Do vasopressin-related peptides induce hippocampal corticosterone receptors? Implications for aging

Abstract

The aged rat shows a decline in hippocampal corticosterone receptors and dysfunction in learning and adrenocortical physiology previously linked to glucocorticoid effects upon the hippocampus. The Brattleboro rat, congenitally lacking vasopressin, also has a low number of hippocampal glucocorticoid receptors, as well as learning and endocrine impairments similar to those seen in the aged. Centrally acting vasopressin analogues correct the receptor loss in the hippocampus in the Brattleboro rat but do not influence the hippocampal receptor deficit in the aged rat. Quantitative and high resolution autoradiographic procedures were utilized to characterize the glucocorticoid receptor deficit in the aged and Brattleboro rats. Quantitative autoradiography showed that in both aged and Brattleboro subjects, losses in receptors were most extreme in the pyramidal layer of the CA3a region. High resolution autoradiography revealed striking differences in the cellular basis of the receptor losses. Brattleboro rats had decreased binding of [3H]corticosterone per neuron, whereas aged subjects, in addition, had significant losses in the number of corticosterone-concentrating neurons. Taken together, our findings indicate that the glucocorticoid receptor deficit in the Brattleboro rat probably represents a vasopressin-influenced defect in the synthesis or degradation of the receptor, whereas in the aged rat the deficit originates from loss of both receptor per neuron and the steroid-concentrating neurons themselves, and thus is most likely a permanent and pharmacologically insensitive deficit.

Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response.

“…The Brattleboro rat has a 24% decrease in the number of cytosolic corticosterone receptors in the hippocampus but no change in receptor affinity ( Table 1). The hippocampal deficit involves only decreases in the numbers of corticosterone receptors per hippocampal neuron and no change in the number of corticosterone concentrating neurons in the hippocampus or in the total number of hippocampal neurons (18). This receptor deficit is apparently related to the congenital absence of central vasopressinergic projections, because treatment with dGVP normal-FIG.…”

“…Aged rats have a 30% decrease in cytosolic corticosterone receptors in the hippocampus, but no change in receptor affinity (Table 1). Accompanying this receptor loss is a decline in the number of pyramidal neurons in the hippocampus (16)(17)(18). This neuronal loss at least partially explains the receptor loss, as it is steroid-concentrating neurons that disappear with age (18).…”

“…Furthermore, such subjects hypersecrete corticosterone, the principal glucocorticoid in the rat; specifically, aged male rats show a delay in terminating corticosterone secretion at the end of stress (15). The aged rat hippocampus has a loss of neurons (16)(17)(18) and, as a result, shows a decrease of corticosterone receptors (19). The lesion data cited above suggest that the age-related destruction of hippocampal neurons might account for the corticosterone hypersecretion at the end of stress.…”

“…Male Brattleboro rats (a strain derived from the Long-Evans strain and congenitally deficient in vasopressin) have a selective depletion of hippocampal corticosterone receptors that can be normalized by treatment with Des-glycinimide arginine vasopressin (dGVP), a centrally acting vasopressin analogue with no peripheral diuretic or corticotropin-releasing effects (18,20). Subjects were injected s.c. daily for 7 days with 2 ug of dGVP dissolved in a slow-release zinc phosphate solution (18).…”

“…Subjects were injected s.c. daily for 7 days with 2 ug of dGVP dissolved in a slow-release zinc phosphate solution (18). Control subjects were injected with the zinc phosphate solution alone.…”