Larson Erin B, Carroll Marilyn E
Department of Psychiatry, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Neuropsychopharmacology. 2007 Jun;32(6):1334-45. doi: 10.1038/sj.npp.1301249. Epub 2006 Nov 29.
Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor alpha (ERalpha) and beta (ERbeta) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERalpha/beta agonist estradiol benzoate (EB), the ERalpha-selective agonist, propyl-pyrazole-triol (PPT), the ERbeta-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX+DMSO controls. Selective activation of ERbeta with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERalpha with PPT did not affect cocaine-seeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERbeta.
临床前和临床研究表明，女性比男性更容易复发，雌激素的神经生物学效应被认为在一定程度上介导了可卡因使用行为中的性别差异。本研究的目的是调查雌激素受体α（ERα）和β（ERβ）在雌激素介导的去卵巢（OVX）雌性大鼠可卡因诱导的消退可卡因觅求行为恢复增加中的作用。大鼠最初在每日2小时的训练中，按照固定比率1（FR 1）强化程序，接受静脉注射可卡因（0.4毫克/千克/次）的自我给药训练。在10天的维持期后，将可卡因溶液替换为生理盐水，并在14天内使自我给药行为消退。然后，给OVX大鼠注射混合的ERα/β激动剂苯甲酸雌二醇（EB）、ERα选择性激动剂丙基吡唑三醇（PPT）、ERβ选择性激动剂二芳基丙腈（DPN）或溶剂对照（二甲基亚砜，DMSO）。治疗共持续9天，在此期间，在给大鼠注射生理盐水或可卡因（5、10或15毫克/千克，腹腔注射）进行激发后，评估大鼠消退可卡因觅求行为的非强化恢复情况。OVX大鼠在维持期或消退期的自我给药行为没有差异。与OVX + DMSO对照组相比，用EB治疗的OVX大鼠在恢复阶段对可卡因的反应更强。用DPN选择性激活ERβ也增加了可卡因诱导的恢复反应，而用PPT选择性激活ERα则不影响可卡因觅求行为。这些结果表明，雌激素影响消退可卡因觅求行为恢复的倾向，并且雌激素介导的可卡因诱导恢复反应的增强涉及ERβ的激活。
