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首页> 外文期刊>Addiction biology >Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex
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Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex

机译：禁欲后复发至可卡因寻找受前额叶皮层中cAMP依赖性蛋白激酶A的调节

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摘要

Abstinence from cocaine self-administration (SA) is associated with neuroadaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc) that are implicated in cocaine-induced neuronal plasticity and relapse to drug-seeking. Alterations in cAMP-dependent protein kinase A (PKA) signaling are prominent in medium spiny neurons in the NAc after repeated cocaine exposure but it is unknown whether similar changes occur in the PFC. Because cocaine SA induces disturbances in glutamatergic transmission in the PFC-NAc pathway, we examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine-seeking. We measured the phosphorylation of cAMP response element binding protein (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking. We also evaluated whether infusion of the PKA inhibitor, 8-bromo-Rp-cyclic adenosine 3′, 5′-monophosphorothioate (Rp-cAMPs), into the dmPFC after abstinence would affect cue-induced cocaine-seeking and PKA-regulated phosphoprotein levels. Seven days of forced abstinence increased the phosphorylation of cAMP response element binding protein and GluA1 in the dmPFC and synapsin I (Ser9) in the NAc. Induction of these phosphoproteins was reversed by a cue-induced relapse test of cocaine-seeking. Bilateral intra-dmPFC Rp-cAMPs rescued abstinence-elevated PKA-mediated phosphoprotein levels in the dmPFC and NAc and suppressed cue-induced relapse. Thus, by inhibiting abstinence-induced PKA molecular targets, relapse reverses abstinence-induced neuroadaptations in the dmPFC that are responsible, in part, for the expression of cue-induced cocaine-seeking. We examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine-seeking. We measured the phosphorylation of cAMP response element binding protein (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking.
机译：可卡因自我管理（SA）的节制与前额叶皮层（PFC）和伏伏核（NAc）的神经适应有关，这些神经适应与可卡因诱导的神经元可塑性和吸毒复发有关。重复可卡因暴露后，NAc中的中棘神经元中cAMP依赖性蛋白激酶A（PKA）信号的变化很明显，但未知PFC是否发生类似变化。由于可卡因SA会诱导PFC-NAc途径中的谷氨酸能传递受到干扰，因此，我们检查了禁欲期间是否在PFC-NAc神经元中发生了PKA介导的分子靶标失调，如果发生，是否有助于寻找可卡因。我们测量了禁欲7天后背囊（dm）PFC和突触前标记突触素I（Ser9，Ser62 / 67，Ser603）中cAMP反应元件结合蛋白（Ser133）和GluA1（Ser845）的磷酸化来自可卡因SA，有或没有提示诱导的可卡因寻求。我们还评估了禁欲后向dmPFC中输注PKA抑制剂，8-溴-Rp-环腺苷3'，5'-单硫代磷酸酯（Rp-cAMPs）是否会影响提示诱导的可卡因寻求和PKA调节的磷蛋白水平。强迫戒断7天增加了dmPFC中的cAMP反应元件结合蛋白和GluA1的磷酸化，以及NAc中的突触蛋白I（Ser9）的磷酸化。这些磷酸蛋白的诱导被可卡因寻找的提示诱导的复发测试所逆转。双边dmPFC内Rp-cAMPs挽救了dmPFC和NAc中禁欲性升高的PKA介导的磷蛋白水平，并抑制了提示诱导的复发。因此，通过抑制禁欲诱导的PKA分子靶标，复发逆转了dmPFC中禁欲诱导的神经适应，这部分归因于线索诱导的可卡因寻求的表达。我们检查了禁欲期间PFC-NAc神经元中PKA介导的分子靶标是否失调，如果发生，是否有助于寻找可卡因。我们测量了禁欲7天后背囊（dm）PFC和突触前标记突触素I（Ser9，Ser62 / 67，Ser603）中cAMP反应元件结合蛋白（Ser133）和GluA1（Ser845）的磷酸化来自可卡因SA，有或没有提示诱导的可卡因寻求。

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