Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats.
Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats.
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DOI：
10.1007/s00213-012-2681-5
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发表时间：
2013-04
影响因子：
3.4
通讯作者：
Aston-Jones, Gary
中科院分区：
文献类型：
--
作者：
Mahler, Stephen V.;Smith, Rachel J.;Aston-Jones, Gary
关键词：
谷氨酸和食欲素/下丘脑红素系统参与了巴甫洛夫线索触发的药物寻找。在这里，我们问食欲素和谷氨酸是否在腹侧被盖区(VTA)内相互作用，以促进大鼠自我给药范式中熄灭的可卡因寻找的恢复。我们首次发现，双侧VTA微量注射食欲素1受体拮抗剂SB-334867(SB)或AMPA和NMDA型谷氨酸受体拮抗剂CNQX/AP-5的鸡尾酒可以减少线索诱发的可卡因寻找的恢复。相反，这两种微量注射或全身注射SB都不会减少可卡因诱导的恢复。此外，单侧VTA OX1R阻断联合对侧VTA谷氨酸阻断减弱了线索诱导的恢复，表明VTA增食欲素和谷氨酸同时是线索诱导恢复所必需的。我们进一步探讨了VTA中谷氨酸作用的受体特异性，发现CNQX而不是AP-5呈剂量依赖性地减弱线索诱导的恢复，表明这种类型的可卡因寻找需要AMPA而不是NMDA受体传递。鉴于OX1和AMPA受体在VTA中对线索诱导的可卡因寻找具有必要的作用，我们假设这些信号通路在这一行为中相互作用。我们发现，AMPA受体的正变构调节剂PepA完全逆转了SB诱导的恢复行为的衰减。VTA内注射Pepa本身并不改变CUE诱导的恢复，这表明用这种药物增强AMPA活性专门补偿OX1R阻断，而不是简单地诱导或增强恢复本身。这些发现表明，线索诱导而不是可卡因诱导的可卡因寻找的恢复依赖于VTA中的食欲素和AMPA受体的相互作用。
Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking. Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm. We first found that bilateral VTA micro-injections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself. These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.
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影响因子：
7.6
作者：
Harris, GC;Aston-Jones, G
通讯作者：
Aston-Jones, G
AMPA受体变构调节剂的插曲选择性的分子机制和亚铁识别：与PEPA的复合物中Glua2和Glua3的结构。
影响因子：
2.9
作者：
Ahmed, Ahmed H.;Ptak, Christopher P.;Oswald, Robert E.
通讯作者：
Oswald, Robert E.
影响因子：
5.3
作者：
Borgland, SL;Malenka, RC;Bonci, A
通讯作者：
Bonci, A
影响因子：
16.2
作者：
Borgland, SL;Taha, SA;Bonci, A
通讯作者：
Bonci, A
DOI：
10.1073/pnas.0507480102
发表时间：
2005-12-27
影响因子：
11.1
作者：
Boutrel, B;Kenny, PJ;de Lecea, L
通讯作者：
de Lecea, L