Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic predisposition to addiction to opioids and other substances is transmitted as a complex genetic trait, which investigators are attempting to characterize using genetic linkage and association. We now report a high-density genome-wide linkage study of opioid dependence. We ascertained 305 DSM-IV opioid dependent affected sibling pairs from an ethnically mixed population of methadone maintained subjects and genotyped their DNA using Affymetrix 10K v2 arrays. Analysis with MERLIN identified a region on chromosome 14q with a non-parametric lod (NPL) of 3.30. Secondary analyses indicated that this locus was relatively specific to the self-identified Puerto Rican subset, as the NPL increased from 3.30 to 5.00 (NPL(Caucasian) = 0.05 and NPL(African Amer.) = 0.15). The 14q peak encompasses the NRXN3 gene (neurexin 3), which was previously identified as a potential candidate gene for addiction. Secondary analyses also identified several regions with gender-specific NPL scores greater than 2.00. The most significant was a peak on (10q) that increased from 0.90 to 3.22 when only males were considered (NPL(female) = 0.05). Our linkage data suggest specific chromosomal loci for future fine-mapping genetic analysis and support the hypothesis that ethnic and gender specific genes underlie addiction susceptibility.
Hum Mol Genet 2007 Jun 01
PMID:Genomewide suggestive linkage of opioid dependence to chromosome 14q. 1740 92

Ethanol exerts numerous pharmacological effects through its interaction with various neurotransmitters. The dopaminergic pathway is associated with cognitive, endocrine, and motor functions, and reinforcement of addictive substances or behaviours. Aldehyde dehydrogenase (ALDH) is a vital enzyme involved with alcohol metabolism and detoxification. In the present study, we investigated the role of cerebral cortex and brain stem dopamine D(2) receptors in the functional regulation on ALDH enzyme activity, in ethanol administrated rats. Two groups of rats were selected viz. control and alcoholic. Cerebral cortex, brain stem and the liver dopamine content was decreased significantly (P < 0.05, 0.05, 0.001, respectively) and homovanillic acid/dopamine (HVA/DA) ratio has significantly increased (P < 0.05, 0.001 and 0.001), respectively in ethanol treated rats when compared to control. Scatchard analysis of [(3)H]YM-09151-2 binding to synaptic membrane preparations of cerebral cortex and brain stem showed a significant decrease (P < 0.001, 0.05, respectively) in B (max) in ethanol treated rats compared to control and the K (d) also decreased significantly (P < 0.05). The ALDH analysis showed a significant increase (P < 0.05) in V (max) in cerebral cortex, plasma and liver of experimental rats when compared with control without having significant change in brain stem but with decreased K (m) (P < 0.001). Our results suggest that decreased function of dopamine mediated through DA D(2) receptor in the cerebral cortex and brain stem enhanced the brain, plasma and liver ALDH activity in ethanol treated rats. This ALDH regulation has significance to correct alcoholics from addiction due to allergic reaction observed in aldehyde accumulation.
Mol Cell Biochem 2007 Oct
PMID:Decreased dopamine D(2) receptor function in cerebral cortex and brain stem: their role in hepatic ALDH regulation in ethanol treated rats. 1753 Jan 88

Neurexins are cell adhesion molecules that help to specify and stabilize synapses and provide receptors for neuroligins, neurexophilins, dystroglycans and alpha-latrotoxins. We previously reported significant allele frequency differences for single nucleotide polymorphisms (SNPs) in the neurexin 3 (NRXN3) gene in each of two comparisons between individuals who were dependent on illegal substances and controls. We now report work clarifying details of NRXN3's gene structure and variants and documenting association of NRXN3 SNPs with alcohol dependence. We localize this association signal with the vicinity of the NRXN3 splicing site 5 (SS#5). A splicing site SNP, rs8019381, that is located 23 bp from the SS#5 exon 23 donor site displays association with P = 0.0007 (odds ratio = 2.46). Including or excluding exon 23 at SS#5 produces soluble or transmembrane NRXN3 isoforms. We thus examined expression of these NRXN3 isoforms in postmortem human cerebral cortical brain samples from individuals with varying rs8019381 genotypes. Two of the splice variants that encode transmembrane NRXN3 isoforms were expressed at significantly lower levels in individuals with the addiction-associated rs8019381 'T' allele than in CC homozygotes. Taken together with recent reports of NRXN3 association with nicotine dependence and linkage with opiate dependence, these data support roles for NRXN3 haplotypes that alter expression of specific NRXN3 isoforms in genetic vulnerabilities to dependence on a variety of addictive substances.
Hum Mol Genet 2007 Dec 01
PMID:Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. 1780 23

Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.
Hum Mol Genet 2008 Jan 01
PMID:Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area. 1792 4

