Enhancing the salience of dullness: behavioral and pharmacological strategies to facilitate extinction of drug-cue associations in adolescent rats.
Enhancing the salience of dullness: behavioral and pharmacological strategies to facilitate extinction of drug-cue associations in adolescent rats.
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DOI：
10.1016/j.neuroscience.2010.05.063
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发表时间：
2010-08-25
期刊：
影响因子：
3.3
通讯作者：
Andersen, S. L.
中科院分区：
文献类型：
--
作者：
Brenhouse, H. C.;Dumais, K.;Andersen, S. L.
戒毒是成瘾治疗的一个组成部分，可以深刻扭转或减轻吸毒的有害后果。这些后果在青春期可能是最有害的。这里提出的研究基于最近的证据，即青春期老鼠比成年人更能抵抗灭绝训练，因此可能需要独特的治疗策略。我们对雄性大鼠进行了无偏向的位置条件作用，结果表明，相对于 80 天大的成年人，被动的、不明确的消退配对会导致 40 天大的青少年的消退延迟。然而，将先前与可卡因相关的环境与缺乏药物的明确配对在青少年中产生的灭绝速度与成人一样快。这些数据表明，更强的新（消退）记忆的获得可能有助于青少年成功消退药物配对关联。药物配对关联很大程度上由前边缘前额叶皮层 (plPFC) 及其对伏隔核的影响控制。该通路通过 D1 多巴胺受体介导传入刺激的动机显着性。 plPFC 上伏隔核输出的 D1 受体在青春期短暂过量产生。由于 D1 受体选择性地响应强效刺激，我们假设青少年 plPFC 阻碍强效药物配对关联与灭绝所需的更微妙、无药物信息之间的竞争。为了利用青少年 plPFC 的这种独特特征，我们旨在通过在消退训练期间激活 plPFC D1 受体来增加无奖励消退记忆的显着性。在第二项研究中，在使用阿托西汀进行消除训练期间，通过提高前额皮质中的多巴胺和去甲肾上腺素，促进了青少年药物提示关联的消除。在第三项研究中，直接显微注射 D1 受体激动剂 SKF38393 模仿了这种效应，也促进了青少年受试者的灭绝。此外，药物干预减弱了随后药物引发的可卡因条件偏好的恢复。我们为治疗这一弱势群体的独特策略制定了潜在的方向。
Extinction of drug-seeking is an integral part of addiction treatment, and can profoundly reverse or ameliorate the harmful consequences of drug use. These consequences may be the most deleterious during adolescence. The studies presented here build from recent evidence that adolescent rats are more resistant to extinction training than adults, and therefore may require unique treatment strategies. We used unbiased place-conditioning in male rats to show that passive, un-explicit extinction pairings resulted in delayed extinction in 40-day-old adolescents relative to 80-day-old adults. However, explicit-pairing of a previously cocaine-associated context with the absence of drug produces extinction in adolescents as rapidly as in adults. These data suggest that successful extinction of drug-paired associations in adolescents may be facilitated by stronger acquisition of a new (extinction) memory. Drug-paired associations are largely controlled by the prelimbic prefrontal cortex (plPFC) and its influence on the nucleus accumbens. This pathway mediates the motivational salience attributed to incoming stimuli through the D1 dopamine receptor. D1 receptors on plPFC outputs to the accumbens are transiently overproduced during adolescence. Since D1 receptors are selectively responsive to potent stimuli, we hypothesized that the adolescent plPFC hinders competition between potent drug-paired associations and the subtler, drug-free information necessary for extinction. To harness this unique profile of the adolescent plPFC, we aimed to increase the salience of unrewarded extinction memories by activating plPFC D1 receptors during extinction training. In a second study, extinction of drug-cue associations was facilitated in adolescents by elevating dopamine and norepinephrine in the PFC during extinction training with atomoxetine. In a third study, direct microinjection of the D1 receptor agonist SKF38393 mimicked this effect, also facilitating extinction in adolescent subjects. Furthermore, pharmacological intervention attenuated subsequent drug-primed reinstatement of cocaine-conditioned preferences. We establish a potential direction for distinct strategies to treat this vulnerable population.
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影响因子：
5.3
作者：
Kreibich, AS;Blendy, JA
通讯作者：
Blendy, JA
影响因子：
2.9
作者：
Font, Laura;Miquel, Marta;Aragon, Carlos M. G.
通讯作者：
Aragon, Carlos M. G.
影响因子：
2.5
作者：
KALSBEEK, A;VOORN, P;UYLINGS, HBM
通讯作者：
UYLINGS, HBM
DOI：
10.1196/annals.1390.000
发表时间：
2007-01-01
期刊：
REWARD AND DECISION MAKING IN CORTICOBASAL GANGLIA NETWORKS
影响因子：
--
作者：
Haddon, Josephine E.;Killcross, Simon
通讯作者：
Killcross, Simon
影响因子：
3.8
作者：
Lin, Shi-Kwang;Pan, Wynn H. T.;Yeh, Pen-Ho
通讯作者：
Yeh, Pen-Ho