furthermore, once learning (i.e., plasticity) had occurred, MMP inhibition had no impact on escalated response patterns and animals previously subjected to MMP inhibition that did not escalate evidenced normal escalations in operant ethanol self-administration once FN-439 treatments were terminated. Thus, the present data identified that an intact MMP system is required for the escalated responding that occurs during acute withdrawal in dependent animals and implicate such escalation as a learned response.     

Pharmaceutical companies and access to medicines – social integration and ethical CSR resolution of a global public choice problem

This article argues that effective corporate social responsibility (CSR) of multinational pharmaceutical companies in developing countries should reflect context, opportunity, proximity, time and impact in accordance with the social integration and ethical approaches to CSR. It proposes a CSR model expressed as CSR=COPTI+SI+E, which acknowledges access-to-medicines as a matter in the global public domain, a public choice problem and a moral responsibility issue for multinational pharmaceutical companies. This model recognises the globalisation of the principle of humanity in communities of place and communities of interest as highlighted by the Global Economic Ethic Manifesto 2009 as an integral part of the responsibilities of multinational pharmaceutical companies. The model reflects a global application of the concept of disadvantaged consumer already known to some national laws. The article suggests an access-to-medicines CSR framework for pharmaceutical companies which may include pricing, patents, testing and clinical trials, research and development, joint public private initiative and appropriate use of drugs.     

Response times seen as decompression times in Boolean concept use

This paper reports a study of a multi-agent model of working memory (WM) in the context of Boolean concept learning. The model aims to assess the compressibility of information processed in WM. Concept complexity is described as a function of communication resources (i.e., the number of agents and the structure of communication between agents) required in WM to learn a target concept. This model has been successfully applied in measuring learning times for three-dimensional (3D) concepts (Mathy and Bradmetz in Curr Psychol Cognit 22(1):41-82, 2004). In this previous study, learning time was found to be a function of compression time. To assess the effect of decompression time, this paper presents an extended intra-conceptual study of response times for two- and 3D concepts. Response times are measured in recognition phases. The model explains why the time required to compress a sample of examples into a rule is directly linked to the time to decompress this rule when categorizing examples. Three experiments were conducted with 65, 49, and 84 undergraduate students who were given Boolean concept learning tasks in two and three dimensions (also called rule-based classification tasks). The results corroborate the metric of decompression given by the multi-agent model, especially when the model is parameterized following static serial processing of information. Also, this static serial model better fits the patterns of response times than an exemplar-based model.     

Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models

Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when a predictor affects a dependent variable indirectly through at least one intervening variable, or mediator. Methods to assess mediation involving multiple simultaneous mediators have received little attention in the methodological literature despite a clear need. We provide an overview of simple and multiple mediation and explore three approaches that can be used to investigate indirect processes, as well as methods for contrasting two or more mediators within a single model. We present an illustrative example, assessing and contrasting potential mediators of the relationship between the helpfulness of socialization agents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax, to facilitate the use of these methods in applications.     

Differential antagonism of cocaine self-administration and cocaine-induced disruptions of learning by haloperidol in rhesus monkeys

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors.     

Agreement and Updating For Self-Locating Belief

In this paper, I argue that some plausible principles concerning which credences are rationally permissible for agents given information about one another’s epistemic and credal states have some surprising consequences for which credences an agent ought to have in light of self-locating information. I provide a framework that allows us to state these constraints and draw out these consequences precisely. I then consider and assess the prospects for rejecting these prima facie plausible principles.     

Alcohol self-administration by rats in the presence of a tangible object

The authors used the sucrose-substitution procedure to train operant self-administration of a 10% alcohol solution in 8 Long-Evans rats. After they established stable responding, they began a 10-session baseline. A 10-session experimental phase followed the baseline phase. During the experimental phase, the authors placed a large glass marble in the center of the experimental chambers before self-administration sessions. The presence of the marble decreased the rats' responding and alcohol intake significantly. The authors discussed the results in terms of distraction and the effects of concurrently available reinforcers on alcohol self-administration.     

