Biology Of Addiction Research Articles

Temporal effect of manipulating NeuroD1 expression with the synthetic small molecule KHS101 on morphine contextual memory

The treatment of opioid addiction is challenging because addicts are highly prone to relapse when the memory of the former drug experience is triggered by emotional or environmental cues. An emerging and promising concept in addiction biology is that by manipulating adult hippocampal neurogenesis, a phenomenon involved in learning and memory, drug reward–like behaviors and relapse can be attenuated. We tested a new synthetic compound, KHS101, in an animal model of drug-associated contextual memory. KHS101 has been reported to increase the expression of neurogenic differentiation 1 (NeuroD1), a transcription factor involved in adult neurogenesis, and to specifically induce neuronal differentiation both in vitro and in vivo. Our results indicated that the subcutaneous injection of 3 mg/kg KHS101 for 7 days before conditioned place preference (CPP) training prolonged CPP extinction, while the same treatment after training accelerated extinction. This effect paralleled that observed following temporally controlled, tetracycline-induced NeuroD1 overexpression. Furthermore, the effect of KHS101 may occur via its induction of NeuroD1 expression as demonstrated by the abolition of the KHS101-mediated modulation of morphine-induced CPP extinction after the stereotaxic injection of lentiviral NeuroD1 small interfering RNA into the dentate gyrus (DG) of the hippocampus. These results suggest that the KHS101-mediated modulation of neurogenesis at a critical stage of the conditioning or the extinction of an opioid-associated experience may disrupt the memory trace of the existing opioid-associated experience to facilitate the extinction of drug-associated contextual memory. This implies that KHS101 has therapeutic potential for the treatment of opioid addiction.

Psychosocial Factors Associated with Relapse in Patients with Alcohol Dependence.

Introduction:Despite the recent developments in the biology of addiction, a significant part of relapse and its management is still influenced by psychosocial factors and the interplay between them. This study aims at finding the extent of association of various psychosocial factors with relapse in patients of alcohol dependence.Materials and Methods:It is a cross-sectional study of two groups of alcohol dependence patients: abstinence (n = 31) and relapse (n = 35). Demographic, clinical, and psychosocial variables were compared between the two groups. Statistical analyses were aimed at finding the extent of association between various factors and relapse.Results:Demographic variables such as family history of substance dependence (odds ratio [OR] =2.09; confidence interval [CI] =0.74–5.90) and past history of ≥2 relapses (OR = 2.71; CI = 0.83–8.87) were associated with relapse in alcohol dependence. Clinical variables such as younger age of onset of dependence (Mean difference = −3.93; 95% CI = −7.66 - −0.21; P = 0.038) and shorter time to develop dependence (Mean difference = −3.08; 95% CI = −5.53 -−0.63; P = 0.014) were significantly associated with relapse. Of the psychosocial variables, coping behavior (OR = 6.54; CI = 1.17–36.74) had the highest association with relapse followed by relapse precipitants (OR = 1.42; CI = 1.16–1.74).Conclusion:Coping behaviors to adverse situations have greater association with relapse among psychosocial variables than the number of high-risk situations a patient experiences. Interventions targeted at improving coping skills can help patients stay abstinent.

Biological Evidence for Paradoxical Improvement of Psychiatric Disorder Symptoms by Addictive Drugs

Addiction biology has focused on the mechanisms of the positive and negative reinforcing actions of addictive drugs but neglected potential benefits. Two new studies provide the first insights into a neurobiology of psychoactive drug instrumentalization. This may help us design better models for addiction neuroscience and opens a new dimension for the development of personalized pharmacotherapy of drug addiction.

The biology of addiction.

In this narrative review, the neurobiological mechanisms underlying substance abuse and addiction are discussed with a particular emphasis on the mechanisms that promote ongoing use and relapse. Addiction is estimated to affect 10-15% or more of the adult population, including physicians. Genetic predisposition, psychological and environmental risk factors, the timing of exposure to the substance, the type of substance used, and the frequency of use influence the individual's susceptibility to addiction. Abused substances act on the brain's reward system, a neural circuit that produces pleasurable feelings in response to stimuli that promote survival, thereby modifying future behavior to seek out similar stimuli. Endogenous activators include food, sex, and social interaction. Drugs of abuse hijack the reward circuit, producing intense activation. Repetitive exposure to substances leads to persistent, altered genetic expression and accumulation of ΔFos-B and corticotropin-releasing factor. High levels of these substances suppress the reward circuit and activate the endogenous stress response, resulting in a generalized state of discord. These changes are enduring and can trigger substance use relapse even after long periods of abstinence.

