背景:可卡因渴求的潜伏期是指在可卡因自我给药的禁欲过程中,提示引起的渴求的逐渐加剧。我们先前表明,禁欲约1个月后,同源GluA1Ca2可渗透AMPAR(CP-AMPAR)在伏隔核核心(NAcc)中等多刺神经元(MSN)的兴奋性突触中积累,此后它们的激活是表达孵育所必需的。因此,了解CP-AMPAR可塑性的潜在机制很重要.
目的:我们假设CP-AMPAR上调代表维甲酸(RA)依赖性稳态可塑性形式,先前在其他大脑区域描述过,其中神经元活动的减少抑制了RA的合成,导致GluA1翻译和CP-AMPAR突触插入。我们使用病毒载体进行了测试,以在延长可卡因自我给药后禁欲期间双向操纵NAcc中的RA信号。
结果:我们使用靶向RA降解酶Cyp26b1的shRNA来增加RA信号传导。这种处理加速了孵育;大鼠在禁欲日(AD)15表达孵育,此时在对照大鼠中尚未检测到。它还加速了用切片生理学测量的CP-AMPAR突触插入。在表达Cyp26b1shRNA的MSN中检测到CP-AMPAR,但不能控制MSN,在AD15-18。接下来,我们使用靶向主要RA合成酶Aldh1a1的shRNA来减少RA信号传导。在表达Aldh1a1shRNA的MSN中,与对照组相比,突触CP-AMPAR在晚期戒断时减少(AD42-60).然而,我们没有检测到这种操作对孵育可卡因寻找的影响(AD40).
结论:这些发现支持以下假设:禁欲期间RA信号的增加有助于CP-AMPAR的积累和可卡因渴望的孵育。
BACKGROUND: Incubation of cocaine craving refers to the progressive intensification of cue-induced craving during abstinence from cocaine self-administration. We showed previously that homomeric GluA1 Ca2+-permeable AMPARs (CP-AMPAR) accumulate in excitatory synapses of nucleus accumbens core (NAcc) medium spiny neurons (MSN) after ∼1 month of abstinence and thereafter their activation is required for expression of incubation. Therefore, it is important to understand mechanisms underlying CP-AMPAR plasticity.
OBJECTIVE: We hypothesize that CP-AMPAR upregulation represents a retinoic acid (RA)-dependent form of homeostatic plasticity, previously described in other brain regions, in which a reduction in neuronal activity disinhibits RA synthesis, leading to GluA1 translation and CP-AMPAR synaptic insertion. We tested this using viral vectors to bidirectionally manipulate RA signaling in NAcc during abstinence following extended-access cocaine self-administration.
RESULTS: We used shRNA targeted to the RA degradative enzyme Cyp26b1 to increase RA signaling. This treatment accelerated incubation; rats expressed incubation on abstinence day (AD) 15, when it is not yet detected in control rats. It also accelerated CP-AMPAR synaptic insertion measured with slice physiology. CP-AMPARs were detected in Cyp26b1 shRNA-expressing MSN, but not control MSN, on AD15-18. Next, we used shRNA targeted to the major RA synthetic enzyme Aldh1a1 to reduce RA signaling. In MSN expressing Aldh1a1 shRNA, synaptic CP-AMPARs were reduced in late withdrawal (AD42-60) compared to controls. However, we did not detect an effect of this manipulation on incubated cocaine seeking (AD40).
CONCLUSIONS: These findings support the hypothesis that increased RA signaling during abstinence contributes to CP-AMPAR accumulation and incubation of cocaine craving.