title: Chronic hypercortisolemia inhibits dopamine synthesis and turnover in the nucleus accumbens: an in vivo microdialysis study.
abstract: Over 60% of patients with Cushing's syndrome suffer from major depression, which frequently abates after correction of the hypercortisolism. The mesolimbic and mesocortical dopaminergic (DAergic) systems are thought to participate in psychiatric disorders. In this study, we investigated whether hypercortisolemia affects indices of DAergic activity in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) of freely moving rats. Cortisol (CORT, 25 mg/kg/day) was infused subcutaneously for 7 days via an osmotic minipump. Microdialysate collection (30-min periods, 2 microl/min) began 24 h after probe placement. Concentrations of dihydroxyphenylalanine (DOPA) in interstitial fluid in the nucleus accumbens (NAc) and perifrontal cortex (PFC) were measured before and after local perfusion with NSD-1015, an irreversible inhibitor of L-aromatic amino acid decarboxylase, to assess local dopamine (DA) biosynthesis. The sum of microdialysate DA, dihydroxyphenylacetic acid, and homovanillic acid was used as an index of local DA turnover. DOPA accumulation after NSD-1015 was markedly attenuated in CORT-treated compared with saline-treated animals (5,703 +/- 1,849 vs. 10,902 +/- 2,454 pg/ml; p < 0.01). In contrast, the two groups did not differ in DOPA accumulation in the PFC. Values for the turnover index of DA were also significantly lower in CORT-treated animals in the NAc but not in the PFC. The results indicate that CORT inhibits DA synthesis and turnover in the NAc but not in the PFC. Region-specific CORT-induced inhibition of DAergic activity may help to explain depressive symptoms in patients with chronic hypercortisolemia and normalization after medical or surgical correction of hypercortisolism.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Md 20892-1620, USA. karel@mail.nih.gov
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Olga
authors.initials: O
authors.lastname: Tjurmina
authors.forename: Milkós
authors.initials: M
authors.lastname: Palkovits
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Christian A
authors.initials: CA
authors.lastname: Koch
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoff
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002908:Chronic Disease; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004791:Enzyme Inhibitors; D006834:Hydrazines; D015102:3,4-Dihydroxyphenylacetic Acid; C004297:3-hydroxybenzylhydrazine; D004298:Dopamine; D006719:Homovanillic Acid