Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.
Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.
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DOI：
10.1016/j.celrep.2022.111440
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发表时间：
2022-09-27
期刊：
影响因子：
8.8
通讯作者：
Dobbs, Lauren K.
中科院分区：
文献类型：
--
作者：
Dai, Kathy Z.;Choi, In Bae;Levitt, Ryan;Blegen, Mariah B.;Kaplan, Alanna R.;Matsui, Aya;Shin, J. Hoon;Bocarsly, Miriam E.;Simpson, Eleanor H.;Kellendonk, Christoph;Alvarez, Veronica A.;Dobbs, Lauren K.
纹状体中多巴胺D2受体（D2 R）的可用性较低可能导致可卡因滥用;尽管纹状体D2 R的低水平如何促进可卡因奖励尚不清楚。纹状体神经元中D2 Rs的过表达或急性可卡因对D2 Rs的激活抑制了纹状体Penk mRNA。相反，D2-纹状体神经元中的低D2 Rs增加纹状体Penk mRNA和脑啡肽肽紧张度，一种内源性μ-阿片激动剂。在脑切片中，甲硫氨酸脑啡肽和抑制脑啡肽catalysts抑制纹状体内GABA的传输。在位置条件反射过程中将可卡因与内吗啡甲硫氨酸脑啡肽配对有助于获得偏好，而μ阿片受体拮抗剂阻断野生型小鼠的偏好。我们认为，提高纹状体脑啡肽增强可卡因奖励抑制纹状体内GABA，以提高纹状体输出。令人惊讶的是，μ-阿片受体拮抗剂不阻断低纹状体D2 Rs小鼠的可卡因偏好，涉及其他阿片受体。脑啡肽的D2 R活性和可卡因的双向调节提供了深入了解可卡因滥用的脆弱性的机制。低纹状体D2受体水平与可卡因滥用有关。Dai等人双向改变纹状体D2受体水平，以探索这种滥用倾向的下游机制。他们提供的证据表明，由低D2受体引起的脑啡肽张力增强与纹状体内GABA抑制和可卡因奖励增强有关。
Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse. Low striatal D2 receptor levels are associated with cocaine abuse. Dai et al. bidirectionally alter striatal D2 receptor levels to probe the downstream mechanisms underlying this abuse liability. They provide evidence that enhanced enkephalin tone resulting from low D2 receptors is associated with suppressed intra-striatal GABA and potentiated cocaine reward.
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影响因子：
16.2
作者：
Creed M;Ntamati NR;Chandra R;Lobo MK;Lüscher C
通讯作者：
Lüscher C
影响因子：
7.6
作者：
Crespo, JA;Manzanares, J;Ambrosio, E
通讯作者：
Ambrosio, E
DOI：
10.1016/0169-328x(92)90178-e
发表时间：
1992-07-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
BRANCH, AD;UNTERWALD, EM;KREEK, MJ
通讯作者：
KREEK, MJ
影响因子：
16.6
作者：
Gallo EF;Meszaros J;Sherman JD;Chohan MO;Teboul E;Choi CS;Moore H;Javitch JA;Kellendonk C
通讯作者：
Kellendonk C
影响因子：
2.3
作者：
Cunningham, Christopher L.;Dickinson, Shelly D.;Okorn, Dobrina M.
通讯作者：
Okorn, Dobrina M.