Rat beta(1-42) peptide (beta/A4) or phosphate buffered saline (PBS) was bilaterally injected into the hippocampus (HIP) or the lateral ventricle (ICV) of 3-month-old Fischer-344 rats. Fifteen months later, the animal's ability to learn a spatial memory task was tested using the Morris water maze. Acquisition of the task was impaired by the bilateral injection of either peptide or PBS into the hippocampus. Hippocampal-injected animals showed an increased average latency to find the platform by approximately 6 s (p < 0.05). However, injection of rat beta-peptide into the hippocampus or lateral ventricles failed to induce behavioral impairment when compared to vehicle injected controls. Retention of this task was not significantly impaired in any group. The spatial acuity test, a trial without the platform, revealed that both groups of animals that received hippocampal injections were impaired, spending 23% less time in the target quadrant compared to ICV-injected animals (p < 0.005). Hippocampal ChAT activity was decreased in beta/A4-injected animals but not significantly (p < 0.06). beta/A4-immunoreactivity was detected at the bottom of the needle track and the adjacent parenchyma of beta/A4 hippocampal-injected animals after 16 months. However, long-term in vivo deposition of beta/A4 in both regions did not result in an upregulation of hippocampal amyloid precursor protein (APP) expression and there was no qualitative neuronal loss in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)