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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EDeveloping new therapies for drug addiction depends on understanding the underlying mechanisms for the process of addiction. Changes in dopamine receptors and brain function are critical in addiction. This article discusses the latest advances in addiction research.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ESubstance-Related Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPsychiatry\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ESubstance-Related Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPsychiatry\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EDeveloping new therapies for drug addiction depends on understanding the underlying mechanisms for the process of addiction. Changes in dopamine receptors and brain function are critical in addiction. Nora D. Volkow, MD, National Institute on Drug Abuse, Bethesda, Maryland, USA, discussed the latest advances in addiction research.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EAll drugs that are abused, including nicotine and alcohol, cause an increase in dopamine levels in the nucleus accumbens, albeit by differing mechanisms (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Nestler EJ. \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2005]. For example, within 1 hour after nicotine intake, a substantial increase in the percentage of basal dopamine occurs, which gradually decreases over several hours [Di Chiara G et al. \u003Cem\u003ENeuropharmacology\u003C\/em\u003E 2004]. A similar trend is seen after methamphetamine intake. In addition, drugs activate the glutamate receptors more potently, with longer-lasting effects, than do normal stimulants, such as food and social interactions. This is termed \u003Cem\u003Esupraphysiological stimulation\u003C\/em\u003E of the receptors and results in downstream neuronal adaptations, such as dopaminergic transmission and enhancement of AMP and N-methyl-D-aspartate.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Dopamine Modulation by Abused Drugs\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1626259989\u0022 data-figure-caption=\u0022Dopamine Modulation by Abused Drugs\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15873\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-4\u0022 class=\u0022first-child\u0022\u003EDopamine Modulation by Abused Drugs\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EDA=dopamine; GABA=gamma-aminobutyric acid; LDT=lateral dorsal tegmentum; NAc=nucleus accumbens; PCP=phencyclidine; PPT=peduncular pontine tegmentum; VTA=ventral tegmental area of Tsai.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Nester El. Is there a common molecular pathway for addiction? \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2005;8(11):1445\u20131449. With permission from the Nature Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-5\u0022\u003EA study of how dopamine levels increase by intravenous methylphenidate (MPH) in humans showed that MPH binds to the dopamine transporter, inhibiting its activity, which allows dopamine to build up within the synaptic cleft, thereby creating an amplification effect of the original stimulator [Volkow ND et al. \u003Cem\u003EJ Pharmacol Exp Ther\u003C\/em\u003E 1999]. In addition, the perception of feeling a high was associated with higher levels of dopamine. However, this increase in dopamine is not observed with oral MPH, which is likely a result of the rate of the dopamine increase. Intravenous MPH causes a rapid rise in dopamine levels, which mimics dopamine cell signaling, whereas oral MPH causes a slower rise in dopamine [Volkow ND et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2011]. A slow rise in dopamine mimics a chronic dopamine signaling effect, which plays a role in cognitive, motivational, and motoric systems and does not produce a high feeling. Interestingly, phasic dopamine primarily stimulates dopamine 1 receptors (D1Rs), whereas tonic dopamine stimulates dopamine 2 receptors (D2Rs). Therefore, the process of drug reward requires that D1Rs are stimulated, and it is optimal if both D1Rs and D2Rs are stimulated. Dr. Volkow suggested that this is why intravenous and inhalation modes of drug administration are more addictive\u2014they cause a rapid rise in dopamine, which mimics the endogenous process of reward.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EIn cocaine abusers, intravenous administration of MPH does not cause an increase in dopamine to the same extent that it does in normal controls (p\u0026lt;0.001) [Volkow ND et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2011]. Even when cocaine abusers are provided with cocaine using-associated cues, the effect of an MPH injection on dopamine is minimal compared with that of normal controls (p\u0026lt;0.001) [Volkow ND et al. \u003Cem\u003EMol Psychiatry.\u003C\/em\u003E In press]. Interestingly, in rats that receive chronic treatment with cocaine, there is substantial attenuation of dopamine signaling through D2Rs, thereby showing a conditioned response [Volkow ND et al. \u003Cem\u003ENeurobiol Learn Mem\u003C\/em\u003E 2002].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe D1Rs and D2Rs are downregulated in the presence of excess dopamine and upregulated in the presence of inadequate dopamine. In one study, mice that received adenovirus carrying the D2Rs had an increase in D2Rs levels that corresponded with a decrease in self-administered alcohol intake [Thanos PK et al. \u003Cem\u003EJ Neurochem\u003C\/em\u003E 2001]. A similar effect is observed in rats, where upregulation of D2Rs corresponds with a decrease in cocaine self-administration.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EDrug addiction also appears to affect brain function, as measured by glucose metabolism evaluated by imaging studies. In an imaging study, lower D2R levels were associated with less activity in the prefrontal cortex [Volkow ND et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2011]. Dr. Volkow highlighted that even at baseline, without stimulation with a drug, drug abusers demonstrated decreased activity in the prefrontal cortex. In another study, patients who did not abuse alcohol but had a family history of alcoholism demonstrated greater levels of D2Rs in the prefrontal cortex, which was associated with greater activity as measured by glucose metabolism in that area (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Volkow ND et al. \u003Cem\u003EArch Gen Psychiatry\u003C\/em\u003E 2006]. Dr. Volkow suggested that this may be a mechanism for why some people are vulnerable to addiction, in terms of increased compulsivity and impulsivity.