Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents

TY - JOUR

T1 - Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents

AU - Nees, F

AU - Witt, S H

AU - Lourdusamy, A

AU - Vollstädt-Klein, S

AU - Steiner, S

AU - Poustka, L

AU - Banaschewski, T

AU - Barker, G J

AU - Büchel, C

AU - Conrod, P J

AU - Frank, J

AU - Gallinat, Jürgen

AU - Garavan, H

AU - Heinz, A

AU - Ittermann, B

AU - Loth, E

AU - Mann, K

AU - Artiges, E

AU - Paus, T

AU - Pausova, Z

AU - Smolka, M N

AU - Struve, M

AU - Schumann, G

AU - Rietschel, M

AU - Flor, H

AU - IMAGEN Consortium

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.

AB - Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.

KW - Adolescent

KW - Adolescent Behavior

KW - Corpus Striatum

KW - European Continental Ancestry Group

KW - Female

KW - Frontal Lobe

KW - Functional Neuroimaging

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Gyrus Cinguli

KW - Health

KW - Humans

KW - Male

KW - Multigene Family

KW - Nerve Tissue Proteins

KW - Personality

KW - Polymorphism, Single Nucleotide

KW - Receptors, Nicotinic

KW - Reward

KW - Risk Factors

KW - Tobacco Use Disorder

U2 - 10.1038/npp.2013.131

DO - 10.1038/npp.2013.131

M3 - SCORING: Journal article

C2 - 23689675

VL - 38

SP - 2081

EP - 2089

JO - NEUROPSYCHOPHARMACOL

JF - NEUROPSYCHOPHARMACOL

SN - 0893-133X

IS - 11

ER -