Behavioral economics of drug self-administration. I. Functional equivalence of response requirement and drug dose

Response requirement and dose of drug per administration are two separate factors that have been demonstrated to control drug self-administration. Recent developments in behavioral economics have shown that these two factors are in fact functionally equivalent for nondrug reinforcers, as indicated by a unit-price analysis. In this review, the unit-price notion was tested for drugs as reinforcers via a re-analysis of ten drug self-administration studies. The results of the re-analysis indicated that response requirement and reinforcer magnitude, the constituents of unit price, have functionally equivalent effects on drug consumption and that a positively decelerating demand curve is produced as unit price increases. This suggests that the behavioral-economic notion of unit price is a more parsimonious explanation of the effects of response requirement and dose in drug self-administration studies, in that it integrates and describes what was previously considered to be two distinct operations.     

Invertebrate models of drug abuse

Susceptibility to drug addiction depends on genetic and environmental factors and their complex interactions. Studies with mammalian models have identified molecular targets, neurochemical systems, and brain regions that mediate some of the addictive properties of abused drugs. Yet, our understanding of how the primary effects of drugs lead to addiction remains incomplete. Recently, researchers have turned to the invertebrate model systems Drosophila melanogaster and Caenorhabditis elegans to dissect the mechanisms by which abused drugs modulate behavior. Due to their sophisticated genetics, relatively simple anatomy, and their remarkable molecular similarity to mammals, these invertebrate models should provide useful insights into the mechanisms of drug action. Here we review recent behavioral and genetic studies in flies and worms on the effects of ethanol, cocaine, and nicotine, three of the most widely abused drugs in the world.     

Behavioral economic analysis of water intake in a laboratory rhesus macaque

Behavioral economics is useful for understanding the influence of environmental manipulation on a variety of behaviors, including drug self-administration, food intake, and stock behavior. The present study employed behavioral economics to investigate the psychologically satisfying amount of water intake in a laboratory rhesus macaque. Our institutional guidelines set a minimum amount of daily water intake. However, no study to date has determined whether that minimum amount is psychologically sufficient. In the present experiment, a monkey lived in an individual cage in which the only water available was delivered by chain pulling. A fixed number of responses was required for water delivery. This fixed ratio (FR) of responses per water delivery was progressively increased from FR 2 to FR 10. The study findings showed that during the FR 2 condition, demand for water was saturated at 131.3 ml/kg body weight (BW) (ranging from 95.1 to 211.2). The monkeys daily intake of water decreased as FR size incrementally increased, approaching an asymptote under the FR 8 and FR 10 conditions. During the FR 8 and FR 10 conditions, responding ceased when this monkey earned 53.5 ml/kg-BW (ranging from 32.7 to 74.9) of water. Therefore, the amount of water obtained under these conditions might provide a psychologically satisfying amount. Although these values were obtained from the behavioral study of one monkey, they were almost equivalent to values in our institutional guidelines that were determined by veterinary observations. These findings imply that behavioral economics is useful for studying the welfare of laboratory animals.     

“Herbal incense”: Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays

Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called “Spice”. The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar “subjective high” with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new “designer” cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics.     

Brain imaging in nonhuman primates: insights into drug addiction

In vivo brain imaging enables the systematic examination of trait and state variables that contribute to the etiology of human diseases. This review highlights the use of in vivo imaging in nonhuman primate models of drug abuse. In efforts to translate findings from laboratory animals to humans, monkey models offer considerable advantages over those that use rodents and other species because of their neurobiological similarity to humans and their longer life span, which makes it possible to study individual subjects over several years. This article provides a brief overview of positron emission tomography (PET), magnetic resonance imaging (MRI)-based techniques, and encephalographic approaches, with a focus on methodological issues that investigators new to the field should consider. We discuss PET imaging studies involving the dopamine (DA) system, with a special emphasis on DA D2 receptors, and describe experimental approaches through which PET imaging data can provide information about the neuropharmacological and neurochemical actions of drugs that modify behavior. We also consider the use of imaging to understand the impact and interactions of genetic predispositions and environmental and physiological modulators on disease states. For MRI-based and encephalographic studies, we describe approaches that can provide new information about brain function. Although much work remains to be done to adapt and apply these techniques for routine use in nonhuman primates, there has been much progress. These techniques will provide the foundation for future studies aimed at developing behavioral and pharmacological treatments for many human diseases.     

Opiate tolerance and dependence: recent findings and synthesis.

