Department of Neurosciences, Medical University of South Carolina, Charleston 29425, USA.
J Neurosci. 2011 Nov 9;31(45):16177-84. doi: 10.1523/JNEUROSCI.3816-11.2011.
Relapse to cocaine-seeking involves impairments in plasticity at glutamatergic synapses in the nucleus accumbens. Integrins are cell adhesion molecules that bind to the extracellular matrix and regulate aspects of synaptic plasticity, including glutamate receptor trafficking. To determine a role for integrins in cocaine-seeking, rats were trained to self-administer cocaine, the operant response extinguished, and cocaine-seeking induced by a conditioned cue or noncontingent cocaine injection. This cocaine self-administration protocol reduced the content of the β3 integrin subunit in postsynaptic density of the accumbens core at 24 h after the last self-administration session. However, after 3 weeks of forced abstinence plus extinction training, the level of β3 was elevated and was further regulated over 120 min during cocaine-induced drug-seeking. A small peptide ligand [arginine-glycine-aspartate (RGD)] that mimics extracellular matrix protein binding to integrins was microinjected into the accumbens core during self-administration or extinction training, or just before cocaine-reinstated drug seeking. The daily RGD injections during self-administration or just before a reinstatement session inhibited cocaine-induced drug-seeking, while RGD microinjection during extinction training was without consequence on reinstated cocaine-seeking. Daily RGD during self-administration also prevented the enduring changes in β3 levels. Finally, reduced surface expression of the GluR2 subunit of the AMPA receptor is associated with cocaine-seeking, and daily RGD microinjections during self-administration training normalized the surface expression of GluR2. Together, these data indicate that the regulation integrins may contribute to cocaine-reinstated drug-seeking, in part by promoting reduced GluR2 surface expression.
复吸可卡因涉及到伏隔核中谷氨酸能突触的可塑性损伤。整合素是细胞黏附分子,与细胞外基质结合并调节突触可塑性的各个方面,包括谷氨酸受体转运。为了确定整合素在可卡因寻求中的作用,训练大鼠自行给予可卡因,操作性反应被消除,条件性线索或非连续可卡因注射诱导可卡因寻求。这种可卡因自我给药方案在最后一次自我给药后 24 小时降低了伏隔核核心中突触后密度的β3 整合素亚基含量。然而,在强制禁欲和消退训练 3 周后,β3 的水平升高,并在可卡因诱导的药物寻求期间进一步调节 120 分钟。一种模仿细胞外基质蛋白与整合素结合的小肽配体[精氨酸-甘氨酸-天冬氨酸(RGD)]在自我给药或消退训练期间或在可卡因复吸药物寻求之前被微注射到伏隔核核心中。在自我给药或复吸期间,每日 RGD 注射抑制可卡因诱导的药物寻求,而在消退训练期间的 RGD 微注射对复吸可卡因寻求没有影响。在自我给药期间每日 RGD 还防止了β3 水平的持久变化。最后,AMPA 受体的 GluR2 亚基的表面表达减少与可卡因寻求有关,并且在自我给药训练期间每日 RGD 微注射使 GluR2 的表面表达正常化。总之,这些数据表明整合素的调节可能有助于可卡因复吸药物寻求,部分原因是促进了 GluR2 表面表达的减少。