Sobrian Sonya K, Jones Barbara L, Varghese Shiny, Holson R Robert
Department of Pharmacology, Howard University College of Medicine, Washington, DC 20059, USA.
Neurotoxicol Teratol. 2003 May-Jun;25(3):311-28. doi: 10.1016/s0892-0362(03)00009-6.
As part of an investigation into the effects of gestational ethanol (ETOH) exposure on the developing dopamine (DA) system, pregnant Sprague-Dawley rats were exposed to one of three conditions: ETOH, pair-fed (PF) to the ETOH group, or ad libitum lab chow controls (LC). In this paper we report behavioral drug challenge effects for offspring of the two control groups (PF and LC). Male and female pups between postnatal days (PNDs) 21 and 23 in age were exposed to one of three intraperitoneal/subcutaneous doses of one of eight drugs chosen to assess the functional status of the DA D(1), D(2), and D(3) receptor subtype, or a saline control. Agonists were SKF 38393, apomorphine (APO), quinpirole (QUIN), and 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin [7-OH-DPAT (DPAT)]; antagonists were spiperone (SPIP), SCH 23390, and two recently developed D(3) antagonists nafadotride (NAF) and PD 152255. Immediately following drug injection, pups were placed in observation cages, where eight behaviors (square entries, grooming, circling, rearing, sniffing, head and oral movements, and yawning) were scored at 3-min intervals for 30 min. Classic behavioral profiles were generally obtained for the high-dose mixed agonists APO, DPAT, and QUIN, which potently increased square entries, rearing, and sniffing, while reducing grooming and head movements. However, low-dose APO had no effect on behavior. The D(1) agonist, SKF 38393, had a strikingly different behavioral profile; it had no effect on square entries at any dose, while increasing grooming and sniffing at the medium dose. The D(1) antagonist, SCH 23390, profoundly decreased all behaviors except oral and head movements, especially at high doses. In contrast, the effects of the D(2) antagonist, SPIP, were limited to increasing sniffing at the medium dose. The two putative D(3) antagonists, NAF and PD 152255, presented strikingly different profiles. NAF induced a pattern of behavioral suppression that resembled the profile of high-dose SCH, while high-dose PD 152255 stimulated behavior. The failure of low-dose APO to have any effect on behavior suggests that the D(2) autoreceptor is not functional in preweanling rats. This hypothesis is further supported by the lack of behavioral suppression seen with low-dose QUIN and DPAT. Failure of NAF to produce behavioral activation at low doses and the stimulatory effects seen with PD 152255 suggests that either the D(3) autoreceptor, the postsynaptic D(3) receptor, or both are not fully functional at this age as well.
作为一项关于孕期乙醇（ETOH）暴露对发育中的多巴胺（DA）系统影响的研究的一部分，将怀孕的斯普拉格-道利大鼠暴露于三种条件之一：ETOH、与ETOH组配对喂养（PF）或自由采食实验室常规饲料对照组（LC）。在本文中，我们报告了两个对照组（PF和LC）后代的行为药物激发效应。对出生后第21至23天（PNDs）的雄性和雌性幼崽腹腔内/皮下注射八种药物之一的三种剂量之一，以评估DA D(1)、D(2)和D(3)受体亚型的功能状态，或注射生理盐水作为对照。激动剂有SKF 38393、阿扑吗啡（APO）、喹吡罗（QUIN）和7-羟基-N,N-二正丙基-2-氨基四氢萘[7-OH-DPAT（DPAT）]；拮抗剂有螺哌隆（SPIP）、SCH 23390，以及两种最近开发的D(3)拮抗剂萘法朵曲（NAF）和PD 152255。药物注射后，立即将幼崽放入观察笼中，每隔3分钟对八种行为（进入方格、梳理毛发、转圈、直立、嗅探、头部和口腔运动以及打哈欠）进行评分，持续30分钟。高剂量混合激动剂APO、DPAT和QUIN通常呈现出典型的行为特征，它们显著增加进入方格、直立和嗅探行为，同时减少梳理毛发和头部运动。然而，低剂量APO对行为没有影响。D(1)激动剂SKF 38393具有显著不同的行为特征；它在任何剂量下对进入方格行为都没有影响，而在中等剂量下增加梳理毛发和嗅探行为。D(1)拮抗剂SCH 23390除了口腔和头部运动外，显著减少所有行为，尤其是高剂量时。相比之下，D(2)拮抗剂SPIP的作用仅限于在中等剂量时增加嗅探行为。两种假定的D(3)拮抗剂NAF和PD 152255呈现出显著不同的特征。NAF诱导出一种行为抑制模式，类似于高剂量SCH的特征，而高剂量PD 152255刺激行为。低剂量APO对行为没有任何影响，这表明D(2)自身受体在断奶前大鼠中不起作用。低剂量QUIN和DPAT未见行为抑制，这进一步支持了这一假设。低剂量NAF未能产生行为激活，而PD 152255有刺激作用，这表明D(3)自身受体、突触后D(3)受体或两者在这个年龄也未完全发挥功能。
