Cav1.2 L-type Ca²⁺ channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels.
Cav1.2 L-type Ca²⁺ channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels.
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DOI：
10.1523/jneurosci.2315-11.2011
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发表时间：
2011-09-21
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通讯作者：
Rajadhyaksha AM
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作者：
Schierberl K;Hao J;Tropea TF;Ra S;Giordano TP;Xu Q;Garraway SM;Hofmann F;Moosmang S;Striessnig J;Inturrisi CE;Rajadhyaksha AM
AMPA受体（AMPAR）的可塑性在多巴胺能通路中的多巴胺能突触已被牵连在持续的可卡因诱导的行为反应，然而，这些变化背后的确切机制仍然未知。利用可卡因致敏作用，我们检测了GluA 1在关键残基丝氨酸（S）845和S831处的磷酸化，以及预先暴露于可卡因的小鼠的脑髓核（NAc）中GluA 1细胞表面水平，以及脑特异性Cav1.2和Cav1.3 L型Ca 2+通道（LTCC）的作用。我们发现更高的基础水平的S845磷酸-GluA 1（P-GluA 1）和细胞表面GluA 1在NAc后，长期戒断可卡因暴露，变化发生独立的LTCC。相反，我们发现，可卡因激发可卡因致敏反应的表达增加S831 P-GluA 1，进一步增加表面GluA 1超过更高的基础水平。内NAc药理学操作表明，Cav1.2激活的CaM激酶II（CaMKII）介导可卡因诱导的S831 P-GluA 1增加，Cav1.2激活的CaMKII和细胞外信号调节激酶2（ERK 2）介导特异性致敏反应的GluA 1细胞表面水平增加。使用表达Cav1.3和ERK 2 siRNA的腺相关病毒载体（AAV）的实验进一步表明，NAc中Cav1.2通路的募集依赖于腹侧被盖区（VTA）Cav1.3 LTCC和ERK 2。综上所述，这些结果确定了介导可卡因诱导的NAc中AMPAR可塑性的候选途径，并提供了一种将多巴胺，LTCCs和GluA 1可塑性与可卡因诱导的持续行为变化联系起来的机制。
AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization we have examined phosphorylation of GluA1 at key residues serine (S)845 and S831, as well as GluA1 cell surface levels in the nucleus accumbens (NAc) of cocaine pre-exposed mice and the role of brain-specific Cav1.2 and Cav1.3 L-type Ca2+ channels (LTCCs), therein. We find higher basal levels of S845 phospho-GluA1 (P-GluA1) and cell surface GluA1 in the NAc following protracted withdrawal from cocaine exposure, changes that occur independently of LTCCs. In contrast, we find that a cocaine challenge that elicits expression of the cocaine sensitized response increases S831 P-GluA1 that further increases surface GluA1 beyond the higher basal levels. Intra-NAc pharmacological manipulations indicate that the Cav1.2-activated CaM kinase II (CaMKII) mediates cocaine-induced increase in S831 P-GluA1 and that both Cav1.2-activated CaMKII and extracellular signal-regulated kinase 2 (ERK2) mediate the increase in GluA1 cell surface levels specific to the sensitized response. Experiments using adenoassociated viral vectors (AAV) expressing Cav1.3 and ERK2 siRNA further indicate that recruitment of the Cav1.2 pathway in the NAc is dependent on ventral tegmental area (VTA) Cav1.3 LTCCs and ERK2. Taken together, these results identify candidate pathways that mediate cocaine-induced AMPAR plasticity in the NAc and provide a mechanism linking dopamine, LTCCs and GluA1 plasticity to cocaine-induced persistent behavioral changes.