Several lines of evidence suggest that endogenous opioid peptides, enkephalin and dynorphin play important roles in modulating the excitability of the hippocampus. However, the information regarding the regulation of these two opioid peptides has been lacking. The purpose of this project was to examine the molecular mechanisms of the expression of enkephalin and dynorphin in the hippocampus by excitatory amino acids or hormones, such as glucocorticoids. Previous results from our laboratory Indicate that stimulation of perforant pathway, which innervate dentate granule cells, elicits differential effects on the hippocampal levels of opioid peptides: increase in enkephalin, but decrease in dynorphin. These results suggest an intimate relationship between the excitatory amino acids and opioid peptides In the hippocampus. To further examine the possible roles of glutamate In regulating the expression of opioid peptides, we have studied the aging rats. The effects of aging on extracellular glutamate and tissue dynorphin content in the hippocampus were examined in Fischer-344 rats. Young adult (4 months) and aged (24 months) rats were trained to find an invisible platform in the Morris water maze. Aged rats were unable to acquire the spatial learning task as rapidly as young controls. There was a significant reduction in extracellular glutamate concentration in both dorsal and ventral hippocampus of aged rats compared to young rats, in the absence of a similar reduction in tissue glutamate concentration. Radioimmunoassay showed an increase in dynorphin A(1-8)-like immunoreactivity [DYN-A(1-8)LI] in both dorsal and ventral hippocampus, but not striatum, of aged rats. Furthermore, among the aged animals the increase in DYN-A(l-.8)LI was inversely correlated with the decrease in extracellular glutamate. These results suggest that the dysregulation of dynorphin observed in cognitively impaired aged rats is related to reduced excitatory transmission within the hippocampal formation.
