Synaptic plasticity in drug reward circuitry

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.     

Drug Abuse in China: Past,Present and Future

Following British importation of opium to China in 1760s, the use and production of the drug in China increased dramatically. This situation was aggravated after the failure of Opium Wars that occurred between the United Kingdom and the Qing Empire in China with the aim of forcing China to import British Opium; this war made China open the door to a free flowing opium trade, with disastrous social and public health consequences. The subsequent rise of the new China created drug-free atmosphere by strict legislation and punishment, in which drug use greatly decreased. However, in the context of governmental reform and the open-door policies of the 1980s, drug abuse has re-emerged as a major public health problem. Today, drug abuse is highly linked to the spread of HIV/AIDS and to drug-related crimes in China. To combat the severe drug problem facing the nation, the Chinese government has adopted the Methadone Maintenance Treatment program, a multi-faceted therapeutic approach that aims to reduce the health and social problem induced by drug epidemics. In addition, traditional Chinese medicine, including herbal therapy and acupuncture, both found to be effective in the prevention of relapse and causes few side effects, making them useful for the treatment of opiate addiction. With continuous application of these therapies and managements that have been proved to be effective in harm reduction in the western countries, we believe that drug abuse and its related problems in China will be brought under control.     

Evolving conceptualizations of cocaine dependence

Cocaine was considered incapable of producing dependence in 1980 but was proclaimed the "drug of greatest national public health concern" by 1984. Clinical consensus in 1980 held that cocaine did not produce a withdrawal syndrome, but recent clinical investigations demonstrate that cocaine produces unique abuse and withdrawal patterns that differ from other major abused drugs. Evolving pre-clinical research over the past two decades now suggests that chronic cocaine abuse produces neurophysiological alterations in specific central nervous system systems that regulate the capacity to experience pleasure. These evolving clinical and pre-clinical constructs have led to applications of promising experimental pharmacological treatments for cocaine abuse.     

Drugs of abuse and immediate-early genes in the forebrain

A diverse array of chemical agents have been self administered by humans to alter the psychological state. Such drugs of abuse include both stimulants and depressants of the central nervous system. However, some commonalties must underlie the neurobiological actions of these drugs, since the desire to take the drugs often crosses from one drug to another. Studies have emphasized a role of the ventral striatum, especially the nucleus accumbens, in the actions of all drugs of abuse, although more recent studies have implicated larger regions of the forebrain. Induction of immediate-early genes has been studied extensively as a marker for activation of neurons in the central nervous system. In this review, we survey the literature reporting activation of immediate-early gene expression in the forebrain, in response to administration of drugs of abuse. All drugs of abuse activate immediate-early gene expression in the striatum, although each drug induces a particular neuroanatomical signature of activation. Most drugs of abuse activate immediate-early gene expression in several additional forebrain regions, including portions of the extended amygdala, cerebral cortex, lateral septum, and midline/intralaminar thalamic nuclei, although regional variations are found depending on the particular drug administered. Common neuropharmacological mechanisms responsible for activation of immediate-early gene expression in the forebrain involve dopaminergic and glutamatergic systems. Speculations on the biological significance and clinical relevance of immediate-early gene expression in response to drugs of abuse are presented.     

Drug testing in oral fluid

Over the last decade there have been considerable developments in the use of oral fluid (saliva) for drug testing. Oral fluid can provide a quick and non-invasive specimen for drug testing. However, its collection may be thwarted by lack of available fluid due to a range of physiological factors, including drug use itself. Food and techniques designed to stimulate production of oral fluid can also affect the concentration of drugs. Current applications are mainly focused on drugs of abuse testing in employees at workplaces where drug use has safety implications, in drivers of vehicles at the roadside and in other situations where drug impairment is suspected. Testing has included alcohol (ethanol) and a range of clinical tests eg antibodies to HIV, therapeutic drugs and steroids. Its main application has been for testing for drugs of abuse such as the amphetamines, cocaine and metabolites, opioids such as morphine, methadone and heroin, and for cannabis. Oral fluid concentrations of basic drugs such as the amphetamines, cocaine and some opioids are similar or higher than those in plasma. Tetrahydrocannabinol (THC), the major species present from cannabis use, displays similar concentrations in oral fluid compared to blood in the elimination phase. However, there is significant local absorption of the drug in the oral cavity which increases the concentrations for a period after use of drug. Depot effects occur for other drugs introduced into the body that allow local absorption, such as smoking of tobacco (nicotine), cocaine, amphetamines, or use of sub-lingual buprenorphine. Screening techniques are usually an adaptation of those used in other specimens, with an emphasis on the parent drug since this is usually the dominant species present in oral fluid. Confirmatory techniques are largely based on mass spectrometry (MS) with an emphasis on Liquid Chromatography-Mass Spectrometry (LC-MS), due to low sample volumes and the low detection limits required. Drug testing outside laboratory environments has become widespread and provides presumptive results within minutes of collection of specimens. This review focuses on the developments, particularly over the last 10 years, and outlines the roles and applications of testing for drugs in oral fluid, describes the difficulties associated with this form of testing and illustrates applications of oral fluid testing for specific drugs.     

