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It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure\u2010induced respiratory and electrocerebral dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala\u2010kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure\u2010induced death; however, counterintuitively, animals in these conditions that did not experience seizure\u2010induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The unexpected effect of high doses of adenosine antagonists on seizure\u2010induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure\u2010induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18059","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T18:33:26Z","timestamp":1720550006000},"page":"2812-2826","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effect of adenosinergic manipulations on amygdala\u2010kindled seizures in mice: Implications for sudden unexpected death in epilepsy"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8750-6810","authenticated-orcid":false,"given":"Benton S.","family":"Purnell","sequence":"first","affiliation":[{"name":"Interdisciplinary Graduate Program in Neuroscience University of Iowa  Iowa City Iowa USA"},{"name":"Iowa Neuroscience Institute University of Iowa  Iowa 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