Recent studies have led to a greater understanding of the behavioral, cellular, and molecular mechanisms underlying opiate tolerance and physical dependence. Behavioral studies have demonstrated that both direct pharmacological effects and the learning of interactions between drug effects and environmental cues are important in these phenomena. Behavioral studies have also revealed that N-methyl-D-aspartate receptors may play a role in their development (or acquisition). Although in early cellular studies no consistent role was found for opioid receptors or endogenous opioid peptides in opiate tolerance and dependence, recent experiments suggest that beta-endorphin, enkephalin, and dynorphin neurons may indeed have a role. Finally, studies at the molecular level suggest that a functional decoupling of opioid receptors from GTP-binding proteins (G proteins) may be important. In this review, we discuss these disparate findings and present a synthesis that shows how they might together contribute to the phenomena of opiate tolerance and physical dependence.     

Functional cell-based uHTS in chemical genomic drug discovery

The availability of genomic information significantly increases the number of potential targets available for drug discovery, although the function of many targets and their relationship to disease is unknown. In a chemical genomic research approach, ultra-high throughput screening (uHTS) of genomic targets takes place early in the drug discovery process, before target validation. Target-selective modulators then provide drug leads and pharmacological research tools to validate target function. Effective implementation of a chemical genomic strategy requires assays that can perform uHTS for large numbers of genomic targets. Cell-based functional assays are capable of the uHTS throughput required for chemical genomic research, and their functional nature provides distinct advantages over ligand-binding assays in the identification of target-selective modulators.     

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist

Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzylidene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.     

An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of Caenorhabditis elegans

Alcohol use disorders are a significant public health concern, for which there are few effective treatment strategies. One difficulty that has delayed the development of more effective treatments is the relative lack of understanding of the molecular underpinnings of the effects of ethanol on behavior. The nematode, Caenorhabditis elegans (C. elegans), provides a useful model in which to generate and test hypotheses about the molecular effects of ethanol. Here, we describe an assay that has been developed and used to examine the roles of particular genes and environmental factors in behavioral responses to ethanol, in which locomotion is the behavioral output. Ethanol dose-dependently causes an acute depression of crawling on an agar surface. The effects are dynamic; animals exposed to a high concentration demonstrate an initial strong depression of crawling, referred to here as initial sensitivity, and then partially recover locomotion speed despite the continued presence of the drug. This ethanol-induced behavioral plasticity is referred to here as the development of acute functional tolerance. This assay has been used to demonstrate that these two phenotypes are distinct and genetically separable. The straightforward locomotion assay described here is suitable for examining the effects of both genetic and environmental manipulations on these acute behavioral responses to ethanol in C. elegans.     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

How contexts promote and prevent relapse to drug seeking

The contexts where drugs are self‐administered play an important role in regulating persistent drug taking and in relapse to such taking after periods of abstinence. Here, we review the behavioral and brain mechanisms enabling contexts to promote and prevent relapse to drug seeking. We review the key brain structures, their neuropharmacology and their connectivity. We discuss the similarities and differences between the mechanisms for context‐induced reinstatement of drug seeking vs. other forms of relapse to drug seeking in animal models and we highlight the numerous deficits in our understanding. We emphasize that current understanding, although significant, defies explanations in terms of models at the level of brain structures and their connectivity. Rather, we show that there is significant functional compartmentalization and segregation within these structures during reinstatement and extinction of drug seeking that parallels their anatomical segregation into circuits and channels. A key challenge is to recognize this complexity, understand how these circuits and channels are organized, as well as understand how different modes of activity of ensembles of neurons within them promote abstinence or relapse to drug seeking.     

In-cell NMR: From target structure and dynamics to drug screening

The cellular environment can affect the structure and function of pharmacological targets and the interaction with potential drugs. Such complexity is often overlooked in the first steps of drug design, where compounds are screened and optimized in vitro, leading to high failure rates in the pre-clinical and clinical tests. In-cell NMR spectroscopy has the potential to fill this gap, as it allows structural studies of proteins and nucleic acids directly in living cells, from bacteria to human-derived, providing a unique way to investigate the structure and dynamics of ligand–target interactions in the native cellular context. When applied to drug screening, in-cell NMR provides insights on binding kinetics and affinity toward a cellular target, offering a powerful tool for improving drug potency at an early stage of drug development.     

Adaptation of a 2D in-gel kinase assay to trace phosphotransferase activities in the human pathogen Leishmania donovani

The protozoan parasite Leishmania donovani undergoes various developmental transitions during its infectious cycle that are triggered by environmental signals encountered inside insect and vertebrate hosts. Intracellular differentiation of the pathogenic amastigote stage is induced by pH and temperature shifts that affect protein kinase activities and downstream protein phosphorylation. Identification of parasite proteins with phosphotransferase activity during intracellular infection may reveal new targets for pharmacological intervention. Here we describe an improved protocol to trace this activity in L. donovani extracts at high resolution combining in-gel kinase assay and two-dimensional gel electrophoresis. This 2D procedure allowed us to identify proteins that are associated with amastigote ATP-binding, ATPase, and phosphotransferase activities. The 2D in-gel kinase assay, in combination with recombinant phospho-protein substrates previously identified by phospho-proteomics analyses, provides a novel tool to establish specific protein kinase-substrate relationships thus improving our understanding of Leishmania signal transduction with relevance for future drug development.     

