Using the in vitro cerebellar slice preparation from young rats (8–12 days old), AMPA produced in addition to dark cell degeneration (DCD), an edematous type of toxicity (edematous damage; ED) in a minority (35%) of Purkinje cells. The intent of this study was to evaluate whether AMPA receptor desensitization is a primary factor that governs the type of toxicity induced by AMPA in the in vitro cerebellar slice preparation. Both the competitive and noncompetitive AMPA antagonists CNQX and GYKI 52466, respectively, blocked ED when given during the entire protocol (30 min AMPA exposure followed by 90 min of recovery). Cyclothiazide (100 μM) and diazoxide (500 μM), two antagonists of AMPA receptor desensitization reversed DCD and unveiled a fulminating ED. Lowering Na⁺ and lowering Cl⁻ proved effective in blocking ED, whereas removal of Ca²⁺ proved to be ineffective. Kainate (KA) (30–100 μM) produced only 50% as much ED as AMPA. This study indicates that AMPA can elicit more than one type of degeneration in the same neuronal population and that a primary governing factor in determining which toxicity is expressed seems to be the ability of AMPA receptors to desensitize.