5alpha-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients.

Abstract

RATIONALE: The implications of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants [i.e., selective brain steroidogenic stimulants (SBSSs)], including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. Allo positively and allosterically modulates GABA action at postsynaptic and extrasynaptic GABAA receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5alpha-reductase type I (5alpha-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), which converts 5alpha-dehydroprogesterone into Allo. HYPOTHESIS: We thus hypothesized that decreased CSF levels of Allo in depressed patients could reflect a brain dysfunction of 5alpha-RI. METHODS: In a pilot study of samples from six patients per group [six depressed patients and six nonpsychiatric subjects (NPS)], we studied the expression of 5alpha-RI messenger RNA (mRNA) in prefrontal cortex Brodmann's area 9 (BA9) and cerebellum from depressed patients obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center (Baltimore, MD) that were age-matched with NPS. RESULTS: The levels of 5alpha-RI mRNA were decreased from 25 +/- 5.8 in NPS to 9.1 +/- 3.1 fmol/pmol neuronal specific enolase (NSE) (t1,10 = 2.7, P = 0.02) in depressed patients. These differences are absent in the cerebellum of the same p