Jikihara H, Ikegami H, Koike K, Wada K, Morishige K, Kurachi H, Hirota K, Miyake A, Tanizawa O
Department of Obstetrics and Gynecology, Osaka University Medical School, Japan.
Endocrinology. 1993 Mar;132(3):953-8. doi: 10.1210/endo.132.3.7679984.
Histidyl-proline-diketopiperazine [Cyclo (His-Pro) (CHP)] was discovered to be one of the metabolites of TRH. To understand the specific role of CHP in rat hypothalamic dopamine neurons, we examined the in vivo effects of intraventricular (icv) infusion of CHP on the release and synthesis of PRL in the rat pituitary and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio in the rat hypothalamus. We also examined the in vitro effects of CHP on the release of [3H]dopamine from dispersed tuberoinfundibular dopamine neurons, [3H]dopamine reuptake in hypothalamic membrane fractions, and PRL release from rat pituitary cultured cells. Female rats were treated by icv infusion of 1 microM CHP daily for 1, 3, and 7 days, using Alzet osmotic pumps. After 1 day of treatment, the serum PRL concentration was significantly decreased. Northern blot analysis of the total RNA isolated from the pituitary glands of control animals using 32P-labeled PRL cDNA as a probe indicated the presence of PRL gene transcript, 1.0 kilobase in size, and its amount was decreased by CHP treatment. CHP did not affect [3H]dopamine release from dispersed tuberoinfundibular dopaminergic neurons at any concentration up to 1 microM. CHP did not inhibit PRL release from cultured pituitary cells at low concentrations (1-100 nM), but it stimulated PRL release at high concentrations (1 and 10 microM). We also examined the concentrations of dopamine and DOPAC in the rat hypothalamus when CHP was administered icv for 1 or 7 days. There was a significant decrease in the DOPAC/dopamine ratio after CHP treatment for 1 day. Furthermore, CHP caused dose-dependent inhibition of [3H]dopamine uptake by the rat hypothalamus similar to other dopamine uptake blockers, such as benztropine and GBR12909. These data suggest that icv administration of CHP might decrease both PRL secretion and accumulation of PRL gene transcripts in the pituitary by decreasing the DOPAC/dopamine ratio and inhibiting dopamine reuptake in the rat hypothalamus.
组氨酰 - 脯氨酸 - 二酮哌嗪[环（组氨酸 - 脯氨酸）（CHP）]被发现是促甲状腺激素释放激素（TRH）的代谢产物之一。为了解CHP在大鼠下丘脑多巴胺能神经元中的具体作用，我们研究了脑室内（icv）注入CHP对大鼠垂体中催乳素（PRL）释放和合成以及大鼠下丘脑中3,4 - 二羟基苯乙酸（DOPAC）/多巴胺比值的体内影响。我们还研究了CHP对分散的结节漏斗多巴胺能神经元释放[³H]多巴胺、下丘脑膜组分中[³H]多巴胺再摄取以及大鼠垂体培养细胞中PRL释放的体外影响。使用Alzet渗透泵，对雌性大鼠每天icv注入1微摩尔CHP，持续1、3和7天。治疗第1天后，血清PRL浓度显著降低。用³²P标记的PRL cDNA作为探针，对从对照动物垂体中分离的总RNA进行Northern印迹分析，结果表明存在大小为1.0千碱基的PRL基因转录本，且其数量因CHP处理而减少。在高达1微摩尔的任何浓度下，CHP均不影响分散的结节漏斗多巴胺能神经元释放[³H]多巴胺。低浓度（1 - 100纳摩尔）时，CHP不抑制培养垂体细胞释放PRL，但高浓度（1和10微摩尔）时，它会刺激PRL释放。我们还研究了icv给予CHP 1天或7天时大鼠下丘脑中多巴胺和DOPAC的浓度。CHP处理1天后，DOPAC/多巴胺比值显著降低。此外，与其他多巴胺摄取阻滞剂如苯海索和GBR12909类似，CHP对大鼠下丘脑[³H]多巴胺摄取产生剂量依赖性抑制。这些数据表明，icv给予CHP可能通过降低DOPAC/多巴胺比值并抑制大鼠下丘脑多巴胺再摄取，从而降低垂体中PRL的分泌和PRL基因转录本的积累。