A Computationally Grounded,Weighted Doxastic Logic

Modelling, reasoning and verifying complex situations involving a system of agents is crucial in all phases of the development of a number of safety-critical systems. In particular, it is of fundamental importance to have tools and techniques to reason about the doxastic and epistemic states of agents, to make sure that the agents behave as intended. In this paper we introduce a computationally grounded logic called COGWED and we present two types of semantics that support a range of practical situations. We provide model checking algorithms, complexity characterisations and a prototype implementation. We validate our proposal against a case study from the avionic domain: we assess and verify the situational awareness of pilots flying an aircraft with several automated components in off-nominal conditions.     

二级强化程序在药物成瘾研究中的应用

二级强化程序是一种以物质的强化效应为基础,评价药物的精神依赖性潜力的方法,将其应用到自身给药实验中,即为二级强化自身给药模型。在这个模型中,动物在条件性刺激的影响下按压杠杆以寻求药物的行为反映了其对成瘾性药物的渴求。使用二级强化程序,人们发现：条件性刺激既能够影响觅药行为的获得和保持,也能够影响这种行为的消退;伏隔核的核区、杏仁核基底外侧部和内侧前额皮层等部位在药物相关的条件性刺激诱导动物产生觅药行为的过程中起重要作用。二级强化程序的应用为开发治疗药物成瘾的物质提供了一条新思路     

Behavioral economics of drug self-administration and drug abuse policy.

The concepts of behavioral economics have proven useful for understanding the environmental control of overall levels of responding for a variety of commodities, including reinforcement by drug self-administration. These general concepts are summarized for application to the analysis of drug-reinforced behavior and proposed as the basis for future applications. This behavioral agenda includes the assessment of abuse liability, the assay of drug-reinforcer interactions, the design of drug abuse interventions, and the formulation of drug abuse public policy. These separate domains of investigation are described as part of an overall strategy for designing model projects to control drug use and testing public policy initiatives.     

Effects of compounding drug-related stimuli: escalation of heroin self-administration

Previous experiments have demonstrated that presenting independently established discriminative stimuli in compound can substantially increase operant responding maintained by food reinforcement or shock avoidance. Recently, this phenomenon was also shown to occur with cocaine self-administration. The present study further assessed the generality of these stimulus-compounding effects by systematically replicating them with heroin self-administration. Rats' nose-poke responses produced intravenous heroin (0.025 mg/kg per infusion) on a variable-ratio schedule when either a tone or a light was present. In the absence of these stimuli, responding was not reinforced. Once discriminative control by the tone and light had been established, the stimuli were presented in compound under extinction (with heroin discontinued) or maintenance conditions (with heroin available during test-stimulus presentations). In extinction, the tone-light compound increased responding approximately threefold compared to tone or light alone. Under maintenance conditions, compounding increased heroin intake approximately twofold. These effects closely matched those obtained earlier with cocaine. This consistency across pharmacological classes and across drug and nondrug reinforcers further confirms that (a) self-administered drugs support conditioning and learning in a manner similar to that supported by other reinforcers; and (b) multiple drug-related cues interact in lawful and predictable ways to affect drug seeking and consumption.     

Effects of mesolimbic dopamine depletion on responding maintained by cocaine and food.

The hypothesis that mesolimbic dopamine is selectively involved in cocaine reinforcement was investigated in the rat. Animals were trained under a multiple schedule in which responding was reinforced by intravenous cocaine (0.75 mg/kg/injection) or food (45-mg pellets) under fixed-ratio 15 schedule requirements in alternate 30-min components of a 2-hr daily session. Infusion of the catecholaminergic neurotoxin 6-hydroxydopamine, but not the vehicle solution, into the region of the nucleus accumbens and olfactory tubercle produced selective reductions in cocaine self-administration without significantly altering responding maintained by food within the same sessions. This effect was reproduced in intact animals by substituting saline for cocaine in the self-administration component. These results support the hypothesis that the reinforcing effects of cocaine are dependent upon mesolimbic dopamine and demonstrate that cocaine self-administration can be disrupted in animals without altering behavior maintained by a nondrug reinforcer.     

Pharmacologic and Behavioral Withdrawal From Addictive Drugs

ABSTRACT— Recent theories suggest that drug withdrawal does not motivate drug use and relapse. However, data now show that withdrawal produces complex changes over time in at least two symptoms (i.e., negative affect and urges) that are highly predictive of relapse. Evidence suggests that falling levels of the drug in the blood and interruption of the drug self-administration ritual both affect these symptoms. Both of these forms of withdrawal motivate renewed drug use in addicted individuals.