Bossert Jennifer M, Adhikary Sweta, St Laurent Robyn, Marchant Nathan J, Wang Hui-Ling, Morales Marisela, Shaham Yavin
Behavioral Neuroscience Branch, IRP-NIDA, NIH, Baltimore, MD, USA.
Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Australia.
Psychopharmacology (Berl). 2016 May;233(10):1991-2004. doi: 10.1007/s00213-015-4060-5. Epub 2015 Sep 7.
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. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement. The ventral subiculum (vSub) sends glutamate projections to NAc shell and vmPFC. Here, we determined whether these projections contribute to context-induced reinstatement.
We trained rats to self-administer heroin (0.05-0.1 mg/kg/infusion) for 3 h per day for 12 days; drug infusions were paired with a discrete tone-light cue. Lever pressing in the presence of the discrete cue was subsequently extinguished in a different context. We then tested the rats for reinstatement in the heroin- and extinction-associated contexts under extinction conditions. We combined Fos with the retrograde tracer Fluoro-Gold (FG) to determine projection-specific activation during the context-induced reinstatement tests. We also used anatomical disconnection procedures to determine whether the vSub → NAc shell and vSub → vmPFC projections are functionally involved in this reinstatement.
Exposure to the heroin but not the extinction context reinstated lever pressing. Context-induced reinstatement of heroin seeking was associated with increased Fos expression in vSub neurons, including those projecting to NAc shell and vmPFC. Anatomical disconnection of the vSub → NAc shell projection, but not the vSub → vmPFC projection, decreased this reinstatement.
Our data indicate that the vSub → NAc shell glutamatergic projection, but not the vSub → vmPFC projection, contributes to context-induced reinstatement of heroin seeking.
在人类中，接触先前与海洛因使用相关的情境可引发复吸。在大鼠中，在不同情境下药物强化反应消退后，接触与海洛因配对的情境会恢复海洛因觅求行为。我们先前证明，腹内侧前额叶皮质（vmPFC）向伏隔核（NAc）壳的投射在这种恢复中起作用。腹侧海马下脚（vSub）向NAc壳和vmPFC发送谷氨酸能投射。在此，我们确定这些投射是否促成情境诱导的恢复。
我们训练大鼠每天自我注射海洛因（0.05 - 0.1毫克/千克/次），持续12天，每天3小时；药物注射与离散的音调 - 灯光提示配对。随后在不同情境下，在离散提示出现时的杠杆按压行为被消退。然后，我们在消退条件下，在与海洛因和消退相关的情境中测试大鼠的恢复情况。我们将Fos与逆行示踪剂荧光金（FG）结合，以确定情境诱导的恢复测试期间投射特异性激活情况。我们还使用解剖学切断程序来确定vSub→NAc壳和vSub→vmPFC投射是否在功能上参与这种恢复。
接触海洛因情境而非消退情境恢复了杠杆按压行为。情境诱导的海洛因觅求恢复与vSub神经元中Fos表达增加有关，包括那些投射到NAc壳和vmPFC的神经元。vSub→NAc壳投射的解剖学切断，但不是vSub→vmPFC投射，减少了这种恢复。
我们的数据表明，vSub→NAc壳谷氨酸能投射而非vSub→vmPFC投射促成情境诱导的海洛因觅求恢复。
