Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk
Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk
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DOI：
10.1038/npp.2014.161
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发表时间：
2014-12-01
影响因子：
7.6
通讯作者：
Zucker, Robert A.
中科院分区：
文献类型：
--
作者：
Heitzeg, Mary M.;Villafuerte, Sandra;Zucker, Robert A.
有人提出，激励动机系统的反应性增强是青少年典型的危险行为（包括酗酒问题）的基础。然而，即使在青少年时期，这些行为也存在相当大的个体差异，这可能有遗传基础，并与日后酒精使用障碍（AUD）的风险差异有关。GABRA2的变体与成人酒精依赖以及表型前体（包括冲动和外化行为）有关。我们研究了GABRA2对从童年到青年期预期金钱奖励过程中伏隔核（NAcc）激活的发展轨迹的影响。对175名参与者进行了金钱激励延迟任务期间的功能性磁共振成像，其中大多数（n = 151）每隔1 - 2年进行重复扫描。一组在8 - 13岁进入研究（n = 76），另一组在18 - 23岁进入研究（n = 99）。大多数参与者是酗酒者的子女（79%），因此患AUD的风险较高。总共完成了473次扫描，涵盖8 - 27岁。与童年和青年期相比，伏隔核在青少年时期的激活增强。GABRA2基因型（单核苷酸多态性rs279858）与伏隔核激活的个体差异有关，特别是在青少年时期，次要等位基因（G）与更强的激活相关。此外，伏隔核激活介导了基因型对酒精问题的影响（n = 104）。这项工作证明了GABRA2基因型对青少年激励动机神经回路的影响，对酗酒易感性有启示作用。这些发现是理解成瘾风险在发育过程中如何呈现个体差异的遗传和神经基础的重要一步。
Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and extemalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n = 151) undergoing repeated scanning at 1 - to 2-year intervals. One group entered the study at age 8-13 years (n = 76) and another entered at age 18-23 years (n = 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.