title: Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus.
abstract: Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ashekhar@iupui.edu
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.forename: Tammy J
authors.initials: TJ
authors.lastname: Sajdyk
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Keim
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Kelley
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiMicco
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology*; D019344:Lactic Acid; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D016584:Panic Disorder / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D000804:Angiotensin II; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid