title: Androgen metabolites impact CSF amines and axonal serotonin via MAO-A and -B in male macaques.
abstract: A number of studies have shown that mutations or deletions of the monoamine oxidase-A (MAO-A) gene cause elevated CNS serotonin and elevated impulsive aggression in humans and animal models. In addition, low cerebrospinal fluid (CSF) 5-hydroxyindole acetic acid (5HIAA) has been documented in a limited number of violent criminal populations and in macaques that exhibit impulsive aggression. To reconcile these different analyses, we hypothesized that CSF 5HIAA reflected degradation of serotonin by the activity of MAO-A; and that low MAO-A activity would result in lower CSF 5HIAA, but overall higher serotonin in the CNS. To test this hypothesis, male Japanese macaques (Macaca fuscata) were castrated, rested for 5-7months, and then treated for 3months with [1] placebo, [2] testosterone (T), [3] dihydrotestosterone (DHT; non-aromatizable androgen) and 1,4,6-androstatriene-3,17-dione (ATD) (steroidal aromatase inhibitor), or [4] flutamide (FLUT; androgen antagonist) and ATD (n=5/group). These treatments enable isolation of androgen and estrogen activities. In the dorsal raphe, MAO-A and MAO-B expressions were determined with in situ hybridization (ISH) and protein expression of aromatase was determined with immunohistochemistry (IHC). CSF concentrations of 5HIAA, 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were determined with liquid chromatography/mass spectrometry (LC/MS). From the same animals, previously published data on serotonin axon density were used as a proxy for CNS serotonin. Aromatase conversion of T to estrogen (E) suppressed MAO-A (positive pixel area, p=0.0045), but androgens increased MAO-B (positive pixel area, p=0.014). CSF 5HIAA was suppressed by conversion of T to E (Cohen's d=0.6). CSF 5HIAA was positively correlated with MAO-A-positive pixel area (r(2)=0.78). CSF 5HIAA was inversely correlated with serotonin axon-positive pixel area (r(2)=0.69). In summary, CSF 5HIAA reflects MAO-A activity rather than global serotonin. Low CSF 5HIAA may, in this paradigm, reflect higher serotonin activity. Androgens lower MAO-A activity via metabolism to E, thus elevating CNS serotonin and decreasing CSF 5HIAA. Since androgens increase certain types of aggression, these data are consistent with studies demonstrating that lower MAO-A activity is associated with elevated serotonin and increased aggression.
authors.affiliation: Division of Reproductive and Development Science, Oregon National Primate Research Center, Beaverton, OR 97006, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, United States; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97201, United States. Electronic address: betheac@ohsu.edu.
authors.forename: C L
authors.initials: CL
authors.lastname: Bethea
authors.affiliation: Division of Reproductive and Development Science, Oregon National Primate Research Center, Beaverton, OR 97006, United States.
authors.forename: K
authors.initials: K
authors.lastname: Phu
authors.affiliation: Division of Reproductive and Development Science, Oregon National Primate Research Center, Beaverton, OR 97006, United States.
authors.forename: A
authors.initials: A
authors.lastname: Kim
authors.affiliation: Division of Reproductive and Development Science, Oregon National Primate Research Center, Beaverton, OR 97006, United States.
authors.forename: A P
authors.initials: AP
authors.lastname: Reddy
mesh_terms: D000588:Amines / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000733:Androstatrienes / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001369:Axons / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology
chemical_list: C115984:1,4,6-androstatrien-3,17-dione; D000588:Amines; D000726:Androgen Antagonists; D000728:Androgens; D000733:Androstatrienes; D047072:Aromatase Inhibitors; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D012701:Serotonin; D013739:Testosterone; D005485:Flutamide; D001141:Aromatase; D008995:Monoamine Oxidase
keywords: CSF 5HIAA; MAO-A; MAO-B; aromatase; male; serotonin