Zhang Xiuwu, Lee Tong H, Davidson Colin, Lazarus Cindy, Wetsel William C, Ellinwood Everett H
Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27710, USA.
Neuropsychopharmacology. 2007 Feb;32(2):377-87. doi: 10.1038/sj.npp.1301101. Epub 2006 Jun 14.
Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.
可卡因滥用者在实现戒毒后的许多年里仍易出现药物渴望和复吸。我们最近发现，在每天注射可卡因后3.5小时给予昂丹司琼（一种5-HT3受体拮抗剂）可逆转先前建立的行为敏化。本研究的目的有两个。首先，由于可卡因不能用作治疗药物，我们研究了培高利特（一种滥用潜力较低的D1/D2受体激动剂）和昂丹司琼是否能逆转行为敏化。其次，我们研究了这些行为变化是否与相应的NMDA和AMPA受体的NR2B和GluR1亚基的表达水平和/或磷酸化变化的平行改变有关。大鼠连续5天注射可卡因或生理盐水，然后停药9天。从停药第10天开始，动物连续5天给予赋形剂、培高利特/生理盐水或培高利特/昂丹司琼。在第二个9天的停药期后，所有动物都用可卡因进行激发以评估行为敏化，并在第二天收集组织进行蛋白质印迹分析。敏化与伏隔核（NAc）壳中NR2B表达增加、NAc核心中Tyr1472磷酸化减少以及前额叶皮质、NAc核心和壳中GluR1亚基的Ser845磷酸化增加有关。培高利特/昂丹司琼治疗，但单独使用培高利特则不能，持续逆转行为敏化以及NMDA和AMPA受体亚基的相关变化。就敏化在慢性可卡因滥用中所起的作用而言，这些临床可用药物的组合可能对治疗该疾病有用。
