Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Room 1102a, Philadelphia, PA 19104, USA.
Neurosci Lett. 2013 Mar 14;537:71-6. doi: 10.1016/j.neulet.2013.01.017. Epub 2013 Jan 24.
Transport of GluA1-containing AMPA glutamate receptors to synapses in the nucleus accumbens, a process that involves phosphorylation of key serine residues by CaMKII, is associated with the reinstatement of cocaine-seeking behavior. A growing body of evidence indicates that the dorsal striatum contributes to aspects of cocaine addiction. However, the potential role of CaMKII-mediated phosphorylation of GluA1 subunits in the dorsolateral (DL) striatum during cocaine reinstatement has not been examined. In this study, rats were trained to self-administer cocaine and were partnered with saline-yoked rats that received injections of saline. Following extinction, each pair of rats received either a systemic priming injection of cocaine (10mg/kg, i.p.) or saline. As expected, cocaine-experienced rats displayed robust reinstatement of cocaine seeking in response to a challenge injection, whereas yoked saline controls did not. The DL striatum was dissected immediately following the reinstatement test session. Results from Western blotting experiments showed increased pGluA1-ser831 and pCaMKII-thr286 in the DL striatum of saline-yoked rats given an acute injection of cocaine. This effect was absent in cocaine-experienced rats that received a saline injection, and no changes were observed following a priming injection of cocaine in cocaine-experienced rats. These results indicate that acute exposure to cocaine in drug naïve rats increased CaMKII-mediated phosphorylation of GluA1-containing AMPA receptors in the DL striatum, an effect that was not observed during cocaine priming-induced reinstatement of drug seeking. It is possible; therefore, that increased phosphorylation of CaMKII and GluA1 following acute cocaine is a compensatory mechanism in the DL striatum.
将 GluA1 含量的 AMPA 谷氨酸受体转运到伏隔核的突触中，这一过程涉及 CaMKII 对关键丝氨酸残基的磷酸化，与可卡因寻求行为的恢复有关。越来越多的证据表明，背侧纹状体有助于可卡因成瘾的某些方面。然而，CaMKII 介导的 GluA1 亚基在可卡因恢复期间在背外侧（DL）纹状体中的磷酸化的潜在作用尚未被研究。在这项研究中，大鼠被训练自我给予可卡因，并与接受盐水注射的盐水配对的大鼠配对。在消退后，每对大鼠接受系统预注射可卡因（10mg/kg，ip）或盐水。正如预期的那样，可卡因经验丰富的大鼠对挑战注射表现出强烈的可卡因寻求恢复，而盐水配对的对照大鼠则没有。在恢复测试后立即分离 DL 纹状体。Western blot 实验的结果表明，在接受急性可卡因注射的盐水配对的大鼠的 DL 纹状体中，pGluA1-ser831 和 pCaMKII-thr286 增加。在接受盐水注射的可卡因经验丰富的大鼠中，这种效应不存在，并且在可卡因经验丰富的大鼠接受可卡因引发的重新注射时，没有观察到变化。这些结果表明，在药物-naïve 大鼠中急性暴露于可卡因会增加 DL 纹状体中含有 GluA1 的 AMPA 受体的 CaMKII 介导的磷酸化，而在可卡因引发的药物寻求恢复期间则没有观察到这种作用。因此，急性可卡因后 CaMKII 和 GluA1 的磷酸化增加可能是 DL 纹状体中的一种代偿机制。
