1School of Biomedical Sciences and Pharmacy, and the Centre for Translational Neuroscience and Mental Health Research, University of Newcastle,Callaghan, NSW 2308, Australia.
J Physiol. 2012 Aug 15;590(16):3677-89. doi: 10.1113/jphysiol.2012.230268. Epub 2012 May 28.
The hypothalamus is a critical controller of homeostatic responses and plays a fundamental role in reward-seeking behaviour. Recently, hypothalamic neurones in the perifornical/lateral hypothalamic area (PF/LHA) have also been implicated in drug-seeking behaviour through projections to extra-hypothalamic sites such as the ventral tegmental area. For example, a population of neurones that expresses the peptide orexin has been strongly implicated in addiction-relevant behaviours. To date, the effect of addictive drugs on synaptic properties in the hypothalamus remains largely unexplored. Previous studies focusing on the PF/LHA neurones, however, have shown that the orexin system exhibits significant plasticity in response to food or sleep restriction. This neuroadaptive ability suggests that PF/LHA neurones could be highly susceptible to modifications by drug exposure. Here, we sought to determine whether cocaine produces synaptic plasticity in PF/LHA neurones. Whole-cell patch-clamp techniques were used to examine the effects of experimenter-administered (passive) or self-administered (SA) cocaine on glutamatergic synaptic transmission in PF/LHA neurones. These experiments demonstrate that both passive and SA cocaine exposure increases miniature excitatory postsynaptic current (mEPSC) frequency in PF/LHA neurones. In addition, SA cocaine reduced the paired-pulse ratio but the AMPA/NMDA ratio of evoked excitatory inputs was unchanged, indicative of a presynaptic locus for synaptic plasticity. Dual-labelling for orexin and excitatory inputs using the vesicular glutamate transporter (VGLUT2), showed that passive cocaine exposure increased VGLUT2-positive appositions onto orexin neurones. Further, a population of recorded neurones that were filled with neurobiotin and immunolabelled for orexin confirmed that increased excitatory drive occurs in this PF/LHA population. Given the importance of the PF/LHA and the orexin system in modulating drug addiction, we suggest that these cocaine-induced excitatory synapse-remodelling events within the hypothalamus may contribute to persistence in drug-seeking behaviour and relapse.
下丘脑是体内平衡反应的关键控制器，在寻求奖励行为中起着基本作用。最近，外侧下丘脑/穹窿周区（PF/LHA）的下丘脑神经元也通过向腹侧被盖区等下丘脑外部位投射而参与觅药行为。例如，表达肽类食欲素的神经元群体强烈参与与成瘾相关的行为。迄今为止，成瘾药物对下丘脑突触特性的影响在很大程度上仍未得到探索。然而，以前的研究集中在 PF/LHA 神经元上，表明食欲素系统在响应食物或睡眠限制时表现出显著的可塑性。这种神经适应性能力表明，PF/LHA 神经元可能非常容易受到药物暴露的改变。在这里，我们试图确定可卡因是否会在 PF/LHA 神经元中产生突触可塑性。全细胞膜片钳技术用于检查实验者给予（被动）或自我给予（SA）可卡因对 PF/LHA 神经元谷氨酸能突触传递的影响。这些实验表明，被动和 SA 可卡因暴露均增加了 PF/LHA 神经元中微小兴奋性突触后电流（mEPSC）的频率。此外，SA 可卡因降低了成对脉冲比，但诱发兴奋性输入的 AMPA/NMDA 比不变，表明突触可塑性的突触前位置。使用囊泡谷氨酸转运体（VGLUT2）对食欲素和兴奋性输入进行双重标记，表明被动可卡因暴露增加了 VGLUT2 阳性突触前对食欲素神经元的接触。此外，用神经生物素填充并免疫标记食欲素的记录神经元的一部分证实，这种 PF/LHA 群体中存在增加的兴奋性驱动。鉴于 PF/LHA 和食欲素系统在调节药物成瘾中的重要性，我们认为，这些可卡因诱导的下丘脑内兴奋性突触重塑事件可能有助于持续的觅药行为和复发。
