Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus.
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.
Shekhar
Anantha
A
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ashekhar@iupui.edu
Johnson
Philip L
PL
Sajdyk
Tammy J
TJ
Fitz
Stephanie D
SD
Keim
Stanley R
SR
Kelley
Pamela E
PE
Gehlert
Donald R
DR
DiMicco
Joseph A
JA
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*
D018377:Neurotransmitter Agents; D000804:Angiotensin II; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid