Serotonergic regulation of type II corticosteroid receptor binding in hippocampal cell cultures: evidence for the importance of serotonin-induced changes in cAMP levels.
The development of the hypothalamic-pituitary-adrenal response to stress is profoundly altered by environmental events. One target for environmental regulation within the hypothalamic-pituitary-adrenal axis is the hippocampal type II corticosteroid (or glucocorticoid) receptor system, which mediates the negative-feedback effects of glucocorticoids on hypothalamic-pituitary-adrenal activity. Thus, adult rats handled early in life show increased hippocampal type II corticosteroid receptor density and increased sensitivity to the inhibitory effects of circulating glucocorticoids on post-stress hypothalamic-pituitary-adrenal activity. Both effects persist throughout life. The effects of handling on type II corticosteroid receptor development are, at least in part, mediated by changes in hippocampal 5-hydroxytryptamine turnover. Moreover, 5-hydroxytryptamine can regulate type II corticosteroid receptor density in cultured hippocampal cells, providing a paradigm for examining the neurochemical mechanisms by which environmental stimuli might regulate neural differentiation. In the present studies, we examined the intracellular mechanisms underlying the effects of 5-hydroxytryptamine on type II corticosteroid receptors ([3H]RU 28362 binding) in hippocampal cell cultures. cAMP, but not cGMP, levels in cultured hippocampal cells were significantly increased by the addition of 5-hydroxytryptamine to the medium. The cAMP response to 5-hydroxytryptamine was biphasic: an initial increase in cAMP levels occurred in response to nanomolar 5-hydroxytryptamine concentrations (EC50 = 7.2 nM), while a second increase was apparent at low micromolar concentrations. 5-Hydroxytryptamine also increased [3H]RU 28362 binding (EC50 = 4.5 nM) with a maximal effect at a concentration of 10 nM. There was no further increase in [3H]RU 28362 binding even with higher, micromolar concentrations of 5-hydroxytryptamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Mitchell
J B
JB
Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montréal, Canada.
Betito
K
K
Rowe
W
W
Boksa
P
P
Meaney
M J
MJ
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D000662:Amphetamines; D000451:Mineralocorticoid Receptor Antagonists; D010879:Piperazines; D011965:Receptors, Glucocorticoid; D012702:Serotonin Antagonists; D015124:8-Bromo Cyclic Adenosine Monophosphate; C018406:1-(3-trifluoromethylphenyl)piperazine; D013148:Spironolactone; D012701:Serotonin; C041006:RU 28318; D000242:Cyclic AMP; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine