Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
Department of Anesthesiology, University of California San Diego, San Diego, CA 92037, USA.
Int J Mol Sci. 2021 Jul 30;22(15):8219. doi: 10.3390/ijms22158219.
Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.
多巴胺 D1 受体 (D1R) 的功能受膜/脂筏驻留蛋白 caveolin-1 (Cav1) 调节。我们研究了背侧纹状体中 Cav1 表达的改变是否会影响间接激动 D1R 的 methamphetamine 的自我给药。表达 Cav1 的慢病毒构建体 (LV-Cav1) 或含有针对 Cav1 的短发夹 RNA 的慢病毒构建体 (LV-shCav1) 分别用于过表达或敲低背侧纹状体中的 Cav1 表达。在固定比率方案下，与 LV-GFP 对照相比，LV-Cav1 增强并且 LV-shCav1 减少了在延长访问方案中对 methamphetamine 的反应。LV-Cav1 和 LV-shCav1 还在剂量反应方案中产生了向上和向下的位移，产生了药物脆弱/抗性表型。LV-Cav1 和 LV-shCav1 并没有改变对蔗糖的反应。在递增比率方案下，LV-shCav1 通常通过降低断点来减少 methamphetamine 和蔗糖的正强化作用。Western blotting 证实 LV-Cav1 大鼠的 Cav1 表达增强，LV-shCav1 大鼠的 Cav1 表达减少。LV-GFP 大鼠的电生理发现表明，在延长的 methamphetamine 自我给药后，背侧纹状体中不存在高频刺激 (HFS) 诱导的长时程增强 (LTP)，这表明 methamphetamine 诱导的可塑性闭塞。LV-Cav1 通过增加钙调蛋白激酶 II 的磷酸化来防止 methamphetamine 诱导的可塑性，这表明了成瘾易感性的一种机制。LV-shCav1 导致 HFS 产生 LTP 的能力明显缺陷，因此，延长的 methamphetamine 无法改变纹状体的可塑性，表明了对成瘾样行为的抵抗力的一种机制。我们的结果表明，Cav1 表达和敲低驱动纹状体可塑性有助于调节对药物和非药物奖励的成瘾，激发了减少精神兴奋剂成瘾的新策略。
