Walker Q David, Ray Rupa, Kuhn Cynthia M
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Neuropsychopharmacology. 2006 Jun;31(6):1193-202. doi: 10.1038/sj.npp.1300915.
Previous data indicate that dopamine neurotransmission is differently regulated in male and female rats. The purpose of the present study was to investigate the dopamine transporter and autoreceptor as potential loci responsible for this sex difference. Fast cyclic voltammetry at carbon-fiber microelectrodes was used to monitor changes in electrically evoked levels of extracellular dopamine in the striata of anesthetized male and female rats before and after administration of an uptake inhibitor, a dopamine D2 antagonist, or a D3/D2 agonist. Administration of 40 mg/kg cocaine ip increased electrically-evoked extracellular dopamine concentrations in both sexes, but to a significantly greater extent in female striatum at the higher stimulation frequencies. The typical antipsychotic, haloperidol, increased dopamine efflux in both sexes but the effect was twice as large in the female striatum. The D3/D2 agonist quinpirole induced an unexpected, transient increase in dopamine efflux following high-frequency stimulation only in females, and evoked dopamine was higher in females across this entire time course. More detailed analysis of cocaine effects revealed no fundamental sex differences in the interaction of cocaine with DAT in vivo or in synaptosomes. These results indicate that nigrostriatal dopamine neurotransmission in the female rat is more tightly regulated by autoreceptor and transporter mechanisms, perhaps related by greater autoreceptor control of DAT activity. Thus, baseline sex differences in striatal dopamine regulation induce different pharmacologic responses. These results contribute to understanding sex differences in stimulant-induced locomotor activity in rats and may have broader implications for neurologic disorders and their pharmacotherapies in humans.
先前的数据表明，多巴胺神经传递在雄性和雌性大鼠中受到不同的调节。本研究的目的是调查多巴胺转运体和自身受体，作为造成这种性别差异的潜在位点。使用碳纤维微电极上的快速循环伏安法，来监测在给予摄取抑制剂、多巴胺D2拮抗剂或D3/D2激动剂之前和之后，麻醉的雄性和雌性大鼠纹状体中电诱发的细胞外多巴胺水平的变化。腹腔注射40mg/kg可卡因可增加两性的电诱发细胞外多巴胺浓度，但在较高刺激频率下，雌性纹状体中的增加幅度明显更大。典型的抗精神病药物氟哌啶醇可增加两性的多巴胺流出，但在雌性纹状体中的作用是雄性的两倍。D3/D2激动剂喹吡罗仅在雌性大鼠中，在高频刺激后诱发出意外的、短暂的多巴胺流出增加，并且在整个时间过程中，雌性的诱发多巴胺水平更高。对可卡因作用的更详细分析表明，可卡因与体内或突触体中的多巴胺转运体（DAT）相互作用，不存在根本的性别差异。这些结果表明，雌性大鼠黑质纹状体多巴胺神经传递，受自身受体和转运体机制的调节更为严格，这可能与自身受体对DAT活性的更大控制有关。因此，纹状体多巴胺调节的基线性别差异会诱导不同的药理反应。这些结果有助于理解大鼠中兴奋剂诱导的运动活动的性别差异，并且可能对人类神经系统疾病及其药物治疗具有更广泛的意义。
