Animal models of neurovascular uncoupling (NVU) would be important tools for developing drugs in neurodegenerative disorders. Pharmacologically induced NVU was established in mice [Tarantini et al., 2015] but only preliminary results are available in rats [Varga et al., 2022]. In the current study we attempted to evoke NVU in a translationally relevant rat population.We used 28-month-old male Long-Evans rats with learning history and stable performance in 5-choice serial reaction time task (5-CSRTT). Morris water-maze (MWM), pot jumping, and touchscreen pairwise discrimination. NVU was induced by a “cocktail” of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (2.5 mg/kg), L-NG-nitroarginine methyl ester (5 mg/kg) and indomethacin (0.5 mg/kg), injected intraperitoneally twice daily for 12 days. Learning performance of the animals was measured in the above-mentioned assays completed with Y-maze spontaneous alternation and tail cuff blood pressure measurements. NVU was assayed by measuring cerebral blood-flow (CBF) in the barrel cortex while the contralateral whisker pad was stimulated. Prostaglandin E2 (PGE2) and 11,12-epoxyeicosatrienoic acid (EET) levels were determined in brain, small intestine and kidney tissue samples postmortem.In MWM and 5-CSRTT significant differences were observed between groups and a 28% decrease (non-significant) was detected in CBF. Brain PGE2 level significantly decreased by 31%. No significant changes were measured in the other assays. Notably, the cocktail-treated animals showed decreased food-intake with consequent body-weight loss.In conclusion, despite the apparent toxicity of the uncoupling cocktail, moderate effects could only be observed in the learning performance of the animals. Further trials are needed to develop an applicable NVU model in the rat.