Addiction is an enormous societal problem. A number of recent studies have focused on adaptations at glutamatergic synapses that may play a role in the behavioral responses to drugs of abuse. These studies have largely focused on NMDA receptor-dependent forms of synaptic plasticity such as NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). A growing body of evidence, however, suggests that metabotropic glutamate receptors (mGluRs) also play important roles in the behavioral responses to drugs of abuse and participate in producing synaptic plasticity at glutamate synapses. In this review, we focus first on the evidence supporting a role for mGluRs in addiction and then on the properties of mGluR-dependent forms of synaptic plasticity, focusing in particular on Gq-linked receptor-induced LTD.
Mol Neurobiol 2007 Dec
PMID:Group I mGluRs and long-term depression: potential roles in addiction? 1795 98

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.
Cell Mol Neurobiol 2008 Jun
PMID:Drug abuse in China: past, present and future. 1799 98

Neuronal nicotinic acetylcholine receptors have been implicated in various measures of nicotine dependence. In this paper, we present findings from an exploratory study of single nucleotide polymorphisms (SNPs) in the CHRNB3 and CHRNA6 genes with tobacco and alcohol phenotypes, including frequency of use and three subjective response factors occurring shortly after initiation of use. Subjects were 1056 ethnically diverse adolescents ascertained from clinical and community settings. The most significant associations were found between two CHRNB3 SNPs (rs4950 and rs13280604) and the three subjective response factors to initial tobacco use. These findings were replicated in a separate community sample of 1524 families participating in the National Longitudinal Study of Adolescent Health. Both CHRNB3 SNPs were found to be associated with similar measures of subjective response to tobacco. These results indicate that early subjective response to nicotine may be a valuable endophenotype for genetic studies aimed at uncovering genes contributing to nicotine use and addiction.
Hum Mol Genet 2008 Mar 01
PMID:The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco. 1805 61

Abuse of psychostimulants such as cocaine and amphetamines has a tremendous social and economic impact. Although replacement therapies are offered for addiction to opioids, nicotine, and alcohol, there is no approved replacement treatment for psychostimulant addiction. Recent studies on an emerging group of benztropine- and rimcazole-based compounds provide hope that replacement therapies for cocaine and amphetamine addiction may come in the near future. A new study (p. 813) now investigates the molecular interaction of the benztropine and rimcazole compounds with their target, the dopamine transporter, and provides an intriguing explanation as to why use of these compounds, unlike cocaine, do not lead to locomotor stimulation and drug discrimination behaviors in animal models.
Mol Pharmacol 2008 Mar
PMID:Distinctions between dopamine transporter antagonists could be just around the bend. 1797 68

DNA microarray studies offer a robust method for nonbiased analysis of whole genome messenger ribonucleic acid expression patterns. A growing number of studies have applied this experimental approach to studies on ethanol either in cell culture of animal models of ethanol exposure or self-administration. Expression profiling has identified novel gene networks responding to ethanol or differing across animal strains with differing responses to ethanol. Recent studies have shown benefit for meta-analysis of microarray data across different laboratories. Gene network analysis offers unique opportunities for understanding the molecular mechanisms of ethanol responses, toxicity and addiction. Eventually, such work may generate novel targets for future pharmacotherapy. To fully capitalize on the prom ise alluded to above, particularly in regard to meta-analysis of microarray data, it is critical that high quality standards are followed in the generation and analysis of microarray studies. This chapter will discuss experience of our laboratory in performing and analyzing microarray studies on ethanol, focusing discussion mainly on short oligonucleotide microarrays (Affymetrix). However, the general principals of technique and analysis that are discussed have broad applicability to other types of microarray platforms and experimental designs.
Methods Mol Biol 2008
PMID:Microarray analysis of ethanol-induced changes in gene expression. 1836 32

The endocannabinoid system is implicated in the regulation of a variety of physiological processes, among which conditioning, motivation, habit forming, memory, learning, and cognition play pivotal roles in drug reinforcement and reward. In this article we will give a synopsis of last developments in research on cannabinoid actions on brain reward circuits coming from behavioral, neurochemical and electrophysiological studies. Central cannabinoid-induced effects as measured by animal models of addiction, in vivo cerebral microdialysis, in vitro and in vivo electrophysiological recording techniques, will be reviewed. Brain sites that have been implicated in the mediation of addictive cannabinoid properties include primarily the ventral tegmental area, the nucleus accumbens, and the medial prefrontal cortex, although the amygdala, the substantia nigra, the globus pallidus, and the hippocampus have also been shown to be critical structures mediating motivational and reinforcing effects of cannabinoids. Putative neurobiological mechanisms underlying these effects will be delineated.
Mol Cell Endocrinol 2008 Apr 16
PMID:Neurobiological mechanisms of cannabinoid addiction. 1837 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>