title: Glucocorticoid modulation of dopamine mediated effects on hypothalamic atrial natriuretic factor neurons.
abstract: Dopamine (DA) plays an important role in cognition, neuroendocrine functions and psychosis.1,2 Whilst stress adversely affects some of these functions, its neurobiological basis remains unclear.3 In the rat hypothalamus, a concurrent activation of D5and D2 receptors by dopamine produces a biphasic effect on the function of atrial natriuretic factor (ANF) neurons.4 Whereas low doses (10-8 and 10-7 M) of DA suppress the release and pro-ANF mRNA expression, high doses (10-6 and 10-5 M) of the amine produce an opposite effect through the interaction of D5 and D2 receptors. We report here that the augmenting effect of DA on the hypothalamic neurons is inhibited by a synthetic glucocorticoid, dexamethasone (DM), in both time-dependent and dose-related manner with an EC50 of 0.1 nM. Furthermore, the inhibition is blocked by 100 nM of RU38486 (P<0.01), a glucocorticoid receptor antagonist, but not by an equivalent dose of RU28318, a mineralocorticoid receptor antagonist. In contrast, DM failed to modulate low doses (10(-8) to 10(-7) M) of DA-induced suppression of ir-ANF release and pro-ANF mRNA expression that was mediated primarily through D2 receptors. We conclude that glucocorticoids markedly alter DA-induced biphasic effects by down-regulating D5, but not D2, receptor-mediated neurobiological events. Hence, in severe stress, high levels of circulating glucocorticoids may render dopamine to act as a potent suppressor of neurons that possess both D5 and D2 receptors. The possibility that this novel mechanism of stress hormone or glucocorticoids may, in part, undermine DA-mediated neurophysiology in critical regions of the brain, which links to psychosis now needs to be considered.
authors.affiliation: Cell Biology Laboratory, Division of Molecular Schizophrenia, Mental Health Research Institute of Victoria, Parkville, Australia 3052.
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Copolov
authors.forename: A T
authors.initials: AT
authors.lastname: Lim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003900:Desoxycorticosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D005938:Glucocorticoids; D011498:Protein Precursors; D011954:Receptors, Dopamine; D013148:Spironolactone; D015735:Mifepristone; D003900:Desoxycorticosterone; C041006:RU 28318; D003907:Dexamethasone; D009320:Atrial Natriuretic Factor; D004298:Dopamine