Genes and (Common) Pathways Underlying Drug Addiction

Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction

A Novel Bioinformatic Approach to Understanding Addiction

Finding the genetic markers that influence complex, multigenic substance addiction phenotypes has been an area of significant medical study. Understanding complex disease traits like addiction has been hampered by the lack of functional insights into novel variants to the human genome. We hypothesized that gene location plays a role in functional genomic neighborhoods. To test whether there is a relationship between opiate, dopamine, and GABA disease and population allele frequencies, we used genes obtained from addiction literature curated by the National Center for Biotechnology Information (NCBI). These addiction and metabolism focused search terms generated opiate, dopamine, and GABA addiction results (N=587 genes). These genes were then projected onto the genome to identify cluster regions of genetic importance for substance addiction. Clusters were defined as regions of the genome with more than six genes within a 1.5Mb linear genomic window. We identified seven hotspots located on chromosomes 4, 6 (2 clusters), 10, 11, and 19. Human polymorphism data was surveyed from the 1148 individuals comprising the 11 sample populations of the HapMap Project dataset. Our analyses demonstrate that when human populations are assessed, ten candidate addiction alleles were identified. Finally assessments of public genome wide association studies show long range linkages to canonical addiction genes. This study delineates a novel method to identify novel candidate addiction variants using a systems biology approach that relies on an interdisciplinary set of data, including genomic, pathway data, and population variation. Important connections to sociological and environmental data are discussed to contextualize addiction data

2008 Progress Report on Brain Research

Highlights new research on various disorders, nervous system injuries, neuroethics, neuroimmunology, pain, sense and body function, stem cells and neurogenesis, and thought and memory. Includes essays on arts and cognition and on deep brain stimulation

Understanding Nicotine Addition: Dependency as a Result of Maladaptive Brain Structure

Nicotine addiction is the most prevalent, destructive dependency found in our culture. Despite its well-documented damaging health risks, nicotine use is still widely accepted and could be conceptualized as a social epidemic. Much of this acceptance may stem from nicotine’s lack of debilitating cognitive effects, as compared to those of other abused drugs. However, what may reign dominantly over nicotine’s legality is simple cultural precedent: tobacco has never been illegal and holds a place in human history. Therefore, attempting to alter this would prove highly unpopular and unsuccessful. This macroscopic irrationality, a blind favor for cultural precedents, parallels the irrational behaviors exhibited in an individual experiencing nicotine dependence. Just as the dependent brain unconditionally craves nicotine, our culture accepts longstanding practices and traditions, despite the contradictory state they may force upon our laws

Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature

Childhood maltreatment is associated with increased severity of substance use disorder and frequent relapse to drug use following abstinence. However, the molecular and neurobiological substrates that are engaged during early traumatic events and mediate the greater risk of relapse are poorly understood and knowledge of risk factors is to date extremely limited. In this study, we modeled childhood maltreatment by exposing juvenile mice to a threatening social experience (social stressed, S-S). We showed that S-S experience influenced the propensity to reinstate cocaineseeking after periods of withdrawal in adulthood. By exploring global gene expression in blood leukocytes we found that this behavioral phenotype was associated with greater blood coagulation. In parallel, impairments in brain microvasculature were observed in S-S mice. Furthermore, treatment with an anticoagulant agent during withdrawal abolished the susceptibility to reinstate cocaine-seeking in S-S mice. These findings provide novel insights into a possible molecular mechanism by which childhood maltreatment heightens the risk for relapse in cocaine-dependent individuals

Nicotine addiction : a review

Nicotine, the major psychoactive compound in tobacco, acts as a potent addictive drug in humans. The addictive nature of nicotine leads to more than 6 million deaths a year. Evidence indicates that nicotine and other drugs of abuse act on central dopaminergic pathways and modulate their neurophysiological mechanisms. Nicotine stimulates dopaminergic pathways and the prefrontal cortex (PFC), inducing enhanced reward perception and increased cognitive function, respectively. These findings are consistent with the fact that nicotine binds to different subtypes of nicotinic acetylcholine receptors present on the neurons found in the PFC and ventral tegmental area of the midbrain. The latter, being the area most involved in addictive behaviour, projects on the limbic system, particularly the nucleus accumbens, and receives afferents from the prefrontal cortex and brainstem. Although dopaminergic pathways and nicotinic acetylcholine receptors are the protagonists of nicotine addiction, several minor pathways and their constituent receptors have been indicated as being either directly or indirectly affected by nicotine. These include serotonergic pathways and central cannabinoid receptors. Despite the scarcity of approved drugs and partial efficacy of approved treatment, insight into nicotine neurophysiological modulation led to better appreciation of nicotine-seeking behaviour and subsequent improved design of pharmacological and behavioural approaches to smoking cessation. Tobacco is the single most preventable cause of death in the world today. Better understanding of the neurobiological mechanisms underlying nicotine addiction will ultimately lead to more effective treatments of both nicotine dependence and nicotine rewarding effects.peer-reviewe

Alcohol addiction: a molecular biology perspective.

Alcohol misuse represents worldwide an important risk factor for death and disability. Excessive alcohol consumption is widely diffused in different ethnicities and alcohol use is part of the lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represents an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors.

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors

Dopaminergic, glutamatergic but not opioidergic mechanisms mediate induction of FOS-like protein by cocaethylene

Cocaethylene is a psychoactive metabolite formed\ud during the combined consumption of cocaine and ethanol. As\ud this metabolite has many properties in common with cocaine, it is conceivable that cocaethylene administration may induce the activity of nuclear transcription factors that regulate the expression of late-response genes. Therefore, the temporal induction of FOS-like protein in rat brain was examined following IP administration of 60 mmol/kg cocaethylene. Immunoreactivity for the protein was detectable at 1 h in striatal neurons and had virtually disappeared 6 h after drug treatment. Administration of\ud specific dopaminergic (SCH-23390; 0.5 mg/kg) and glutamatergic (MK-801; 1 mg/kg) receptor antagonists prior to cocaethylene indicated a significant role for dopamine (D1) and Nmethyl-D-aspartate receptor subtypes in mediating the nuclear induction of the aforementioned transcription factor protein. In contrast, no significant effects on FOS-like protein in discrete neurons of the caudate putamen were found when spiradoline (U-62066), a kappa opioid-receptor agonist, was administered either IP (10 mg/kg) or directly (50 nmol) into the brain parenchyma. In addition, we uncovered a differential sensitivity of Long–Evans rats to the behavioral effects of cocaethylene, with the psychoactive metabolite producing significantly less behavioral activity (e.g., locomotion, rearing, and continuous sniffing)than that produced by cocaine (molar equivalent of 60 mmol/kg cocaethylene). These findings indicate both common and disparate effects of cocaethylene and its parent compound, cocaine, on receptor pathways that regulate target alterations in gene expression and drug-induced motor behavior