Russell Shayla E, Puttick Daniel J, Sawyer Allison M, Potter David N, Mague Stephen, Carlezon William A, Chartoff Elena H
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478.
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478
J Neurosci. 2016 May 25;36(21):5748-62. doi: 10.1523/JNEUROSCI.2875-12.2016.
Dependence is a hallmark feature of opiate addiction and is defined by the emergence of somatic and affective withdrawal signs. The nucleus accumbens (NAc) integrates dopaminergic and glutamatergic inputs to mediate rewarding and aversive properties of opiates. Evidence suggests that AMPA glutamate-receptor-dependent synaptic plasticity within the NAc underlies aspects of addiction. However, the degree to which NAc AMPA receptors (AMPARs) contribute to somatic and affective signs of opiate withdrawal is not fully understood. Here, we show that microinjection of the AMPAR antagonist NBQX into the NAc shell of morphine-dependent rats prevented naloxone-induced conditioned place aversions and decreases in sensitivity to brain stimulation reward, but had no effect on somatic withdrawal signs. Using a protein cross-linking approach, we found that the surface/intracellular ratio of NAc GluA1, but not GluA2, increased with morphine treatment, suggesting postsynaptic insertion of GluA2-lacking AMPARs. Consistent with this, 1-naphthylacetyl spermine trihydrochloride (NASPM), an antagonist of GluA2-lacking AMPARs, attenuated naloxone-induced decreases in sensitivity to brain stimulation reward. Naloxone decreased the surface/intracellular ratio and synaptosomal membrane levels of NAc GluA1 in morphine-dependent rats, suggesting a compensatory removal of AMPARs from synaptic zones. Together, these findings indicate that chronic morphine increases synaptic availability of GluA1-containing AMPARs in the NAc, which is necessary for triggering negative-affective states in response to naloxone. This is broadly consistent with the hypothesis that activation of NAc neurons produces acute aversive states and raises the possibility that inhibiting AMPA transmission selectively in the NAc may have therapeutic value in the treatment of addiction.
Morphine dependence and withdrawal result in profound negative-affective states that play a major role in the maintenance of addiction. However, the underlying neurobiological mechanisms are not fully understood. We use a rat model of morphine dependence to show that GluA1 subunits of AMPA glutamate receptors in the nucleus accumbens (NAc), a brain region critical for modulating affective states, are necessary for aversive effects of morphine withdrawal. Using biochemical methods in NAc tissue, we show that morphine dependence increases cell surface expression of GluA1, suggesting that neurons in this area are primed for increased AMPA receptor activation upon withdrawal. This work is important because it suggests that targeting AMPA receptor trafficking and activation could provide novel targets for addiction treatment.
依赖性是阿片类药物成瘾的一个标志性特征，其定义为躯体和情感性戒断症状的出现。伏隔核（NAc）整合多巴胺能和谷氨酸能输入，以介导阿片类药物的奖赏性和厌恶性特性。有证据表明，NAc内依赖α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体的突触可塑性是成瘾的基础。然而，NAc中的AMPA受体（AMPARs）对阿片类药物戒断的躯体和情感症状的影响程度尚未完全了解。在此，我们表明，向吗啡依赖大鼠的NAc壳内微量注射AMPAR拮抗剂NBQX可预防纳洛酮诱导的条件性位置厌恶以及对脑刺激奖赏的敏感性降低，但对躯体戒断症状没有影响。使用蛋白质交联方法，我们发现，吗啡处理后，NAc中谷氨酸受体1（GluA1）而非谷氨酸受体2（GluA2）的表面/细胞内比率增加，这表明缺乏GluA2的AMPARs插入到了突触后。与此一致的是，缺乏GluA2的AMPARs的拮抗剂1-萘乙酰精胺三盐酸盐（NASPM）减弱了纳洛酮诱导的对脑刺激奖赏敏感性的降低。纳洛酮降低了吗啡依赖大鼠中NAc GluA1的表面/细胞内比率和突触体膜水平，这表明从突触区域对AMPARs进行了代偿性清除。总之，这些发现表明，慢性吗啡增加了NAc中含GluA1的AMPARs的突触可用性，这是触发对纳洛酮的负性情感状态所必需的。这与NAc神经元的激活产生急性厌恶性状态的假设大致一致，并增加了在NAc中选择性抑制AMPA传递可能在成瘾治疗中具有治疗价值的可能性。
吗啡依赖和戒断会导致严重的负性情感状态，这在成瘾的维持中起主要作用。然而，潜在的神经生物学机制尚未完全了解。我们使用吗啡依赖的大鼠模型表明，伏隔核（NAc）中AMPA谷氨酸受体的GluA1亚基，这一对于调节情感状态至关重要的脑区，对于吗啡戒断的厌恶性效应是必需的。通过对NAc组织使用生化方法，我们表明吗啡依赖增加了GluA1的细胞表面表达，这表明该区域的神经元在戒断时准备好增加AMPAR的激活。这项工作很重要，因为它表明靶向AMPAR的运输和激活可为成瘾治疗提供新的靶点。
