Previous research has demonstrated increased mRNA expression and peptide content in an opioid system localized to hippocampal dentate granule cells in aged rats. This raises the possibility that dysregulation of dynorphin in the aged brain is a reactive response to antecedent change(s) in this circuitry, a hypothesis that was examined by separately manipulating in young rats the three neural/neuro-endocrine systems identified. Of the three models examined only removal of the perforant path reproduced the effect of aging on dynorphin in the hippocampal formation. An immunotoxin was used to selectively remove septo-hippocampal cholinergic neurons in young rats. No alteration in hippocampal opioid peptides was produced by this treatment. We also examined effects of exposure to excess corticosterone. Adrenalectomized rats exhibited a significant decrease in hippocampal dynorphin-A (1-8) content, which was reversed by corticosterone replacement at a concentration approximately normal basal levels. Dynorphin-A (1-8) content, however, was not reliably increased by exposure to excess corticosterone. In contrast, perforant path removal was found to reproduce the effect of aging on dynorphin content; either aspiration of the entrohinal cortex or knife cut transections of the perforant path reliably increased hippocampal dynorphin content. These results support the conclusion that age-related deterioration in the septohippocampal cholinergic system and elevated exposure to corticosterone are not sufficient to induce an elevation in hippocampal dynorphin content. Only removal of ther perforant path innervation was found to replace elevation in hippocampal dynorphin content observed in aged rats with hippocampal-dependent learning impairment.
