There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching several interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes;2)Ascertainment of the consequences of over- or under-expressing candidate genes identified in human studies;3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation;4) Studying influences of interactions between variants at different genomic loci;5)Elucidating haplotype-specific levels of expression differences in vivo, and 6) allowing us to monitor synaptic connectivities and their modulation by drug administration and alterations in haplotypes in cell adhesion and other impoprtant brain molecules. Interest mechanisms of reward, reinforcement and learning have led to continuing focus on these systems during this year, as we have established much of the groundwork for identification of wiring differences in brain slices. In continuing studies of knockouts of candidate genes that are interesting because they encode drug targets and/or are expressed in circuits of interest, we have reported novel data concerning the differential influences of these knockouts on a) adaptive responses to cocaine (neurotensin KOs) b) stress engendered by social defect (mu/OPRM1 knockouts)c) antidepressants and analgesics (OPRM1 knockouots) d) substance-induced dopamine release (mu/OPRM1 knockouts) e) brain circuitry (DAT/SLC6A3 knockouts) and f) pain responses (DAT/SLC6A4, SERT/SLC6A4 and mu/OPRM1 knockouts). We have moved forward with studies of the influences of cell adhesion gene alterations by studies of mice with altered expression of the four genes for which our human genome wide association datasests provide the msot consistent replication. We have submitted data that mice with homozygous or heterozygous deletion of the gene for which we have the strongest evidence in humans, CDH13, dramatically reduce preference for cocaine paired environments. These results display specificity, since cocaine retains locomotor stimulation and since these knockout mice can perform at normal (or supranormal) levels in Morris water maze and other comparison behaviors. Initial data supports the possibility that the magnitude of extinction and reinstatement are also reduced in CDH13 knockouts. These animals thus provide one of the best mouse confirmations of a genome wide association result from a complex, polygenic human locus.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$1,022,479
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
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Takamatsu, Y; Hagino, Y; Sato, A et al. (2015) Improvement of learning and increase in dopamine level in the frontal cortex by methylphenidate in mice lacking dopamine transporter. Curr Mol Med 15:245-52
Kasahara, Y; Arime, Y; Hall, F S et al. (2015) Region-specific dendritic spine loss of pyramidal neurons in dopamine transporter knockout mice. Curr Mol Med 15:237-44
Musci, Rashelle J; Masyn, Katherine E; Benke, Kelly et al. (2015) The effects of the interplay of genetics and early environmental risk on the course of internalizing symptoms from late childhood through adolescence. Dev Psychopathol :1-13
Drgonova, Jana; Walther, Donna; Singhal, Sulabh et al. (2015) Altered CSMD1 Expression Alters Cocaine-Conditioned Place Preference: Mutual Support for a Complex Locus from Human and Mouse Models. PLoS One 10:e0120908
Zhong, Xiaoming; Drgonova, Jana; Li, Chuan-Yun et al. (2015) Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction-associated genes. Ann N Y Acad Sci 1349:83-95
Drgonova, Jana; Walther, Donna; Wang, Katherine J et al. (2015) Mouse model for PTPRD associations with WED/RLS and addiction: reduced expression alters locomotion, sleep behaviors and cocaine-conditioned place preference. Mol Med :
Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott et al. (2015) Memory impairment and reduced exploratory behavior in mice after administration of systemic morphine. J Exp Neurosci 9:27-35
Musci, Rashelle J; Uhl, George; Maher, Brion et al. (2015) Testing gene × environment moderation of tobacco and marijuana use trajectories in adolescence and young adulthood. J Consult Clin Psychol 83:866-74
Hall, F S; Itokawa, K; Schmitt, A et al. (2014) Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems. Neuropharmacology 76 Pt A:146-55
Kitanaka, Nobue; Kitanaka, Junichi; Hall, F Scott et al. (2014) Agmatine attenuates methamphetamine-induced hyperlocomotion and stereotyped behavior in mice. Behav Pharmacol 25:158-65

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