Brain science of onset of dependence
Mechanisms of addictive behavior onset: from animal model analyses to human behavior investigations

○Naoyuki Hironaka1,2
三菱化学メディエンス株式会社薬理研究所1, 科学技術振興機構CREST2
Pharmacology Research Dept., Mitsubishi Chemical Medience Corp.1, Japan Science and Technology Agency CREST, Atsugi, Japan2

One of the key factors inducing drug addiction (dependence) lies in the intrinsic activity of drugs. Animal behavioral experiments of drug dependence developed so far have been aimed at detecting such drug effects. Three representative animal experiments, drug self-administration, drug discrimination, and conditioned place preference, are available to examine reinforcing effect, subjective effect, and rewarding effect associated with drug experience, respectively. The mesolimbic dopaminergic neural system, which originates from the ventral tegmentum area and projects to the nucleus accumbens, is primarily responsible for these drug effects. Moreover, other brain areas such as the prefrontal cortex, the hippocampus, and the amygdala are also implicated in drug dependence. For example, we have found that the synchronized oscillated EEG in the hippocampus is important in the formation of conditioned place preference of cocaine in rats and the drug-associated memory is related to de novo synthesis of dopamine D1 receptor in the hippocampus (Takano et al, Brain Res., 2010; Tanaka et al, Neuropharmacol., 2011). However, in recent years, it is beginning to be recognized that simply searching for the neural substrates of drug effects is not sufficient for understanding addiction. New animal models to investigate the vulnerability to addictive behaviors are required. So-called non-chemical addiction such as gambling and Internet browsing spurs on this trend. The development of the animal behavior models of behavioral characteristics such as impulsiveness, response to stressful events, and decision making is in progress, but no single animal model is sufficient to investigate the neural substrates of vulnerability to addictive behaviors at the moment. Close collaboration of human behavioral studies and animal neuroscientific studies are necessary for the better understanding and treatment for addictive behaviors.
Brain imaging analyses of reward system

○Tetsuya Suhara1
放射線医学総合研究所 分子イメージング研究センター 分子神経イメージングプロジェクト1
Molecularneuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences1

The molecular imaging using positron emission tomography enables to visualize various brain molecules with radio labeled ligand. The release of endogenous dopamine can be measured by indirect method with [11C]raclopride PET. Since synaptic dopamine competes with [11C]raclopride for D2 receptor binding, dopamine release is thought to decrease [11C]raclopride binding potential (BP). We used nicotine gum aiming to administer nicotine in nonsmokers as in smokers. Smokers showed significant decreases in [11C]raclopride BP in the ventral caudate and ventral putamen in response to nicotine, but nonsmokers did not. Reduction of BP in the ventral striatum was correlated with the degree of nicotine dependence. Decrease in [11C]raclopride BP is thought to reflect dopamine release following nicotine administration in smokers. Enhanced dopamine release in smokers may underlie reinforced rewarding effect of nicotine in dependence after repeated exposure. On the other hand, post synaptic dopamine receptor is also involved in the reward system, reduced D1 receptor binding was observed in ventral striatum of smokers. Individuals with lower striatal D1 receptor showed more pronounced overestimation of low probabilities and underestimation of high probabilities. The role of D1 receptor seems to be important in the molecular mechanism of risky choice, and impaired decision making observed in drug and gambling addiction.
Genomic mechanisms underlying individual differences in sensitivity to addictive substances

○池田和隆1, 西澤大輔1
○Kazutaka Ikeda1, Daisuke Nishizawa1
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science1

Sensitivity to addictive substances is individually different, which hampers efficient use of addictive substances as medicines and treatment of dependence on the substances. These individual differences are caused by genetic as well as environmental factors. We have found associations of several single-nucleotide polymorphisms (SNPs) with sensitivity to opioids, ethanol, methamphetamine, by investigating genetic and clinical data of patients with postoperative pain or dependence on addictive substances. We found associations between opioid sensitivity and SNPs of mu opioid receptor (Hayashida et al., Pharmacogenomics, 2008; Fukuda et al., Pain, 2009) and G protein activated inwardly rectifying potassium channel (Nishizawa et al., PLoS ONE, 2009) by candidate gene analyses. Furthermore, we conducted a multistage genome-wide association study, and found that SNPs within a 2q33.3-2q34 chromosome region were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery (Nishizawa et al., Mol Psychiatry, 2013). The best candidate SNP, rs2952768, was also associated with analgesic requirements in patients who underwent abdominal surgery, vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders, and "Reward Dependence" score on a personality questionnaire in healthy subjects. Furthermore, this SNP was significantly associated with the expression of a neighboring gene, CREB1. These results demonstrate that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Identification of genetic factors for individual differences in sensitivity to addictive substances provides a better understanding of mechanisms underlying dependence and valuable information for the personalized treatment of drug dependence and pain.
Understanding of mechanisms underlying brain impairment due to alcohol and its clinical approach

○鵜飼渉1, 橋本恵理1, 白坂知彦1, 石井貴男1, 吉永敏弘1, 金田博雄1, 木川昌康1, 館農勝1, 齋藤利和1
○Wataru Ukai1, Eri Hasimoto1, Tomohiro Shirasaka1, Takao Ishii1, Toshihiro Yoshinaga1, Hiroo Kaneta1, Yoshiyasu Kigawa1, Masaru Tateno1, Toshikazu Saito1
Dept Neuropsychiatry, Sapporo Medical Univ1

Prenatal alcohol exposure is invariably detrimental to the developing central nervous system and can cause behavioral/cognitive and mental/social problems, defined as fetal alcohol spectrum disorder (FASD). Abnormalities in cortical and limbic system development have been linked to FASD, but the underlying cellular pathogenesis in the brain remains elusive. A number of studies have found alterations in several presynaptic and postsynaptic components of the GABAergic systems, especially in reduced levels of GAD67 as observed in human and animal samples of schizophrenia and FASD. In, additon, parvalbumin (PV)-positive interneurons, which is being acknowledged as a cellular basis for cognitive and executive brain function were reported severely disrupted.
Stem cell-based regenerative therapy promises great benefits for patients with incurable brain diseases. We studied the involvement of corticolimbic GABAergic interneuron disruption in cognitive and social impairment in FASD and the effect of stem cell treatment. We used an animal model of FASD created in fetal rats by the binge-like administration of ethanol during the peak of GABAergic cell generation of dams (E11-E14). We show that aspects of cognitive and social dysfunction are reversed by intravenous administration of fetal rat brain-derived neural stem cells (NSCs) at 45 days, a time point when neural developments are already completed. We also show that alterations of PV-containing GABAergic interneurons and synaptic density protein levels are essential for the therapeutic efficacy of intravenous NSC treatment in this animal model. Our results establish a new role for PV-containing GABAergic interneurons in the behavioral abnormalities of cognitive and social dysfunction associated with FASD and suggest new therapeutic mechanisms for stem cell treatment.
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