Elwan M A, Soliman M R
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee 32307, USA.
Pharmacology. 1995 Aug;51(2):73-83. doi: 10.1159/000139319.
The present study was conducted to investigate the effects of repeated administration of opiates on the binding characteristics of D1 and D2 dopamine receptors in specific rat brain regions. Male Sprague-Dawley rats (150-175 g) were adapted for 1 week under controlled conditions (22 +/- 1 degree C, 40% relative humidity, 12 h light:12 h dark illumination cycle). After the adaptation period, rats were randomly assigned into six groups (n = 15/group) for two sets of experiments; one for D1 and the other for D2 receptor binding evaluation. In each set, group 1 served as saline control, group 2 was treated with morphine (1 mg/kg/day for 7 days) and group 3 was treated with naloxone (2 mg/kg/day for 7 days). Following the third day of morphine injection, rats showed restlessness, hyperactivity, increased urination, diarrhea, lacrimation, irritability and squealing on touch, head and body shakes and salivation just prior to morphine dosage. These observed signs are typical for morphine withdrawal. One hour after the last injection, rats were sacrificed by decapitation, brains were removed and kept at -70 degrees C. The frozen brains were further dissected into cortex (CTX), hypothalamus (HYPO), hippocampus (HIPP) and midbrain (MID), pooled (5/pool), homogenized and used for radioreceptor assays. For D1 binding study, 3H-SCH-23390 was used as ligand and for D2 receptor binding 3H-YM-09151-2 was employed. Following repeated morphine or naloxone treatment, Bmax values for 3H-SCH-23390 binding to membranes of HYPO and MID were increased and decreased, respectively, whereas Kd values were significantly decreased in both HYPO and MID of morphine and naloxone-treated animals. In rat brain CTX, both morphine and naloxone decreased Kd and Bmax values of 3H-SCH-23390 binding, however the decrease in Bmax values noted after morphine administration was not statistically significant. Decrease in both Bmax and Kd values of dopamine D1 receptors were observed after naloxone but not morphine treatment in HIPP. Morphine administration increased the density of D2 receptors in HIPP and MID and decreased the affinity of 3H-YM-09151-2 binding in CTX, HIPP and MID. Naloxone treatment resulted in increased number of 3H-YM-09151-2 binding sites in CTX, HYPO and HIPP. While naloxone treatment increased Kd values of 3H-YM-09151-2 in HYPO and HIPP, it decreased these values in CTX and MID. It is concluded that repeated intermittent treatment with opiates induces alterations in D1 and D2 dopamine receptors binding properties and that these changes are regionally specific.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究旨在探讨反复给予阿片类药物对大鼠特定脑区D1和D2多巴胺受体结合特性的影响。雄性Sprague-Dawley大鼠（150 - 175克）在可控条件下（22±1摄氏度，相对湿度40%，12小时光照：12小时黑暗光照周期）适应1周。适应期过后，将大鼠随机分为六组（每组n = 15）进行两组实验；一组用于D1受体结合评估，另一组用于D2受体结合评估。在每组实验中，第1组作为生理盐水对照组，第2组用吗啡治疗（1毫克/千克/天，共7天），第3组用纳洛酮治疗（2毫克/千克/天，共7天）。在吗啡注射第三天后，大鼠在每次吗啡给药前表现出不安、多动、排尿增多、腹泻、流泪、易怒、轻触时尖叫、头部和身体颤抖以及流涎。这些观察到的症状是吗啡戒断的典型表现。最后一次注射1小时后，通过断头处死大鼠，取出大脑并保存在-70摄氏度。将冷冻的大脑进一步解剖为皮质（CTX）、下丘脑（HYPO）、海马体（HIPP）和中脑（MID），合并（每组5个）、匀浆并用于放射受体分析。对于D1结合研究，使用3H-SCH-23390作为配体，对于D2受体结合研究，使用3H-YM-09151-2。反复给予吗啡或纳洛酮治疗后，3H-SCH-23390与HYPO和MID膜结合的Bmax值分别升高和降低，而吗啡和纳洛酮治疗组动物的HYPO和MID中的Kd值均显著降低。在大鼠脑CTX中，吗啡和纳洛酮均降低了3H-SCH-23390结合的Kd和Bmax值，然而吗啡给药后Bmax值的降低无统计学意义。在HIPP中，纳洛酮治疗后观察到多巴胺D1受体的Bmax和Kd值均降低，而吗啡治疗后未观察到这种情况。吗啡给药增加了HIPP和MID中D2受体的密度，并降低了CTX、HIPP和MID中3H-YM-09151-2结合的亲和力。纳洛酮治疗导致CTX、HYPO和HIPP中3H-YM-09151-2结合位点数量增加。虽然纳洛酮治疗增加了HYPO和HIPP中3H-YM-09151-2的Kd值，但在CTX和MID中却降低了这些值。得出的结论是，反复间歇性给予阿片类药物会诱导D1和D2多巴胺受体结合特性发生改变，且这些变化具有区域特异性。（摘要截取自400字）
