Effects of chronic substance P treatment and intracranial fetal grafts on learning after hippocampal kainic acid lesions.

The purpose of this experiment was to investigate whether the neurokinin substance P (SP) can enhance adaptive graft effects on learning and memory functions in animals with lesions of the hippocampus. Adult male Wistar rats received a bilateral kainic acid (KA) lesion of the dorsal hippocampus. One week postlesion, bilateral grafts of fetal hippocampal tissue suspension were applied into the damaged region in half of the animals, whereas the other half received sham transplants (physiological saline). Animals of the control group received a bilateral sham lesion of the hippocampus and sham transplants. One week after transplantation surgery, the rats were tested in the place version of the Morris water maze over a period of 9 weeks. Then they were tested for SP-induced conditioned place preference and on a step-through inhibitory avoidance task. All animals received IP injections of either SP (5 or 50 micrograms/kg) or the SP vehicle (0.5 ml/kg). The treatment with SP or the vehicle was begun 1 week after transplantation and was performed 5 days a week over a period of 10 weeks. During behavioral tests in the water maze and avoidance task, application of the substances was performed 5 h after testing. For the conditioned place preference test, the conditioning trials were performed immediately after drug administration; the test trials were given 24 h later. Chronic administration of 50 micrograms/kg SP, but not 5 micrograms/ kg SP, was found to improve water maze performance in lesioned animals with and without grafts. Unexpectedly, the lesion group with the graft without additional SP treatment was not superior to the lesion group devoid of the graft in this task. The rats without lesions of the hippocampus still showed a conditioned place preference to 50 micrograms/kg SP after 9 weeks of repeated SP applications. In the inhibitory avoidance task, the grafts facilitated retention performance independent of whether SP treatment was given. The morphological analysis of the transplants revealed higher graft volumes and a higher diameter of large pyramidal neurons (> 10 microns) in rats chronically treated with 50 micrograms/kg SP.