Huerta Sanchez Laura L, Tadros Mirette G, Doan Hoa H T, Vo Sylvie V, Chaudhari Sanil R, Li Taylor L, James Peter B, Na Audrey Y, Cano Fernando J, Kippin Tod E, Szumlinski Karen K
Department of Psychological and Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United States.
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, United States.
Front Psychiatry. 2025 Aug 14;16:1627477. doi: 10.3389/fpsyt.2025.1627477. eCollection 2025.
The incubation of craving is a behavioral phenomenon in which cue-elicited craving increases during a period of drug abstinence. Incubated cocaine-craving is associated with increased extracellular glutamate within the medial prefrontal cortex (mPFC) and this release, particularly within the prelimbic (PL) subregion, is necessary for incubated cocaine-craving. A potential candidate mediating these incubation-driving effects of glutamate release within the PL are alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
To investigate the role of mPFC AMPA receptors (AMPARs) in incubated craving, male and female Sprague-Dawley rats were trained to self-administer cocaine for 6 h/day for 10 consecutive days. Either during early or later withdrawal, rats were infused intra-PL with the AMPA/kainate receptor antagonist NBQX (0 or 1 µg/0.5 µl per side), followed by 30-min tests for cue-induced responding. Immunoblotting was also conducted to relate the expression of incubated cocaine- and sucrose-craving to AMPAR subunit expression within mPFC subregions.
Intra-PL NBQX blocked incubated craving expressed in late, but not early, withdrawal. In contrast, an intra-PL NBQX infusion increased cue-induced cocaine-seeking in female rats tested in early withdrawal. No incubation-related changes in AMPAR subunit expression were detected within the PL or IL of rats of either sex and no estrus-associated changes in subunit expression were detected in female rats exhibiting incubated cocaine-craving. In contrast, elevated GluA1 expression was observed within the IL of male rats exhibiting an incubation of sucrose-craving.
Together, these findings indicate a necessary role for AMPAR/kainate receptors within the PL in driving incubated cocaine-craving and suggest that AMPAR/kainate receptors located within the IL may be involved also in sucrose-craving selectively in males.
渴求的潜伏期是一种行为现象，即线索诱发的渴求在药物戒断期间会增加。潜伏期可卡因渴求与内侧前额叶皮质（mPFC）细胞外谷氨酸增加有关，这种释放，尤其是在前边缘（PL）亚区域内的释放，是潜伏期可卡因渴求所必需的。介导PL内谷氨酸释放的这些潜伏期驱动效应的一个潜在候选者是α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体。
为了研究mPFC AMPA受体（AMPARs）在潜伏期渴求中的作用，将雄性和雌性Sprague-Dawley大鼠连续10天每天训练6小时自行注射可卡因。在早期或晚期戒断期间，给大鼠PL内注射AMPA/海人藻酸受体拮抗剂NBQX（每侧0或1μg/0.5μl），然后进行30分钟的线索诱导反应测试。还进行了免疫印迹，以将潜伏期可卡因和蔗糖渴求的表达与mPFC亚区域内AMPAR亚基的表达相关联。
PL内注射NBQX可阻断晚期而非早期戒断时出现的潜伏期渴求。相比之下，在早期戒断时接受测试的雌性大鼠中，PL内注射NBQX会增加线索诱导的可卡因寻求行为。在任何性别的大鼠的PL或IL内均未检测到与潜伏期相关的AMPAR亚基表达变化，在表现出潜伏期可卡因渴求的雌性大鼠中也未检测到与发情期相关的亚基表达变化。相比之下，在表现出蔗糖渴求潜伏期的雄性大鼠的IL内观察到GluA1表达升高。
总之，这些发现表明PL内的AMPAR/海人藻酸受体在驱动潜伏期可卡因渴求中起必要作用，并表明位于IL内的AMPAR/海人藻酸受体也可能仅在雄性中选择性地参与蔗糖渴求。
