Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking.
Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking.
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DOI：
10.1523/jneurosci.0005-12.2012
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发表时间：
2012-04-04
期刊：
影响因子：
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通讯作者：
Shaham Y
中科院分区：
文献类型：
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作者：
Bossert JM;Stern AL;Theberge FR;Marchant NJ;Wang HL;Morales M;Shaham Y
在人类中，暴露于以前与海洛因使用有关的环境可能会引起复发。在大鼠中，暴露于海洛因配对的背景下，在不同的背景下，药物强化的反应消失后恢复海洛因寻求。这种效应通过抑制核壳中的谷氨酸或多巴胺传递或腹内侧前额叶皮层（vmPFC）的失活而减弱。在这里，我们使用了一个解剖不对称断开程序，以证明从vmPFC的神经元投射之间的相互作用，以arrhebens壳和当地多巴胺D1突触后受体有助于上下文诱导的恢复海洛因寻求。我们还将神经元活动的标记物Fos与逆行示踪剂Fluoro-Gold（FG）相结合，以评估上下文诱导的恢复期间该通路的激活。大鼠接受了12天的自我注射海洛因的训练;药物输注与离散的音调-灯光提示配对。杠杆压随后熄灭在非药物相关的背景下，在离散的线索的存在。然后，在灭绝条件下，在海洛因或海洛因相关的背景下对大鼠进行测试。蝇蕈醇+巴氯芬注射到一个半球的vmPFC和D1-家族受体拮抗剂SCH 23390注射到对侧或同侧海马壳减少上下文诱导的恢复。将蝇蕈醇+巴氯芬单侧注射到vmPFC或将SCH 23390单侧注射到海马壳中没有影响。上下文诱导的恢复与vmPFC神经元中Fos表达增加相关，包括那些投射到小脑壳的神经元，同侧投射中的双标记比对侧投射中的双标记更高。我们的研究结果表明，从腹侧mPFC的approximatergic预测的激活，以前牵连在抑制可卡因复吸，促进海洛因复吸。
In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (vmPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from vmPFC to accumbens shell and local dopamine D1 postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold (FG) to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 days; drug infusions were paired with a discrete tone-light cue. Lever-pressing was subsequently extinguished in a non-drug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol+baclofen into vmPFC in one hemisphere and D1-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol+baclofen into vmPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in vmPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.