Date of Award
Program or Major
Doctor of Philosophy
Recent evidence indicates that the activation of a calcium-dependent proteinase, calpain, results in the formation of new glutamate receptors in the hippocampus (Lynch, Halpain, & Baudry, 1982), a brain area commonly thought to play a crucial role in mammalian memory formation. In vitro, this effect is correlated with a long-lasting enhancement of efficacy in synaptic transmission (long-term potentiation, LTP) following brief pulses of electrical stimulation in the hippocampus (Dunwiddie & Lynch, 1979). Because the induction properties of LTP are similar to the behavioral properties of memory, it has been proposed to be the physiological basis of memory (Lynch & Baudry, 1984). If the calcium-dependent activation of calpain is responsible for the induction of LTP and ultimately memory formation, then pharmacologically blocking the calcium-calpain interactions should block those forms of memory dependent on this mechanism.
Three experiments were conducted to assess the effects of leupeptin, a proteinase (calpain) inhibitor on aversively motivated spatial memory in rats. In Experiment One, either leupeptin (8 mg/ml isotonic saline) or isotonic saline was infused continuously into the cerebrospinal fluid, and rats were trained in a one-way avoidance task with one-hour intertrial intervals, three trials per day, for 11 days. Leupeptin significantly impaired rats' acquisition of this task. Experiment Two assessed rats' performance in a win-stay or a win-shift avoidance task, and it was found that rats in the win-shift group learned the task more efficiently. This win-shift avoidance task was then used in Experiment Three to assess the temporal dependence of leupeptin's behavioral effects by introducing a delay of 1 min, 15 min, or 30 min between the information and choice trials. Leupeptin impaired choice performance at the 30 min delay only. In addition, leupeptin significantly impaired previously-acquired avoidance responding. Because a time-dependent memory deficit was observed, these data are considered to be consistent with the biological model of memory formation advanced by Lynch & Baudry (1984), however no adequate explanation of leupeptin's deleterious effects on previously acquired responding presently exists.
OTTO, TIMOTHY ANDREW, "EFFECTS OF LEUPEPTIN ON AVERSIVELY MOTIVATED SPATIAL MEMORY" (1986). Doctoral Dissertations. 1497.