Age-dependent loss of corticosterone modulation of central serotonin 5-HT1A receptor binding sites

Abstract

A loss of endocrine and neurotransmitter system interactions, including corticosterone regulation of 5-HT1A receptors, may underlie the age-related deficits in the hypothalamic-pituitary-adrenal (HPA) axis including adapting to stress. In this study, female Fischer 344 rats, (ages 3, 13, and 18 months), were bilaterally adrenalectomized and supplemented for 3 weeks with placebo or corticosterone (200 mg or 600 mg) containing 21 day sustained-release pellets implanted subcutaneously (LC, MC, or HC, respectively). Scatchard analysis using the 5-HT1A receptor agonist [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) demonstrated a significant decrease in hippocampal receptor density in 3 month and 13 month MC groups (-35.2 and -32.1%, respectively) as compared to age-matched LC groups; a significant decline in 5-HT1A receptor density in 3 month and 13 month HC groups was found compared to age-matched MC groups (-16.7 and -22.0%, respectively). However, these hormone treatments (LC or HC) failed to alter hippocampal 5-HT1A binding site density in the 18 month groups. Cortical 5-HT1A receptor densities were altered in a similar age-dependent manner. In contrast, the density of hypothalamic 5-HT1A receptors in the 18 month LC group was significantly increased above that in the 3 month LC group. An additional indicator of the hippocampal response to corticosterone, the distribution of glial fibrillary acidic protein (GFAP), revealed an age-related decline in responsiveness to hormone treatment in the oldest group. The present study has identified an age-associated deficit in the regulation of hippocampal 5-HT1A receptors by corticosterone which may underly the diminished capacity of the aging HPA axis to cope with stress.

Corticosterone regulation of serotonin transporter and 5‐HT1A receptor expression in the aging brain

“…In contrast, the 5-HT 2A receptor in the hippocampus failed to respond to these hormonal conditions at any age. The baseline density of cortical 5-HT 1A receptors showed a limited dependence on plasma corticosterone concentrations, in agreement with previous data from our laboratory obtained via equilibrium binding analysis (Maines et al, 1998). Thus, the hippocampus appears to be a region of interest in which This decrease in 5-HTT sites resulted in levels of binding that were significantly lower than that in 13-and 18-month HC groups as well, showing an age-dependent effect.…”

“…In animal models that manipulate corticosterone concentrations, the 5-HT 1A receptor down-regulates in density in young animals when exposed to high levels of circulating corticosterone (Mendelson and McEwen, 1992). Equilibrium binding studies have also demonstrated that 5-HT 1A receptor density is differentially regulated by varied corticosterone across aging, with decreased hippocampal regulation in older age groups (Maines et al, 1998), and, thus, represent changes in the regulation of the serotonergic system by glucocorticoids with aging.…”

“…These sustained-release pellets provided levels of circulating corticosterone equivalent to low (LC), normal (MC) ,and high or hypercortisolemic levels of corticosterone (HC), respectively. This model has been fully characterized with respect to plasma corticosterone levels achieved across ages and shown to produce no significant cell loss following 21-day exposure (Maines et al, 1998).…”

(+)‐Methamphetamine‐induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia

“…Makisumi et al (1998) suggest that glucocorticoids are permissive for the hyperthermic response and MA (10 mg/kg 3 4) induces a marked increase in corticosterone that lasts for at least 3 days . Interestingly, we also noted slightly higher 5-HT levels in the ADX groups, an observation that may benefit from further investigation since it is known that the serotonergic system and corticosterone are linked (Fuller, 1992;Maines et al, 1998;Meijer et al, 1997). Taken together, the data suggest that hyperthermia and/or increased corticosterone levels may have a larger role in MA-induced serotonergic reductions than in dopaminergic reductions.…”

Perioperative normothermia depends on intraoperative warming procedure, extent of the surgical intervention and age of the experimental animal

“…This may be an explanation for the more frequent accidental hypothermia in the elderly and the difficulties of the older experimental animals in the present study, since shivering thermogenesis is more energy consuming than the non-shivering thermogenesis observed in younger rats. Furthermore, it is known that elderly subjects possess a diminished capacity of the hypothalamic-pituitary-adrenal axis and a reduced corticosterone output and thus have major problems coping with stress (Maines et al, 1998;Workel et al, 2001). This may explain the difficulties of the older rats in our study to maintain body temperature in the course of the combined surgical intervention.…”