title: Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions.
abstract: Since impairing gamma-aminobutyric acidA (GABAA) receptor-mediated inhibition in the dorsomedial hypothalamus (DMH) of rats elicits a panic-like response, experiments were conducted to test if rats with GABA dysfunction in the DMH would be vulnerable to precipitation of a panic-like response after intravenous sodium lactate infusions. Rats were implanted with unilateral infusion cannula into the DMH which were connected with Alzet minipumps that chronically infused (3.5 nmol/microliter /h) either a-CSF (vehicle), dl-(racemic), l-(active) or d-(inactive) isomers of allylglycine (AG), an inhibitor of GABA synthesis. Another group of rats had l-allylglycine pumps implanted in the paraventricular nucleus of the hypothalamus (PVN) as anatomical controls. Animals were tested in the social interaction (SI) test and given sodium lactate infusions (10 ml/kg/15 min) before Alzet pump implantations and on days 4, 7, and 14 after pump placement. Rats were also tested in the elevated plus-maze on treatment day 4. Chronic impairment of GABA function in the DMH and not PVN resulted in rats being more anxious in the SI test on treatment days 4, 7, and 14 and in the elevated plus-maze on day 4 compared to a-CSF and d-AG infusions. Further, rats with GABA dysfunction in the DMH, and not PVN, exhibited significant increases in heart rate and blood pressure following IV sodium lactate infusions. There were significant decreases in DMH glutamic acid decarboxylase activity and GABA content in rats receiving 7 days of dl-AG or l-AG infusions. These results indicate that chronic reduction of GABA function in the DMH leads to the development of panic-like disorder in this animal model.
authors.affiliation: Department of Psychiatry, Indiana University Medical Center, Indianapolis 46202, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shekhar
authors.forename: S R
authors.initials: SR
authors.lastname: Keim
authors.forename: J R
authors.initials: JR
authors.lastname: Simon
authors.forename: W J
authors.initials: WJ
authors.lastname: McBride
mesh_terms: D000501:Allylglycine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D007262:Infusions, Intravenous; D019344:Lactic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D016584:Panic Disorder / Q000139:chemically induced / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012919:Social Behavior; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D018756:GABA Antagonists; D000501:Allylglycine; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase