Memory improvement with the metabolic enhancer methylene blue

The goal of this dissertation was to investigate the memory retention effects of methylene blue (MB) in both appetitive and aversive memory tasks in rats. Methylene blue is a metabolic enhancer that improves memory retention in a variety of tasks including inhibitory avoidance, object recognition, spatial memory, and extinction of Pavlovian fear conditioning. Low dose MB has no side effects on behavior. MB works as a metabolic enhancer by increasing brain cytochrome oxidase activity and oxygen consumption. The first experiment was conducted to examine the effects of MB treatment in normal rats in the hole board spatial memory task, to determine if it could enhance memory of discrimination learning of rewarded versus non-rewarded trials. Subjects treated with MB discriminated better between rewarded and non-rewarded trials as compared to control subjects, indicated by a greater number of correct responses on rewarded trials than non-rewarded trials. The second experiment was conducted to determine the effects of MB administered following acquisition trials in Pavlovian fear conditioning. Methylene blue-treated subjects demonstrated greater conditioned freezing to the tone conditioned stimulus (CS) without significant effects on context freezing. MB subjects also had higher freezing scores following extinction, indicating that they retained stronger fear-conditioning than controls. The third experiment was conducted to characterize extinction in the congenitally helpless (CH) rat, an animal model of posttraumatic stress disorder and depression, and to determine if low dose MB could facilitate fear extinction memory in these subjects. CH rats exhibited abnormally high conditioned freezing in response to the CS tone. They failed to show the gradual decrement in freezing characteristic of the normal extinction curves seen in control subjects. Administration of MB to CH rats significantly ameliorated their fear extinction deficit. It was concluded that MB is a very promising treatment for memory enhancement, and if administered post-training and in low doses, may be a potent memory-enhancing compound with little to no side effects. MB provides an important therapeutic advantage because it optimizes neuronal energy metabolism during memory formation, while avoiding side effects of drugs acting on synaptic transmission elsewhere in the brain.