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bioRxiv · 10.1101/2025.05.21.655393

AMPA receptor activation within the prelimbic cortex is necessary for incubated cocaine-craving

Sanchez, L. L. H.·Tadros, M. G.·Doan, H. H. T.·Chaudhari, S. R.·Vo, S. V.·Li, T. L.·James, P. B.·Na, A. Y.·Cano, F. J.·Szumlinski, K. K.
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Abstract

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 receptors (AMPARs). To investigate the role of mPFC 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 AMPAR antagonist NBQX (0 or 1 {micro}g/0.5 {micro}l per side), followed by 30-min tests for cue-reinforced 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. 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 AMPARs within the PL in driving incubated cocaine-craving and suggest that AMPARs located within the IL may be involved also in sucrose-craving selectively in males.

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Sanchez, L. L. H., Tadros, M. G., Doan, H. H. T., Chaudhari, S. R., Vo, S. V., Li, T. L., James, P. B., Na, A. Y., Cano, F. J., Szumlinski, K. K.. 2025-05-23. AMPA receptor activation within the prelimbic cortex is necessary for incubated cocaine-craving. https://doi.org/10.1101/2025.05.21.655393

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