The realization of the concept of Harm Reduction in Russia

By the present moment cases of HIV infection among injecting narcotic users (INU) have been registered in more than 100 countries. To prevent HIV infection, the program "Harm Reduction" has been developed in Britain; the program states that the prevention of HIV infection must be considered more important than the prevention of the use of narcotic drugs, as this infection is a growing danger for both drug users and public health in general. Breaking drug dependence must not be the only aim of services working with drug addicts, because this will exclude persons decisively disposed to the mode of life including the prolonged use of drugs from the sphere of their activity. Active INU having no contacts with organizations which must give them treatment and assistance find themselves in dangerous situations more often than INU maintaining contacts with such organizations. Penetration into such hidden group and its education must be the primary task. Propaganda plays a decisive role in this process, as the only way to penetrate into such group is to develop work in its territory, so that drug addicts, supplied with the necessary means could change their behavior in the desired direction. In the Russian Federation work on the project "Harm Reduction" has been carried out in 50 regions. This work has contributed to conducting teaching seminars, working out teaching programs, as well as to augmenting the interest among specialists of different professions to the problem of decreasing the spread of HIV infection. The importance of information distributed by the narcological service and the probability that very responsible persons take correct decisions on the basis of their understanding the situation have increased. The rating of public organization has risen.     

Banning all drug promotion is the best option pending major reforms

Drug promotion should be evaluated according to its impact on health, access to information, informed consent, and wealth. Drug promotion currently does more harm than good to each of these objectives because it is usually misleading. This is a systemic problem. Whilst improved regulation and education will address it to some degree, major reforms to payment systems for drug companies and doctors are also required. Until all these systemic reforms can be put in place, the best policy option is to ban the promotion of drugs to doctors and the public. Consequently, pending major reforms, it is appropriate for governments to restrict drug promotion as much as is politically achievable.     

Injection drug use and HIV/AIDS transmission in China

After nearly three decades of being virtually drug free, use of heroin and other illicit drugs has re-emerged in China as a major public health problem. One result is that drug abuse, particularly heroin injection, has come to play a predominant role in fueling China's AIDS epidemic. The first outbreak of HIV among China's IDUs was reported in the border area of Yunnan province between China and Myanmar where drug trafficking is heavy. Since then drug-related HIV has spread to all 31 provinces, autonomous regions and municipalities. This paper provides an overview to HIV/AIDS transmission through injection drug use in China. It begins with a brief history of the illicit drug trade in China, followed by a discussion of the emergence of drug related AIDS, and a profile of drug users and their sexual partners who have contracted the virus or who are vulnerable to infection. It ends by summarizing three national strategies being used by China to address both drug use and AIDS as major health threats.     

Addictive drugs and their relationship with infectious diseases

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.     

Robust detection of point mutations involved in multidrug-resistant Mycobacterium tuberculosis in the presence of co-occurrent resistance markers

Tuberculosis disease is a major global public health concern and the growing prevalence of drug-resistant Mycobacterium tuberculosis is making disease control more difficult. However, the increasing application of whole-genome sequencing as a diagnostic tool is leading to the profiling of drug resistance to inform clinical practice and treatment decision making. Computational approaches for identifying established and novel resistance-conferring mutations in genomic data include genome-wide association study (GWAS) methodologies, tests for convergent evolution and machine learning techniques. These methods may be confounded by extensive co-occurrent resistance, where statistical models for a drug include unrelated mutations known to be causing resistance to other drugs. Here, we introduce a novel ‘cannibalistic’ elimination algorithm (“Hungry, Hungry SNPos”) that attempts to remove these co-occurrent resistant variants. Using an M. tuberculosis genomic dataset for the virulent Beijing strain-type (n = 3,574) with phenotypic resistance data across five drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin), we demonstrate that this new approach is considerably more robust than traditional methods and detects resistance-associated variants too rare to be likely picked up by correlation-based techniques like GWAS.     

