Cocaine preference and neuroadaptations are maintained by astrocytic NMDA receptors in the nucleus accumbens.
Cocaine preference and neuroadaptations are maintained by astrocytic NMDA receptors in the nucleus accumbens.
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DOI：
10.1126/sciadv.abo6574
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发表时间：
2022-07-22
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
与可卡因有关的记忆会引起渴望，并干扰使用者停止使用可卡因的能力。通过促进消退来降低线索药物记忆的强度可能对可卡因成瘾的治疗具有治疗价值。在这里，我们证明了表达的GluN 1/2A/2C NMDA受体电流的星形胶质细胞在核内的核心。选择性消融GluN 1亚单位从星形胶质细胞在脑桥核增强消退可卡因偏好记忆，但不影响可卡因条件反射或恢复。重复可卡因暴露上调GluN 2C亚基表达和增加星形胶质细胞NMDA受体电流。此外，脑内抑制含GluN 2C/2D受体和GluN 2C亚基缺失促进可卡因记忆的消退。可卡因诱导的神经适应，包括树突棘成熟和AMPA受体的招聘在GluN 2C基因敲除小鼠缺席。外源性给予重组磷脂酰肌醇蛋白聚糖4可恢复GluN 2C基因敲除小鼠可卡因偏好记忆的保留受损。总之，这些结果确定了一个以前未知的星形胶质细胞GluN 2C含有NMDA受体的机制，维持可卡因偏好记忆。星形胶质细胞NMDA受体是消除可卡因记忆的潜在治疗靶点。
Cocaine-associated memories induce cravings and interfere with the ability of users to cease cocaine use. Reducing the strength of cue-drug memories by facilitating extinction may have therapeutic value for the treatment of cocaine addiction. Here, we demonstrate the expression of GluN1/2A/2C NMDA receptor currents in astrocytes in the nucleus accumbens core. Selective ablation of GluN1 subunit from astrocytes in the nucleus accumbens enhanced extinction of cocaine preference memory but did not affect cocaine conditioning or reinstatement. Repeated cocaine exposure up-regulated GluN2C subunit expression and increased astrocytic NMDA receptor currents. Furthermore, intra-accumbal inhibition of GluN2C/2D-containing receptors and GluN2C subunit deletion facilitated extinction of cocaine memory. Cocaine-induced neuroadaptations including dendritic spine maturation and AMPA receptor recruitment were absent in GluN2C knockout mice. Impaired retention of cocaine preference memory in GluN2C knockout mice was restored by exogenous administration of recombinant glypican 4. Together, these results identify a previously unknown astrocytic GluN2C-containing NMDA receptor mechanism underlying maintenance of cocaine preference memory. Astrocytic NMDA receptors are potential therapeutic targets for the extinction of cocaine memories.
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影响因子：
4.7
作者：
Gupta SC;Yadav R;Pavuluri R;Morley BJ;Stairs DJ;Dravid SM
通讯作者：
Dravid SM
影响因子：
4
作者：
Kruyer A;Kalivas PW
通讯作者：
Kalivas PW
影响因子：
4.4
作者：
Alsaad HA;DeKorver NW;Mao Z;Dravid SM;Arikkath J;Monaghan DT
通讯作者：
Monaghan DT
影响因子：
17.7
作者：
Kalivas, PW;Volkow, ND
通讯作者：
Volkow, ND
影响因子：
2.7
作者：
Carmack, Stephanie A.;Kim, Jeesun S.;Anagnostaras, Stephan G.
通讯作者：
Anagnostaras, Stephan G.