Understanding drug addiction-depression comorbidity: Underlining neurobiology and development of novel targeted pharmacotherapy

Understanding drug addiction-depression comorbidity: Underlining neurobiology and development of novel targeted pharmacotherapy

Cocaine promotes oxidative stress and microglial-macrophage activation in rat cerebellum.

Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.

Advances in nicotine research in Addiction Biology.

The aim of Addiction Biology is to advance our understanding of the action of drugs of abuse and addictive processes via the publication of high-impact clinical and pre-clinical findings resulting from behavioral, molecular, genetic, biochemical, neurobiological and pharmacological research. As of 2013, Addiction Biology is ranked number 1 in the category of Substance Abuse journals (SCI). Occasionally, Addiction Biology likes to highlight via review important findings focused on a particular topic and recently published in the journal. The current review summarizes a number of key publications from Addiction Biology that have contributed to the current knowledge of nicotine research, comprising a wide spectrum of approaches, both clinical and pre-clinical, at the cellular, molecular, systems and behavioral levels. A number of findings from human studies have identified, using imaging techniques, alterations in common brain circuits, as well as morphological and network activity changes, associated with tobacco use. Furthermore, both clinical and pre-clinical studies have characterized a number of mechanistic targets critical to understanding the effects of nicotine and tobacco addiction. Together, these findings will undoubtedly drive future studies examining the dramatic impact of tobacco use and the development of treatments to counter nicotine dependence.

Public Discourse on the Biology of Alcohol Addiction: Implications for Stigma, Self-Control, Essentialism, and Coercive Policies in Pregnancy

International media have reported cases of pregnant women who have had their children apprehended by social services, or who were incarcerated or forced into treatment programs based on a history of substance use or lack of adherence to addiction treatment programs. Public discourse on the biology of addiction has been criticized for generating stigma and a diminished perception of self-control in individuals with an addiction, potentially contributing to coercive approaches and criminalization of women who misuse substances during pregnancy. We explored whether this is the case based on literature from social psychology, ethics, addiction research, science communication, and philosophy. The literature shows that the relationship between public discourse on biological aspects of addiction and issues such as stigma and perceptions of diminished self-control are unclear, largely due to the complexity of these phenomena. However, concerns about the biological approach are nevertheless legitimate given the broader social and policy context of women’s health.

Recent updates on incubation of drug craving: a mini‐review

Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving.

Physician Education in Addiction Medicine

Physician Education in Addiction Medicine

Addiction neuroethics: the promises and perils of neuroscience research on addiction

Addiction neuroethics: the promises and perils of neuroscience research on addiction

Addiction: Childhood Trauma, Stress and the Biology of Addiction

According to the National Survey on Drug Use and Health (NSDUH), it is estimated that 22.6 million Americans have a substance dependency or abuse problem. Alcohol is reported to be the most widely used intoxicant in the United States, with increased rates seen during teenage years. Marijuana is the most abused drug in the United States, followed by prescription painkillers, with other drugs used to a lesser extent. Substance dependence or abuse reportedly peaks in adults aged 18 to 25. Various stressors experienced in early childhood have been shown to alter the development and functioning of different areas of the brain. The present review summarizes the impact of early environmental stress and trauma as risk factors for addiction.

Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment

ObjectiveThe study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD.MethodsDiagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD.ResultsIn bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0–6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count × high trauma, P = 0.026) and early onset PTSD (allele count × high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history.ConclusionA cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.

Optogenetics: potentials for addiction research

Research on the biology of addiction has advanced significantly over the last 50 years expanding our understanding of the brain mechanisms underlying reward, reinforcement and craving. Novel experimental approaches and techniques have provided an ever increasing armory of tools to dissect behavioral processes, neural networks and molecular mechanisms. The ultimate goal is to reintegrate this knowledge into a coherent, mechanistic framework of addiction to help identify new treatment. This can be greatly facilitated by using tools that allow, with great spatial and temporal specificity, to link molecular changes with altered activation of neural circuits and behavior. Such specificity can now be achieved by using optogenetic tools. Our review describes the general principles of optogenetics and its use to understand the links between neural activity and behavior. We also provide an overview of recent studies using optogenetic tools in addiction and consider some outstanding questions of addiction research that are particularly amenable for optogenetic approaches.

