Department of Pharmacology and Toxicology University of Utah, Salt Lake City, UT 84112, USA.
Drug Alcohol Depend. 2012 Nov 1;126(1-2):87-94. doi: 10.1016/j.drugalcdep.2012.04.020. Epub 2012 May 28.
Pre-clinical studies indicate that high-dose, non-contingent methamphetamine (METH) administration both rapidly and persistently decreases serotonergic neuronal function. Despite research indicating the hippocampus plays an important role in METH abuse and is affected by METH use, effects of METH self-administration on hippocampal serotonergic neurons are not well understood, and were thus an important focus of the current study. Because humans often administer METH in a binge-like pattern, effects of prior METH self-administration on a subsequent "binge-like" METH treatment were also examined.
Rats were treated as described above, and sacrificed 1 or 8d after self-administration or 1h or 7d after the final binge METH or saline exposure. Hippocampal serotonin (5-hydroxytryptamine; 5HT) content and transporter (SERT) function were assessed.
METH self-administration per se had no persistent effect on hippocampal 5HT content or SERT function. However, this treatment attenuated the persistent, but not acute, hippocampal serotonergic deficits caused by a subsequent repeated, high-dose, non-continent METH treatment administered 1 d the last self-administration session. No attenuation in persistent deficits were seen when the high-dose administration of METH occurred 15d after the last self-administration session.
The present findings demonstrate that METH self-administration alters serotonergic neurons so as to engender "tolerance" to the persistent serotonergic deficits caused by a subsequent METH exposure. However, this "tolerance" does not persist. These data provide a foundation to investigate complex questions including how the response of serotonergic neurons to METH may contribute to contingent-related disorders such as dependence and relapse.
临床前研究表明，大剂量、非条件性的甲基苯丙胺（METH）给药会迅速且持续地降低 5-羟色胺能神经元的功能。尽管有研究表明海马在 METH 滥用中起着重要作用，并且受到 METH 使用的影响，但 METH 自我给药对海马 5-羟色胺能神经元的影响还不太清楚，因此是当前研究的一个重要焦点。由于人类经常以狂欢样的方式给予 METH，因此还研究了先前的 METH 自我给药对随后的“狂欢样”METH 治疗的影响。
如上所述对大鼠进行处理，并在自我给药后 1 或 8 天或最后一次狂欢样 METH 或生理盐水暴露后 1 或 7 天处死。评估海马 5-羟色胺（5-羟色胺；5HT）含量和转运体（SERT）功能。
METH 自我给药本身对海马 5HT 含量或 SERT 功能没有持久影响。然而，这种治疗减轻了随后重复、大剂量、非连续 METH 治疗 1 天后持续但非急性的海马 5-羟色胺能缺陷，最后一次自我给药后。当 METH 的高剂量给药发生在最后一次自我给药后 15 天时，没有观察到持续性缺陷的衰减。
本研究结果表明，METH 自我给药改变了 5-羟色胺能神经元，从而对随后的 METH 暴露引起的持续性 5-羟色胺能缺陷产生“耐受性”。然而，这种“耐受性”不会持续存在。这些数据为研究复杂问题提供了基础，包括 5-羟色胺能神经元对 METH 的反应如何有助于依赖和复发等与条件相关的疾病。