Development of effective therapeutics for polysubstance use disorders

Traditional pharmacotherapies for substance use disorders have focused on mono-substance abuse. However, recent epidemiological studies have found polysubstance use disorders (PUD) are becoming more prevalent and the abuse of adulterated drugs has led to increasing unintentional overdose deaths. Unfortunately, there are no approved pharmacological agents for PUD. Hence, a therapeutic model of interest to address this growing epidemic is immunopharmacotherapy, where individuals are inoculated with conjugate vaccines formulated with haptens that mimic the drug of abuse. These conjugate vaccines have demonstrated significant therapeutic potential against mono-substance abuse, thus recent studies have applied this model to address PUD. This review presents immunopharmacotherapeutic advancements against polysubstance abuse and discusses necessary developments for conjugate vaccines in order to effectively treat this unaddressed epidemic.     

Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats.

Club drug abuse is a growing problem in the United States. Beyond addiction and toxicity are endocrine effects which are not well characterized. Specifically, the changes in appetite following exposure to drugs of abuse are an interesting but poorly understood phenomenon. Serum hormones such as leptin, ghrelin, growth hormone (GH), and neuropeptide-Y (NP-Y) are known to affect appetite, but have not been studied extensively with drugs of abuse. In this work, we examine the effects of club drugs 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) and methamphetamine (METH) (doses of 5, 20 and 40 mg/kg) on serum concentrations of these hormones in adult male Sprague-Dawley rats 6, 12, 24 and 48 hours after drug administration. In a dose-dependent manner, MDMA was shown to cause transient significant decreases in serum leptin and GH followed by a base line recovery after 24 hours. Conversely, serum ghrelin increased and normalized after 24 hours. Interestingly, serum NP-Y showed a steady decrease in both treatment of MDMA and METH at different time points and dosages. In humans, abuse of these drugs reduces eating. As evident from these data, acute administration of METH and MDMA had significant effects on different serum hormone levels involved in appetite regulation. Future studies should be performed to see how chronic, low dose drug administration would affect hormone levels and try to answer questions about the physiological mechanisms involved in the anorexic paradigm observed in drug use.     

Recent Developments in Nanotechnology and Risk Assessment Strategies for Addressing Public and Environmental Health Concerns

Nanotechnology is a novel emerging technology that allows the manipulation of materials at the scale comparable to the size of a single molecule (i.e., < 100 nm). There have been many new developments in this technology, resulting in complex exposure and health risk implications. Nanotechnology offers major benefits to humankind; however, there is growing concern regarding the potential adverse interactions of engineered nanoparticles at cellular or sub-cellular levels. The nanotech community is therefore experiencing growing calls for legislation to minimize or prevent exposure to nanoparticles. This article focuses on recent developments in nanotechnology including current manufacturing techniques, uses of nanoscale particles, and implications for particle toxicity and human exposure pathways. Current risk assessment methods are reviewed in the context of nanoparticle exposure routes and regulation for human and environmental health protection. This study provides a better understanding of the factors governing risks from nanoparticles and current strategies for protecting environmental and public health.     

Hallucinogenic botanicals of America: a growing need for focused drug education and research

Botanical sources for medicines in America have been known since long before the arrival of Columbus. Nevertheless, both scientists and the general public are often unaware that some of these botanical drugs are also potent intoxicants. We provide a quick overview of hallucinogenic and dissociative drugs harvested from nature or that are openly and legally cultivated in the United States. Examples of harmful outcomes reported in the media are contrasted with existing responsible ingestion by others, some of whom have the protected right to do so for traditional or sacramental religious purposes. Despite an ongoing and expensive effort to warn people of the potential harms of recreational drug use, little is known about the extent of use of these psychoactive botanicals, and the recent explosion of information available via the Internet could herald a storm of morbidity to come. Mounting more targeted research and educational efforts today may reduce later use and abuse, inform society about the special circumstances of religious use, and better prepare clinicians and other health care providers about the issues involved when people choose to indigenously source psychoactive drugs for human consumption.     

