BETA-AMYLOID(1-40) EFFECTS ON BEHAVIOR AND MEMORY

Beta amyloid 1-40 is a primary protein in plaques found in the brains of patients with Alzheimer's disease. There is evidence that unaggrega ted soluble beta-amyloid may be neurotoxic and may have behavioral eff ects on some types of memory. In the current study, the 1-40 fragment of beta-amyloid protein ( beta A4), or vehicle, was bilaterally inject ed into the rostral hippocampus of rats performing under stable food-m aintained schedules of reinforcement or under a delayed conditional di scrimination procedure. Under the first procedure, rats were trained t o stability under a multiple fixed interval 15 s, fixed ratio 30 reinf orcement schedule. This reinforcement schedule has proven sensitive to low-dose drug effects. Acute bilateral hippocampal beta A4 (1.0, 2.0 and 3.0 mu l of 10(-3) M) administration did not significantly alter r esponding, compared to vehicle, under either reinforcement condition. Following the acute single-injection regimen, rats were administered c hronic daily beta A4 (1 mu l of 10(-3) M), bilaterally, for 15 days. N o significant changes in lever-pressing performance were observed duri ng the chronic injection regimen, but performance declined significant ly 30 days after termination of the chronic daily regimen. Histologica l examination revealed three of six rats showed positive reactions und er Thioflavin S staining in and around the area of cannulae terminatio n. The second assessment employed a delayed conditional discrimination procedure to evaluate the effects of intrahippocampal injections of b eta A4 on short-term working memory. This conditional discrimination p rocedure assesses appropriate responding, dependent on a previously pr esented stimulus, after delays of various lengths have been imposed be tween the stimulus and the response opportunity. Delay values ranged f rom 0.01 s to 20 s. Under this procedure, accuracy was unaffected acro ss all delay values following single bilateral intrahippocampal inject ions of beta A4 (1.0, 2.0 and 3.0 mu l of 10(-3) M). Thus, the soluble unaggregated form of beta A4, injected into the dorsal hippocampus, d oes not appear to have behavioral effects on performance or short-term working memory in rats, but multiple repeat injections produced perfo rmance decrements several weeks later. Repeated injection of beta A4 t hrough indwelling cannulae shows promise for development of an animal model of Alzheimer's disease.