Operant leverpressing and wheelrunning were differentially reduced by PAPP (p-aminopropiophenone)-induced methemoglobinemia

Cyanide is a potent toxin that binds to cytochrome oxidase blocking electron transfer and the synthesis of adenosine triphosphate (ATP). Many antidotes to cyanide poisoning oxidize hemoglobin to methemoglobin (metHb), which serves as a scavenger of the cyanide anion. However, sufficiently high levels of metHb can be toxic because metHb cannot bind O2 until it is reduced. The purpose of the proposed study was twofold: (1) Characterize the time course of metHb formation for different doses of p-aminopropiophenone (PAPP), a drug that oxidizes hemoglobin and can be used as an antidote to cyanide intoxication; and (2) Determine whether the effort of an operant response affects the behavioral toxicity of metHb, since more effortful responses presumably are more energetically demanding. In Experiment I, the oral metHb kinetics of p-aminopropiophenone (PAPP) were studied; four doses of PAPP (1, 5, 10, and 20 mg/kg) or the vehicle, polyethylene glycol 200 (PEG200), were delivered via a gavage tube to separate groups of rats. In Experiment II, rats were trained to press a lever or run in an activity wheel at any time during a 12-hour light/dark cycle for their entire daily food intake; five presses or turns were required for the delivery of each food pellet. The same doses of PAPP were delivered p.o. shortly before the onset of darkness, 2100 h. Results from Exp I showed that PAPP induced a dose-dependent rapid increase and relatively slower exponential-like decline in metHb concentration. In Exp. II, the same doses of PAPP induced a dose-dependent reduction in hourly outputs of leverpresses and wheelturns however; wheelturns were reduced significantly more than leverpresses. When the best-fitting metHb curves from Experiment I were superimposed on the time scale for outputs of wheelturns and leverpresses, reduction of output was inversely related to the kinetics of metHb formation. These findings are consistent with the conclusion that PAPP-induced metHb formation reduced the output of wheelrunning more than leverpressing because the more energetically demanding response of wheelrunning was more affected by metHb induced hypoxemia. Furthermore, these data suggest that although certain longacting metHb formers might be useful prophylactics for warfighters, it will be critical to determine the energetic loads of required battlefield activities because even low (10%) therapeutic metHb levels might impair the performance of those activities.