Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA.
Center for Collaborative Biotechnology, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA.
Neuropharmacology. 2018 Jan;128:293-300. doi: 10.1016/j.neuropharm.2017.10.024. Epub 2017 Oct 20.
The incubation of cue-reinforced cocaine-seeking coincides with increased extracellular glutamate within the ventromedial prefrontal cortex (vmPFC). The vmPFC is comprised of two subregions that oppositely regulate drug-seeking, with infralimbic (IL) activity inhibiting, and prelimibic (PL) activity facilitating, drug-seeking. Thus, we hypothesized that increasing and decreasing endogenous glutamate within the IL would attenuate and potentiate, respectively, cue-reinforced drug-seeking behavior, with the converse effects observed upon manipulations of endogenous glutamate within the PL. Male Sprague-Dawley rats were trained to self-administer cocaine (0.25 mg/infusion; 6 h/day X 10 days), the delivery of which was signaled by a tone-light cue. Rats were then subdivided into 3 or 30 day withdrawal groups. For testing, rats were microinjected with vehicle, 20 mM of the mGlu2/3 agonist LY379268 (to lower endogenous glutamate), or 300 μM of the excitatory amino acid transporter inhibitor threo-β-benzyloxyaspartate (TBOA; to raise endogenous glutamate) into either the IL or PL (0.5 μl/side) and then given a 30-min test for cue-reinforced drug-seeking. Vehicle-infused rats exhibited incubated responding on the cocaine-associated lever. Neither LY379268 nor TBOA altered behavior at 3 days withdrawal, indicating that glutamate within neither subregion regulates cue-reinforced drug-seeking during early withdrawal. At 30 days withdrawal, intra-PL LY379268 microinjection significantly decreased drug-seeking behavior, while the effect was more modest when infused intra-IL. Interestingly, intra-IL TBOA attenuated incubated drug-seeking during protracted withdrawal, but did not affect behavior when infused intra-PL. These results argue that glutamate release within the PL in response to drug-seeking likely drives the manifestation of incubated cocaine-seeking during protracted withdrawal.
在腹内侧前额皮质（vmPFC）内，与可卡因寻求相关的线索会引发细胞外谷氨酸的增加。vmPFC 由两个相反调节药物寻求的亚区组成，扣带回下（IL）的活动抑制，而扣带回前（PL）的活动促进药物寻求。因此，我们假设，在 IL 内增加和减少内源性谷氨酸分别会减弱和增强与线索相关的可卡因寻求行为，而在 PL 内操纵内源性谷氨酸会产生相反的效果。雄性 Sprague-Dawley 大鼠接受可卡因（0.25 mg/次；6 小时/天 X 10 天）自我给药训练，可卡因的给药由声音光线索信号表示。然后，大鼠被分为 3 天或 30 天戒断组。在测试中，大鼠接受 vehicle、20 mM mGlu2/3 激动剂 LY379268（降低内源性谷氨酸）或 300 μM 兴奋性氨基酸转运体抑制剂 threo-β-苯甲氧基天冬氨酸（TBOA；升高内源性谷氨酸）的单侧微量注射进入 IL 或 PL（0.5 μl/侧），然后进行 30 分钟的线索增强药物寻求测试。接受 vehicle 注射的大鼠在可卡因相关的杠杆上表现出孵育反应。在 3 天戒断时，LY379268 或 TBOA 均未改变行为，表明在早期戒断期间，两个亚区中的谷氨酸均不调节线索增强的药物寻求。在 30 天戒断时，PL 内 LY379268 微量注射显著降低药物寻求行为，而在 IL 内注射时效果更为温和。有趣的是，IL 内 TBOA 在长期戒断期间减轻了孵育的药物寻求，但在 PL 内注射时对行为没有影响。这些结果表明，在药物寻求期间，PL 内的谷氨酸释放可能导致长期戒断期间孵育可卡因寻求的表现。
