Hypothalamic site of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Administration of TCDD produced a significant decrease in the serum concentration of prolactin (PRL) detected in rats after 4 hr compared to pair-fed vehicle controls and noninjected controls. This effect of TCDD was reversed by pimozide, a dopamine receptor antagonist. These data suggest that TCDD decreased the release of PRL from the adenohypophysis either by a direct effect on the gland or by altering the dopamine concentration in the median eminence (ME). Concentrations of TCDD from 5 to 500 ng/ml had no direct effect on the ability of the adenohypophysis to secrete PRL in vitro. However, the dopamine concentration increased to 3.24 +/- 0.07 ng per ME in TCDD-treated rats compared to 2.81 +/- 0.08 ng in vehicle controls. This is a dramatic alteration in the dopamine concentration, since the dopamine is being measured in the portal circulation which exhibits a rapid turnover. The rate constant of dopamine depletion after alpha-methyl-p-tyrosine and the turnover rate were also significantly elevated in the ME of TCDD-treated rats. These data provide the first biochemical evidence for a hypothalamic site of action of TCDD. Since dopamine is inhibitory to PRL release from the adenohypophysis, increased ME steady-state concentrations and turnover of this catecholamine may be responsible for the decreased concentration of serum PRL detected within 4 hr of TCDD injection. Thus, one of the early modes and sites of action of TCDD is to elevate the dopaminergic activity of the tuberoinfundibular nucleus. A hypothalamic site of action for TCDD may result in a number of the endocrinological effects known to be produced by exposure to TCDD.
Russell
D H
DH
Department of Pharmacology and Therapeutics, University of South Florida College of Medicine 33612-4779.
Buckley
A R
AR
Shah
G N
GN
Sipes
I G
IG
Blask
D E
DE
Benson
B
B
D000818:Animals; D004147:Dioxins / Q000633:toxicity*; D004298:Dopamine / Q000032:analysis; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D011954:Receptors, Dopamine; D011388:Prolactin; D004298:Dopamine