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Family History of Alcoholism Affects Brain Function\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1626259989\u0022 data-figure-caption=\u0022Family History of Alcoholism Affects Brain Function\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/8\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15875\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003EFamily History of Alcoholism Affects Brain Function\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003ECG=anterior cingulate gyrus; D2R=dopamine 2 receptor; OFC=orbitofrontal cortex.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced from Volkow ND et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. \u003Cem\u003EArch Gen Psychiatry\u003C\/em\u003E 2006;63(9):999\u20131008. With permission from the American Medical Association.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-10\u0022\u003EIt has been observed that rats that are chronically exposed to alcohol, cocaine, or opiates are hypersensitive to other stressors, which in turn lead them to further compensate for that stress with the drug. In addition, several genomewide association studies found that nicotine receptors a4, \u03b13, and b4 were associated with nicotine dependence [Berrettini W et al. \u003Cem\u003EMol Psychiatry\u003C\/em\u003E 2008; Schlaepfer IR et al. \u003Cem\u003EBiol Psychiatry\u003C\/em\u003E 2008; Bierut LJ et al. \u003Cem\u003EHuman Mol Genet\u003C\/em\u003E 2007]. These subunits of the nicotine receptor are expressed in the medial habenula. Interestingly, a study in monkeys found that the habenula is involved in a negative reward process, in which increased activity in the habenula results in no reward by inhibiting dopamine neurons [Kimura M et al. \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2007]. Dr. Volkow noted that these data suggest that smokers may be ingesting nicotine to inhibit the activity of the habenula, thereby preventing the habenula from affecting dopamine activity.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EDr. Volkow pointed out that drug addiction is a dynamic disease that occurs in cycles. Exposure to the drug in combination with stressors results in the anticipation and craving for the drug [Koob GF, Volkow ND. \u003Cem\u003ENeuropsychopharmacology\u003C\/em\u003E 2010]. The craving leads to the binge or intoxication phase. Therefore, there are periods of abstinence, craving, and intoxication. The abstinence or negative affect stage, before craving, is the point at which patients can be engaged. In one study, cocaine users were told that they would be receiving the drug but that they should refuse it [Volkow ND et al. \u003Cem\u003EAnnu Rev Pharmacol Toxicol\u003C\/em\u003E 2012]. They were able to not only inhibit the nucleus accumbens but also activate the right inferior prefrontal cortex, which Dr. Volkow called the \u201cbrake system\u201d of the brain. However, Dr. Volkow pointed out that this cannot be done when patients are in a state of intoxication. Therefore, patients have to be taught to predict when exposure will occur so that they can prevent further use of the drug.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EAnother approach to treat addicts is the use of a medication, such as MPH, to improve the function of the prefrontal cortex to allow them to better follow an intervention. In a study of cocaine abusers, administration of MPH resulted in increased activity in the prefrontal cortex, which was associated with improvement in Stroop test scores [Goldstein RZ, Volkow ND. \u003Cem\u003ENeuropsychopharmacology\u003C\/em\u003E 2011]. Other potential treatments for addiction include repetitive transcranial magnetic stimulation or direct current stimulation for tobacco addiction [Wing VC et al. \u003Cem\u003EBrain Stimulation\u003C\/em\u003E 2013] and a vaccine against cocaine and nicotine addiction [Shen XY et al. \u003Cem\u003EClin Pharmacol Ther\u003C\/em\u003E 2012]. A mechanism behind addiction vaccines is that vaccine-stimulated antibodies could delay the absorption of the drug across the blood-brain barrier. A Phase 3 trial of a vaccine against nicotine addiction was performed. Dr. Volkow commented that results of the trial were disappointing but likely because only a small number of patients were able to achieve an effective titer. Therefore, the challenge of developing an effective vaccine is ensuring that patients are antigenic.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EA major challenge for the National Institute of Drug Addiction is the changing perception of marijuana as a nonharmful drug. For the last 3 years, more children in Grade 12 use marijuana than smoke cigarettes [Johnston LD et al. \u003Cem\u003EMonitoring the Future National Results on Drug Use: 1975\u20132013: Overview, Key Findings on Adolescent Drug Use.\u003C\/em\u003E Ann Arbor: Institute for Social Research, The University of Michigan. 2014]. This is important because persistent cannabis use is associated with mental illness and lower IQ. Discontinuation of cannabis use did not resolve the loss in IQ. Indeed, chronic use of cannabis is associated with neuropsychological decline, beginning in childhood and continuing to midlife [Meier MH et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2012]. In another study, frequent use of cannabis in adolescence was associated with loss of axonal fiber connectivity by up to \u223c90%, particularly in the hippocampus, hippocampal commissure, and splenium [Zalesky A et al. \u003Cem\u003EBrain\u003C\/em\u003E 2012]. Dr. Volkow pointed out that the hippocampus is involved in intelligence, so this finding may explain why a decrease in IQ is associated with cannabis use.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EAdvances in addiction research help uncover the underlying mechanisms related to addictive behaviors and the process of addiction as a result of drug use. New strategies for the treatment of addiction are on the horizon but require further study.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/8\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp7se\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp7se\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}