Perseverative behavior in rats with methamphetamine-induced neurotoxicity.
Perseverative behavior in rats with methamphetamine-induced neurotoxicity.
复制标题
甲基苯丙胺诱导的神经毒性大鼠的持续行为。
DOI：
10.1016/j.neuropharm.2012.09.021
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发表时间：
2013
影响因子：
4.7
通讯作者：
Keefe,KristenA
中科院分区：
文献类型：
--
作者：
Son,Jong-Hyun;Kuhn,James;Keefe,KristenA
甲基苯丙胺导致单胺耗竭，被认为有助于认知和行为功能障碍。以前，我们报道，甲基苯丙胺诱导的神经毒性与受损的刺激反应协会的形成。此外，主观观察表明，行为灵活性可能会受到影响。因此，本研究探讨是否甲基苯丙胺神经毒性诱导持续行为。用（±）-甲基苯丙胺（4 × 10 mg/kg，2小时间隔）或生理盐水预处理大鼠。三周后，训练大鼠按下操作室一侧的杠杆，然后从另一侧的杂志中取出注射器，直到它们达到标准（> 50次注射/30分钟）。在连续四次按标准执行任务后，处死大鼠并取出大脑用于单胺测定。甲基苯丙胺预处理的大鼠纹状体多巴胺和前额叶5-羟色胺损失超过50%。甲基苯丙胺和生理盐水预处理的大鼠在达到标准所需的会议次数或在标准水平表现的连续四次会议中的杠杆按压和/或头部进入的总数方面没有差异。然而，甲基苯丙胺预处理的大鼠获得的运动员较少，因为它们在本应取回运动员或返回杠杆时进行了额外的按压和头部进入。甲基苯丙胺预处理的大鼠在两种行为之间切换的速度也明显慢于对照组。有趣的是，即使在盐水预处理的对照组中，额外的压力与前额皮质中的降钙素转运蛋白结合呈负相关。这些数据表明，甲基苯丙胺诱导的部分单胺毒性与持续性行为有关，持续性行为的程度可能取决于额叶皮质的5-羟色胺神经支配。
Methamphetamine induces monoamine depletions thought to contribute to cognitive and behavioral dysfunctions. Previously, we reported that methamphetamine-induced neurotoxicity is associated with impaired formation of stimulus–response associations. Additionally, subjective observations suggested that behavioral flexibility might be affected. Thus, the present study examined whether methamphetamine neurotoxicity induces perseverative behavior. Rats were pretreated with (±)-methamphetamine (4 × 10 mg/kg, 2-hr intervals) or saline. Three weeks later, rats were trained to press a lever on one side of an operant chamber and then retrieve the reinforcer from a magazine on the opposite side until they reached criterion (>50 reinforcers/30-min). After four consecutive sessions performing the task at criterion, rats were sacrificed and brains removed for monoamine determinations. Methamphetamine-pretreated rats had ∼50% loss of striatal dopamine and prefrontal serotonin. Methamphetamine- and saline-pretreated rats were not different in the number of sessions required to reach criterion or in the total numbers of lever presses and/or head entries made across the four consecutive sessions at criterion-level performance. However, methamphetamine-pretreated rats earned fewer reinforcers, because they made extra lever-presses and head entries when they should have been retrieving the reinforcer or returning to the lever. Latencies for methamphetamine-pretreated rats to switch between the two behaviors also were significantly slower than latencies for controls. Interestingly, the degree of additional lever-presses negatively correlated with serotonin-transporter binding in the prefrontal cortex, even in saline-pretreated controls. These data suggest that methamphetamine-induced partial monoamine toxicity is associated with perseveration and that the degree of perseveration may depend on serotonin innervation of the frontal cortex.