昆虫触角感器类型及其功能研究进展

触角感器是昆虫对环境变化产生行为响应的重要基本结构单元,作为昆虫内部神经系统与外部环境进行信息交流的关键接口,受到广泛关注。由于不同环境压力的作用,长期适应性进化使昆虫触角上着生有不同类型的感器,且执行着差异化的生物学功能。触角感器在昆虫识别寄主、寻找配偶、躲避天敌等行为变化中具有重要作用,若深入理解昆虫行为变化的内在机理,则有必要清晰认识昆虫触角感器类型与潜在功能。本文对已有研究结果进行系统性综述与总结。截止目前,共发现有61种昆虫触角感器类型,且触角感器存在种内与种间特征差异。同时针对12种常见的触角感器功能进行梳理,提出昆虫触角感器未来可深入开展的研究方向。本文全面了解各昆虫触角感器类型特征和功能,为从形态结构方面进行昆虫分类研究提供新视角,也为今后从化学生态学角度深入开展昆虫行为对环境改变的适应性等研究提供科学依据。     

Sex differences and ovarian hormones in animal models of drug dependence

Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies.     

The possible impact of human embryonic stem cells on safety pharmacological and toxicological assessments in drug discovery and drug development

The successful establishment of human embryonic stem cell (hESC) lines has raised high expectation for their future applications. The major focus of hESC research has been on their potential use in replacement therapies. However, the most immediate application of hESCs may be in establishment of humanised in vitro tests, which have potential to reduce problems of interspecies variations in safety assessments. Improved prediction of human hazard would increase patient safety and reduce the number of laboratory animals needed for toxicological and safety pharmacological testing, leading to improved efficiency of drug discovery and development in term of cost and time. The current review describes some of the newest research programmes on the use of hESCs for safety evaluations of conventional drugs. It provides an overview of the possible impact of hESCs and their derivates on regulatory drug safety assessments and discusses the potential effects on the product pipeline organisation. The review additionally summarizes initiatives in establishing quality criteria for hESC expansion and differentiation. Such criteria are necessary in order to achieve high standardisation and throughput of pharmacological and toxicological tests. Finally, it will discuss the actions needed to scientifically prove the relevance and reliability of safety tests based on hESCs.     

Large-scale elucidation of drug response pathways in humans

Elucidating signaling pathways is a fundamental step in understanding cellular processes and developing new therapeutic strategies. Here we introduce a method for the large-scale elucidation of signaling pathways involved in cellular response to drugs. Combining drug targets, drug response expression profiles, and the human physical interaction network, we infer 99 human drug response pathways and study their properties. Based on the newly inferred pathways, we develop a pathway-based drug-drug similarity measure and compare it to two common, gold standard drug-drug similarity measures. Remarkably, our measure provides better correspondence to these gold standards than similarity measures that are based on associations between drugs and known pathways, or on drug-specific gene expression profiles. It further improves the prediction of drug side effects and indications, elucidating specific response pathways that may be associated with these drug properties. Supplementary Material for this article is available at www.liebertonline.com/cmb.     

Use of environmental challenges in behavioral toxicology

The term environmental challenges encompasses variables that are either known or suspected to affect a baseline of behavior. Environmental challenges can be used to provide information that is important for characterizing the behavioral effects of prior exposure to a toxicant, as well as for revealing effects of the toxicant that may not otherwise be apparent in the baseline under investigation. The use of environmental challenges can be applied in studies of all known classes of behavior, and in each case is limited only to the extent that appropriate variables can be identified and manipulated. Use of environmental challenges may be particularly relevant for studies of schedule-controlled operant behavior because many of the controlling variables have already been well specified. The rationale for using environmental challenges to characterize the behavioral effects of toxicants is very similar to that for using pharmacological challenges; both represent promising new research strategies in behavioral toxicology.     

Importance of behavioral manipulations and measures in rat models of brain damage and brain repair

The relevance of careful behavioral measures and manipulations in animal research on neural plasticity and brain damage has become increasingly clear. Recent research in adult rats indicates that an understanding of neural restructuring after brain damage requires an understanding of how it is influenced by postinjury behavioral experiences. Other research indicates that optimizing pharmacological and other treatments for brain damage may require their combination with rehabilitative training. Assessing the efficacy of a treatment approach in animal models requires the use of sensitive behavioral measures of functional outcome. In research on restorative plasticity after brain damage, procedures for handling and housing rats should promote the quality of behavioral measures and manipulations.