Nation Jack R, Cardon Aaron L, Heard Heather M, Valles Rodrigo, Bratton Gerald R
Department of Psychology, Texas A & M University, College Station, TX 77843, USA.
Department of Veterinary Anatomy and Public Health, Texas A & M University, College Station, TX 77843, USA.
Psychopharmacology (Berl). 2003 Jul;168(1-2):236-243. doi: 10.1007/s00213-003-1405-2. Epub 2003 Mar 25.
Intravenous self-administration of cocaine at low doses is increased by chronic low-level exposure to lead during gestation and lactation (perinatal lead exposure). Insofar as drug potency is increased by early lead exposure, it must be considered that cocaine-seeking and relapse after periods of withdrawal similarly may be enhanced by perinatal lead exposure.
Employing an animal model, the present study examined the effects of lead exposure during gestation and lactation on cocaine-induced reinstatement of drug-seeking, when animals were tested as adults.
Adult female rats were gavaged once daily with 0 or 16 mg lead for 30 days prior to breeding with non-exposed males. This exposure regimen continued until offspring were weaned at postnatal day (PND) 21. At PND 120, male offspring were trained to self-administer cocaine intravenously (IV) [0.50 mg/kg cocaine per infusion on a fixed-ratio schedule where two lever presses resulted in drug delivery (FR-2 schedule)]. After steady-state responding was established, cocaine reinstatement responding was assessed for each group within an extinction paradigm. During the initial 1 h of reinstatement testing, the previous baseline contingencies were in place, i.e. animals operated under an FR-2 schedule for an infusion of 0.50 mg/kg cocaine. During the 2 h, 3 h, and 4 h of testing saline infusions were substituted for cocaine infusions. After responding extinguished during hour 4, reinstatement of responding was tested by administering an intraperitoneal (IP) priming injection of 0.00, 5.00, 10.00, or 20.00 mg/kg cocaine. Following these injections, lever responding for saline infusions was monitored during hour 5.
The number of saline infusions self-administered during hour 5 increased in a dose-dependent fashion for both controls (group 0-mg) and lead-exposed (group 16-mg) animals. However, lead-exposed animals self-administered significantly more saline infusions than controls at the 5.00 mg/kg and 10.00 mg/kg doses. This apparent metal-related increase in sensitivity to cocaine was evident with blood lead in metal-exposed test animals returning to control levels. However, brain lead levels remained elevated in lead-exposed test animals, relative to controls.
The results of this investigation suggest that low-level lead exposure during gestation and lactation increases sensitivity to the relapse phase of drug abuse. It is further apparent that this increased sensitivity to the reinstatement of drug-seeking behavior is long-lasting.
孕期和哺乳期长期低水平接触铅（围产期铅暴露）会增加低剂量可卡因的静脉自我给药量。鉴于早期铅暴露会增强药物效力，必须考虑围产期铅暴露同样可能会增强戒断期后对可卡因的寻求和复吸。
本研究采用动物模型，研究孕期和哺乳期铅暴露对成年动物可卡因诱导的觅药行为复燃的影响。
成年雌性大鼠在与未接触铅的雄性大鼠交配前30天，每天一次灌胃给予0或16毫克铅。这种暴露方案持续到产后第21天（PND 21）幼崽断奶。在PND 120时，雄性幼崽接受静脉注射可卡因自我给药训练[在固定比率方案下，每次输注0.50毫克/千克可卡因，两次杠杆按压可获得药物（FR-2方案）]。在建立稳定反应后，在消退范式中评估每组的可卡因复燃反应。在复燃测试的最初1小时内，维持先前的基线条件，即动物按照FR-2方案操作以输注0.50毫克/千克可卡因。在测试的第2小时、第3小时和第4小时，用生理盐水输注替代可卡因输注。在第4小时反应消退后，通过腹腔注射0.00、5.00、10.00或20.00毫克/千克可卡因进行复燃反应测试。注射后，在第5小时监测杠杆对生理盐水输注的反应。
对照组（0毫克组）和铅暴露组（16毫克组）动物在第5小时自我给药的生理盐水输注次数均呈剂量依赖性增加。然而，在5.00毫克/千克和10.00毫克/千克剂量下，铅暴露组动物自我给药的生理盐水输注次数明显多于对照组。这种与金属相关的对可卡因敏感性的明显增加在金属暴露测试动物的血铅恢复到对照水平时很明显。然而，相对于对照组，铅暴露测试动物的脑铅水平仍然升高。
本研究结果表明，孕期和哺乳期低水平铅暴露会增加对药物滥用复燃阶段的敏感性。进一步明显的是，这种对觅药行为复燃的敏感性增加是持久的。
