Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, USA.
J Neurosci. 2012 Apr 4;32(14):4982-91. doi: 10.1523/JNEUROSCI.0005-12.2012.
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 (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) 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 to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-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 ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC 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.
在人类中，暴露于先前与海洛因使用相关的环境中会引发复发。在大鼠中，在不同环境中消退药物强化反应后，暴露于海洛因配对的环境中会重新引发海洛因寻求。这一效应可通过抑制伏隔核壳中的谷氨酸或多巴胺传递，或通过抑制腹内侧前额叶皮层（mPFC）来减弱。在这里，我们使用解剖学上不对称的断开连接程序来证明腹侧 mPFC 到伏隔核壳的谷氨酸能投射与局部多巴胺 D1 突触后受体之间的相互作用有助于情境诱导的海洛因寻求的恢复。我们还结合神经元活动标志物 Fos 与逆行示踪剂 Fluoro-Gold 来评估在这种途径中在情境诱导的海洛因寻求恢复过程中的激活。大鼠接受了 12 天的海洛因自我给药训练；药物输注与离散的音-光线索配对。随后，在存在离散线索的情况下，在非药物相关环境中消退了按压杠杆。然后，在海洛因或消退相关环境中在消退条件下测试大鼠。在一侧腹侧 mPFC 中注射 muscimol + baclofen，在对侧或同侧伏隔核壳中注射 D1-家族受体拮抗剂 SCH 23390 ，可减少情境诱导的海洛因寻求恢复。单侧注射 muscimol + baclofen 到腹侧 mPFC 或 SCH 23390 到伏隔核壳均无影响。情境诱导的海洛因寻求恢复与腹侧 mPFC 神经元中 Fos 表达的增加有关，包括那些投射到伏隔核壳的神经元，同侧投射的双标记比对侧投射的高。我们的结果表明，先前与可卡因复发抑制有关的腹侧 mPFC 到伏隔核壳的谷氨酸能投射的激活促进了海洛因的复发。
