title: The anxiogenic drug FG-7142 increases serotonin metabolism in the rat medial prefrontal cortex.
abstract: The neural mechanisms underlying anxiety states are believed to involve interactions among forebrain limbic circuits and brainstem serotonergic systems. Consistent with this hypothesis, FG-7142, a partial inverse agonist at the benzodiazepine allosteric site of the GABAA receptor, increases c-Fos expression within a subpopulation of brainstem serotonergic neurons. Paradoxically, FG-7142 has no effect on extracellular serotonin concentrations, as measured using in vivo microdialysis, in certain anxiety-related brain structures. This study tested the hypothesis that FG-7142 alters serotonin metabolism within one or more nodes of a defined anxiety-related forebrain circuit. Rats received one of four treatments (vehicle, 1.9, 3.8, or 7.5 mg/kg FG-7142, i.p.) and brains were collected 1 h following treatment. Thirteen forebrain regions were microdissected and analyzed for l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations using high pressure liquid chromatography with electrochemical detection. FG-7142 (7.5 mg/kg) increased l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations in the prelimbic cortex but not in several other regions studied including subdivisions of the amygdala and bed nucleus of the stria terminalis. These data demonstrate that FG-7142 alters brain tryptophan concentrations and serotonin metabolism in specific components of an anxiety-related forebrain circuit including the medial prefrontal cortex, an important structure involved in executive function and the regulation of emotional behavior.
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK. a.evans@bristol.ac.uk
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Evans
authors.forename: Jolane K
authors.initials: JK
authors.lastname: Abrams
authors.forename: J Adriaan
authors.initials: JA
authors.lastname: Bouwknecht
authors.forename: David M
authors.initials: DM
authors.lastname: Knight
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D002243:Carbolines / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism
chemical_list: D002243:Carbolines; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C035874:FG 7142; D014364:Tryptophan