Publication trends in addiction research

As opportunities to use and abuse drugs have tremendously increased during the past 50 years, so has addiction research. Here, we provide a systematic review on publication trends in the addiction research field. We examined publication trends in different subject categories of journals including general and multi-disciplinary science, neuroscience, pharmacology, psychiatry and, as a final and most important category, substance abuse. In this first report, we provide a brief comprehensive overview on what has been published in terms of addiction in the general and multi-disciplinary science category versus Addiction Biology within the past decade. We reviewed the literature within three time windows 1999/2000, 2004/2005 and 2009/2010 and selected the number of publications (1) according to the country/region where the original study was conducted; (2) according to the drug classes; (3) according to animal versus human studies; (4) and in terms of methodological trends such as genetic association studies and neuro-imaging. We found a 350% increase in addiction-related publications in the general and multi-disciplinary science category within the past decade. This increase, however, was mainly due to increased publication output from the United States. Concerning drug classes, alcohol-, nicotine- and psychostimulant-related publications clearly increased between 1999 and 2010, whereas published papers related to opioids decreased over time. There were also strongly increasing trends for genetic and imaging studies in the addiction field over time. These publication trends are also reflected to a certain degree by published studies in Addiction Biology.

Oxytocin as a potential mediator and modulator of drug addiction

[Extract] Oxytocin, a nine amino acid neuropeptide, first discovered by Sir Heury Dale in 1906, is a potent modulator of a variety of brain functions including emotions, mood, social and sexual behaviour and learning and memory (Gimpl & Fahrenholz 2001). It has been reported that oxytocin also profoundly influences the neurobiological processes underlying drug addiction (Sarnyai & Kovacs 1994). In particular, we and others have demonstrated the inhibitory effects of oxytocin on acute behavioural effects, sensitisation and tolerance as well as on self-administration of the psychostimulant cocaine (Sarnyai & Kovacs 1994). These results raise the possibility of the development of oxytocin-based medication for psychostimulant addiction. However, despite these well-documented effects, the mechanism of action of this neuropeptide on the addictive processes is still unknown. Two papers in this issue of Addiction Biology may shed some lights on this question.

Post-Translational Modification Biology of Glutamate Receptors and Drug Addiction

Post-translational covalent modifications of glutamate receptors remain a hot topic. Early studies have established that this family of receptors, including almost all ionotropic and metabotropic glutamate receptor subtypes, undergoes active phosphorylation at serine, threonine, or tyrosine residues in their intracellular domains. Recent evidence identifies several glutamate receptor subtypes to be direct substrates for palmitoylation at cysteine residues. Other modifications such as ubiquitination and sumoylation at lysine residues also occur to certain glutamate receptors. These modifications are dynamic and reversible in nature and are regulatable by changing synaptic inputs. The regulated modifications significantly impact the receptor in many ways, including interrelated changes in biochemistry (synthesis, subunit assembling, and protein–protein interactions), subcellular redistribution (trafficking, endocytosis, synaptic delivery, and clustering), and physiology, usually associated with changes in synaptic plasticity. Glutamate receptors are enriched in the striatum and cooperate closely with dopamine to regulate striatal signaling. Emerging evidence shows that modification processes of striatal glutamate receptors are sensitive to addictive drugs, such as psychostimulants (cocaine and amphetamine). Altered modifications are believed to be directly linked to enduring receptor/synaptic plasticity and drug-seeking. This review summarizes several major types of modifications of glutamate receptors and analyzes the role of these modifications in striatal signaling and in the pathogenesis of psychostimulant addiction.

Toward a cultural biology of addiction

Addressing the issues examined in the introduction, this article suggests an integrative ‘cultural biology of addiction’, which aims at encouraging a continuing dialogue between neuroscientists and those engaged in social studies of addiction. This cultural biology of addiction provides an alternative framework that brings together seemingly contradictory social-constructionist and biologically reductionist claims about addictions.

The Biology and Psychosociology of Women and Addiction

The Biology and Psychosociology of Women and Addiction

Reward Processing by the Opioid System in the Brain

The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.