Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.
Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.
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DOI：
10.1007/s00213-010-2119-x
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发表时间：
2011-05
影响因子：
3.4
通讯作者：
Markou, Athina
中科院分区：
文献类型：
--
作者：
Vlachou, Styliani;Guery, Sebastien;Froestl, Wolfgang;Banerjee, Deboshri;Benedict, Jessica;Finn, M. G.;Markou, Athina
γ-氨基丁酸（GABA）是脑内主要的抑制性神经递质，参与中枢奖赏过程的调节。GABAB受体激动剂或阳性调节剂的急性或慢性给药减少了各种滥用药物的自我给药。此外，GABAB受体激动剂抑制线索诱导的尼古丁和可卡因寻求行为的恢复。由于与GABAB受体激动剂相比其不良副作用较少，因此与激动剂相比，GABAB受体阳性调节剂是用于治疗药物依赖性的潜在改进的治疗化合物。我们检查了GABAB受体阳性调节剂N-[（1 R，2 R，4S）-双环[2.2.1]庚-2-基]-2-甲基-5-[4-（三氟甲基）苯基]-4-嘧啶胺（BHF 177）对尼古丁自我给药和固定比例5强化方案下食物维持反应的急性作用是否在重复给药后得以维持。还检查了急性BHF 177给药对线索诱导的尼古丁和食物寻找行为（一种假定的复发动物模型）的影响。BHF 177重复给药14天可减少尼古丁自我给药，在治疗的最后7天观察到较小的耐受性，而BHF 177对食物维持反应的影响最小。急性BHF 177给药剂量依赖性地阻断了10天消退期后线索诱导的尼古丁（而非食物）寻求行为的恢复。这些结果表明，BHF 177选择性地阻断尼古丁自我给药，并防止线索诱导的尼古丁寻求恢复，对食物反应的影响最小，对线索诱导的食物寻求恢复没有影响。因此，GABAB受体阳性调节剂可以是用于治疗尼古丁依赖的不同方面的有用的治疗剂，其通过减少尼古丁摄入促进戒烟并预防人类吸烟复发。
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABAB receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABAB receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABAB receptor agonists, GABAB receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. We examined whether the acute effects of the GABAB receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self-administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. These results showed that BHF177 selectively blocked nicotine self-administration and prevented cue-induced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABAB receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans.
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影响因子：
2.5
作者：
Le Foll B;Wertheim CE;Goldberg SR
通讯作者：
Goldberg SR
影响因子：
2.8
作者：
Brebner, K;Childress, AR;Roberts, DCS
通讯作者：
Roberts, DCS
DOI：
10.1111/j.1530-0277.2008.00792.x
发表时间：
2008-12-01
影响因子：
3.2
作者：
Leggio, Lorenzo;Ferrulli, Anna;Addolorato, Giovanni
通讯作者：
Addolorato, Giovanni
影响因子：
2.3
作者：
Fadda, P;Scherma, M;Fratta, W
通讯作者：
Fratta, W
影响因子：
2.3
作者：
ENGBERG, G;KLINGPETERSEN, T;NISSBRANDT, H
通讯作者：
NISSBRANDT, H