Rationale

Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats.

Methods

To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release.

Results

CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization.

Conclusions

CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

中文翻译：

---

CYP2D在甲基苯丙胺诱导的纹状体多巴胺和5-羟色胺释放与行为敏化中在大鼠脑中的作用

基本原理

细胞色素P450 2D（CYP2D）酶代谢许多成瘾性药物，包括甲基苯丙胺。大脑中CYP2D代谢的变化可能会改变中枢神经系统药物/代谢物的浓度，从而影响成瘾倾向和神经精神病学预后。这些成分可以通过大鼠的行为敏化来建模。

方法

为了研究CYP2D在脑中对甲基苯丙胺诱导的行为致敏的作用，在每天7次甲基苯丙胺（0.5 mg / kg皮下注射）每次注射前20小时，对大鼠进行CYP2D不可逆抑制剂（或赋形剂）的集中预处理。体内脑微透析用于评估脑中药物和代谢物的浓度以及神经递质的释放。

结果

CYP2D抑制剂（与媒介物相比）预处理可增强甲基苯丙胺诱导的刻板印象致敏作用。CYP2D抑制剂预处理可增加脑中甲基苯丙胺的浓度，并降低脑中p-羟化代谢率。在第1天和第7天进行微透析后，CYP2D抑制剂的预处理加剧了刻板症的致敏性，并增强了背侧纹状体中多巴胺和5-羟色胺的释放。第1天的脑中甲基苯丙胺和苯丙胺的浓度与多巴胺和5-羟色胺的释放有关，而多巴胺和5-羟色胺的释放又与各疗程中的刻板印象反应斜率有关（即第1天到第7天），用作敏化度的量度。

结论

CYP2D介导的甲基苯丙胺在大脑中的代谢足以改变行为敏感性，大脑药物浓度以及纹状体多巴胺和5-羟色胺的释放。此外，第1天的甲基苯丙胺诱导的神经递质释放可能是随后的行为敏化的重要预测指标。这表明大脑中CYP2D对甲基苯丙胺诱导的行为敏化的新贡献，并暗示人脑CYP2D6的广泛变异可能导致差异的甲基苯丙胺反应和慢性作用。