Methylene blue alters retention of inhibitory avoidance responses

Abstract

These experiments examined the effects of methylene blue on retention, by rats and mice, of an inhibitory avoidance response. The studies using mice investigated the effects of graded doses of methylene blue administered shortly before or after training. A 500-mg/kg dose impaired retention in mice (tested 3 days after training) if administered 15 min, but not 30 or 5 min, prior to training. Further studies with rats indicated that retention was enhanced by a low dose (1.0 mg/kg) administered immediately after training (tested 1 day after training). Retention in rats was not affected by a 1.0-mg/kg dose given 15 min before training, 6 h after training, or 15 min before testing. These results are interpreted in the light of methylene blue's actions on blood hemoglobin and carbohydrate metabolism.These studies examined the effects of methylene blue (MB) on memory storage processes. We selected MB because it has two distinct actions on blood hemoglobin (Hb), depending on dose. In low doses, MB converts methemoglobin (MHb) to Hb, and in high doses, it does the reverse (Harvey, 1975). It is thought that this dual action of MB occurs in the following way. When administered in low doses, MB acts as an electron acceptor in the transfer of electrons from reduced pyridine nucleotides to MHb. MB is reduced to leukomethylene blue, which in turn reduces MHb to Hb nonenzymatically. In addition, as electrons are transferred from nicotinamide adenine dinucleotide phosphate (NADPH) to MB, there is an increase in glucose oxidation via the pentose phosphate pathway as a result of oxidation of NADPH (Smith & Thron, 1972). In high doses, MB oxidizes the ferrous iron of reduced Hb to the ferric form and produces MHb (Harvey, 1975).It is well known that hypoxia is effective in producing amnesia in the type of inhibitory avoidance task used in this study (Anderson & Robichaud, 1975). It was thought that, in high doses, MB should produce amnesia because of the hypoxia produced by conversion of Hb to MHb. In low doses, MB might be expected to facilitate retention by converting MHb to Hb, thereby increasing the oxygen-carrying capacity of erythrocytes and by stimulating the pentose phosphate shunt, an important pathway for central glucose metabolism, particularly during stress (Himwich, 1976; Maker, Clarke, & Lajtha, 1976). MATERIALS AND METHODSThe subjects were male Swiss-Webster mice (22-36 g) and male Fischer 344 rats (112-230 g). The mice were housed eight to a cage, and the rats were housed individually. The animals were maintained on a standard light~ark cycle (LD 12:12, lights on at 7:00 a.m.). Food and water were available ad lib. Following adaptation to laboratory conditions for at least 5 days, the animals were trained in a one-trial inhibitory avoidance step-through task. Training and testing were performed between the hours of 1:00 and 5:00 p.m.The training apparatus used for the mice consisted of a small transparent start compartment separated from a larger black compartment by a guillotine door (Haycock & McGaugh, 1973;Jarv...

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

“…The observed improvement in memory retention following postextinction MB administration is consistent with the results of a number of previous animal MB studies supporting the conclusion that posttraining administration of low-dose (1-4 mg/kg) MB improves memory retention in different tasks (Martinez Jr. et al 1978;Callaway et al 2002Callaway et al , 2004. For example, successful memory retention is improved by posttraining MB administration in an inhibitory avoidance task (Martinez Jr. et al 1978).…”

“…For example, successful memory retention is improved by posttraining MB administration in an inhibitory avoidance task (Martinez Jr. et al 1978).…”

“…For example, posttraining MB administration improves memory retention tested 24 h after inhibitory avoidance training (Martinez Jr. et al 1978). Corresponding low doses of MB also increase spatial memory retention in a holeboard food search task (Callaway et al 2002(Callaway et al , 2004.…”

The brain metabolic enhancer methylene blue improves discrimination learning in rats

“…Methylene blue (MB) is a brain metabolic enhancer that has been demonstrated to improve memory retention when given post-training in low doses in a variety of simple appetitive and aversive learning tasks in rats (Callaway et al 2002(Callaway et al ,2004Gonzalez-Lima and Bruchey, 2004;Martinez Jr et al 1978;Riha et al 2005). The present results indicate that MB could also facilitate more complex learning such as in discrimination tasks that require repeated days of training.…”

“…Despite these reports, and in order to control for any state-dependent learning or side-effects that may occur by administering MB pre-training, administration occurred following training in these behavioral studies. MB enhances memory of the events preceding its administration (Martinez Jr et al 1978), so the time of injection must follow the target memory task.…”