Repeated maternal separation: differences in cocaine-induced behavioral sensitization in adult male and female mice
Repeated maternal separation: differences in cocaine-induced behavioral sensitization in adult male and female mice
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DOI：
10.1007/s00213-004-1989-1
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发表时间：
2005-03-01
影响因子：
3.4
通讯作者：
Miczek, K
中科院分区：
文献类型：
--
作者：
Kikusui, T;Faccidomo, S;Miczek, K
理论基础：反复的母体分离深刻地改变了成人的应激反应，下丘脑-垂体-肾上腺轴的发育，尤其是GABA能和单胺能系统。目的：探讨反复短暂的母体分离应激是否增加了成年雄性和雌性小鼠对可卡因的行为敏感度，以及海马糖皮质激素受体和伏隔多巴胺转运体是否同时发生变化。方法：从出生后第1~13天，每天将一半的小鼠从巢中分离1h。从出生后第50天开始，所有小鼠都注射可卡因(10.0 mg/kg)或生理盐水，连续10d。在第50、54和59天，通过跟踪系统在开阔的场地上评估运动能力。大约10天和40天后，所有的小鼠都被给予7.5 mg/kg的可卡因。结果：反复的母体分离使大鼠的多动反应增加到10.0 mg/kg可卡因，无论性别。在表情测试中(第69/71天，99天)，雄性，但不是雌性，有母体分离史的小鼠对可卡因表现出显著的敏感性多动反应。母系分离且无可卡因敏化史的雄性小鼠对7.5 mg/kg可卡因表现出交叉敏化。免疫组织化学分析显示，无论母体分离经历如何，女性海马CA1区糖皮质激素受体和伏隔核多巴胺转运体蛋白的表达均高于男性。结论：反复母体分离是一种应激源，可导致大鼠对低剂量可卡因的敏感性升高，表现为多动。此外，糖皮质激素受体和多巴胺转运体表达的性别差异可能是可卡因行为敏化的性别差异的原因。
Rationale: Repeated maternal separations profoundly alter the adult stress response, the development of the hypothalamic-pituitary-adrenal axis, and prominently, the GABAergic and monoaminergic systems. These neural changes are postulated to influence the vulnerability to drugs of abuse implicating glucocortocoids in the behavioral responses to psychomotor stimulants.Objective: To investigate whether repeated brief maternal separation stress increases behavioral sensitization to cocaine in adult male and female mice, and to assess any concurrent changes in hippocampal glucocorticoid receptors and accumbal dopamine transporters.Methods: Half of the litters were separated from the nest for 1 h/day from post-natal days 1 to 13. Starting on post-natal day 50, all mice were injected with either cocaine (10.0 mg/kg) or saline for 10 consecutive days. Locomotor activity was assessed in an open field on days 50, 54 and 59 via a tracking system. Approximately 10 and 40 days later, all mice were challenged with 7.5 mg/kg cocaine.Results: Repeated maternal separation increased the hyperlocomotor response to 10.0 mg/kg cocaine regardless of gender. During expression tests (days 69/71, 99), male, but not female, mice with a history of maternal separation exhibited significant sensitized hyperactivity in response to cocaine. Male mice that were maternally separated and had no history of cocaine sensitization, demonstrated cross-sensitization to 7.5 mg/kg cocaine. Immunohistochemical analysis revealed that the hippocampal CA1 glucocorticoid receptor and nucleus accumbens dopamine transporter proteins were expressed more in females than in males, regardless of maternal separation experience.Conclusions: Repeated maternal separation is a stressor that can induce heightened sensitivity to low doses of cocaine, as expressed by hyperactivity. Furthermore, sex differences in glucocorticoid receptor and dopamine transporter expression may be responsible for the sexual dimorphic expression of behavioral sensitization to cocaine.