Prioritising Healthcare Workers for Ebola Treatment: Treating Those at Greatest Risk to Confer Greatest Benefit

The Ebola epidemic in Western Africa has highlighted issues related to weak health systems, the politics of drug and vaccine development and the need for transparent and ethical criteria for use of scarce local and global resources during public health emergency. In this paper we explore two key themes. First, we argue that independent of any use of experimental drugs or vaccine interventions, simultaneous implementation of proven public health principles, community engagement and culturally sensitive communication are critical as these measures represent the most cost‐effective and fair utilization of available resources. Second, we attempt to clarify the ethical issues related to use of scarce experimental drugs or vaccines and explore in detail the most critical ethical question related to Ebola drug or vaccine distribution in the current outbreak: who among those infected or at risk should be prioritized to receive any new experimental drugs or vaccines? We conclude that healthcare workers should be prioritised for these experimental interventions, for a variety of reasons.     

Ecopharmacognosy and the responsibilities of natural product research to sustainability

The recently developed term “ecopharmacognosy” is defined as the study of sustainable, biologically active, natural resources. As a philosophical approach, it provides a conceptual framework for developing new strategies and new scientific perspectives which may improve future global food and health care product accessibility and assure beneficial outcomes. In this brief article some facets of how the precepts of ecopharmacognosy may apply in developing new medicinal products may be developed, based on sustainability and the use of integrated technologies.Although from a medicinal agent perspective, plants remain a primary source of global health care, these resources are not being pursued by major pharmaceutical companies as sources of new agents, and essentially all tropical diseases, as well as most microbially based diseases, remain outside the scope of their drug discovery programs. Countries and regions therefore must address their own drug discovery needs for “local” and some global diseases. In addition, the cost of drug importation is so high that development of local resources, i.e. traditional medicines, may be the only rational alternative approach. At the same time, network pharmacology is exploring the many diverse effects of both individual and complex natural products at the gene level, and this is offering new opportunities to rethink and restructure the core, long-standing, Western, magic bullet philosophy to drug discovery. Other ecopharmacognosy changes underway include the computer-aided design of natural product derivatives, based on molecular docking, which is providing targetable enzyme substrates, and remote sensing technologies which can assess natural materials non-invasively for critical constituents as a part of rethinking quality control strategies in the field. Furthermore, there are the hyphenated chromatographic and spectroscopic procedures to quantitatively analyze single and multicomponent plant mixtures for bioactive markers to enhance quality control and, thereby, patient care. The relationship of these evolving approaches will serve as practical examples to the philosophies of ecopharmacognosy. In summary, with respect to health care, ecopharmacognosy poses the long-term practical question for drugs, “How Green is Your Medicine?”     

Lipids and drugs of abuse

Drug abuse continues to take an enormous economic and social toll on the world. Among the costs are reduced productivity, increased need for medical services and stress on families. Treatments that allow affected individuals to reduce compulsive drug use are lacking and novel approaches to their development will likely come from increased understanding of the consequences of chronic exposure to reinforcing drugs. The purpose of this review is to explore the role of lipids in drug abuse and to present a rationale for an increased focus on the interactions between drugs of abuse and lipids in the brain. Small molecular weight lipids function as neuromodulators in the brain and, as such, play a role in the synaptic plasticity that occurs following exposure to drugs of abuse. In addition, the membrane lipid bilayer consists of lipid subdomains and emerging evidence suggests that protein function can be altered by transient associations with these subdomains. Finally, lipidomics is a very new field devoted to the exploration of changes in cellular lipid constituents during phenotypic alterations. Enhanced research in all of these areas will likely provide useful insights into and, perhaps, therapeutic targets for the treatment of drug abuse.     

Iron chelators as anti-infectives; malaria as a paradigm

Malaria is the major life threatening parasitic disease and the cause of a global public health problem. The failure of vector eradication programs and the appearance and spread of drug resistant parasites have posed the urgent challenge of developing effective, safe and affordable anti-malarial drugs. The design of such drugs is largely based on the targeting of agents to the parasite-based machinery for host digestion and to the products of hemoglobin catabolism. Iron chelators, by depriving intracellular parasites from essential iron, lead to selective suppression of parasite growth. However, by acting on parasite-impaired macrophages, chelators can also expedite resumption of phagocytosis and elimination of parasites. In order to be clinically effective, chelators need to be maintained in the blood for extensive time periods. Therapeutic doses can be attained with appropriate drug combinations and formulations or delivery devices and these must be presented in a form well tolerated by the host. The early documentation that chelation therapy has activity against human malaria has paved the road for the design of novel and more efficient remedies based on short-term iron deprivation.