Prefrontal Cortical Mechanisms Underlying BDNF's Ability to Suppress Cocaine-see

此药应用于干预早期戒断可卡因的自我给药抑制。 持续的可卡因寻求和潜在的神经适应。我们将这种方法建立在 哪种脑源性神经营养因子(BDNF)注入大鼠背内侧前额叶皮质(DmPFC) 大鼠在最后一次可卡因自我给药后立即抑制ERK中的可卡因寻求 MAP的激酶依赖方式。脑源性神经营养因子逆转可卡因诱导的ERK和CREB去磷酸化 在可卡因自我给药结束后2小时内给予dmPFC。如果BDNF管理在以下时间延迟 自我给药结束时，对线索诱导的可卡因寻求没有影响。因此，在比赛结束后的头几个小时 结束反复的可卡因暴露似乎对BDNF的行动至关重要。我们假设这个时机是 与ERK和CREB去磷酸化的暂时性有关，这种去磷酸化在22小时后恢复 可卡因自我管理的终结。此外，本提案中提供的初步数据表明， 纹状体富集型酪氨酸磷酸酶(STEP)在可卡因SA诱导dmPFC中ERK去磷酸化中的作用。 在此基础上，我们将研究突触活动(目标1和2)和激酶-2的作用。 磷酸酶平衡(目标3和4)在PFC内BDNF使ERK磷酸化正常化能力中的作用 DmPFC，并抑制有可卡因SA病史的大鼠寻找可卡因的行为。

This application focuses on intervention during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and underlying neuroadaptations. We have based this approach on findings in which brain-derived neurotrophic factor (BDNF) infused into the dorsomedial prefrontal cortex (dmPFC) of rats immediately after the last cocaine self-administration session suppresses cocaine-seeking in an ERK MAP kinase-dependent manner. BDNF reverses cocaine-induced dephosphorylation of ERK and CREB in the dmPFC within 2 hr after the end of cocaine self-administration. If BDNF administration is delayed after the end of self-administration, it has no effect on cue-induced cocaine-seeking. Thus, the first few hr after the end of repeated cocaine exposure appear to be critical for BDNF's actions. We hypothesize that this timing is linked to the transient nature of ERK and CREB dephosphorylation (or "shutoff') that recovers by 22 hr after the end of cocaine self-administration. Further, preliminary data presented in this proposal implicate the striatal-enriched tyrosine phosphatase (STEP) in cocaine SA-induced ERK dephosphorylation in the dmPFC. Based on this foundation, we will investigate the role of synaptic activity (Aim 1 and 2) and kinase- phosphatase balance (Aims 3 and 4) in the ability of intra-PFC BDNF to normalize ERK phosphorylation in dmPFC during early withdrawal and suppress cocaine-seeking in rats with a cocaine SA history.