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The Journal of Neuroscience, September 6, 2006, 26(36):9205-9215; doi:10.1523/JNEUROSCI.2491-06.2006

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Behavioral/Systems/Cognitive
Angiotensin-II Is a Putative Neurotransmitter in Lactate-Induced Panic-Like Responses in Rats with Disruption of GABAergic Inhibition in the Dorsomedial Hypothalamus

Anantha Shekhar,^1,2 Philip L. Johnson,¹ Tammy J. Sajdyk,¹ Stephanie D. Fitz,¹ Stanley R. Keim,¹ Pamela E. Kelley,¹ Donald R. Gehlert,³ and Joseph A. DiMicco²

Departments of ¹Psychiatry and ²Pharmacology and Toxicology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, and ³Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Correspondence should be addressed to Dr. Anantha Shekhar, Department of Psychiatry, Indiana University School of Medicine, 1111 West 10th Street, Suite 313, Indianapolis, IN 46202. Email: ashekhar{at}iupui.edu

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.

Key words: anxiety; circumventricular organs; GABA; medial preoptic nucleus; organum vasculosum lamina terminalis; saralasin; stress; subfornical organ; losartan; AT₁ receptor

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Received Feb. 22, 2006; revised July 15, 2006; accepted July 17, 2006.

Correspondence should be addressed to Dr. Anantha Shekhar, Department of Psychiatry, Indiana University School of Medicine, 1111 West 10th Street, Suite 313, Indianapolis, IN 46202. Email: ashekhar{at}iupui.edu

This article has been cited by other articles:

				T. Sajdyk, P. Johnson, S. Fitz, and A. Shekhar Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior J Psychopharmacol, August 1, 2008; 22(6): 633 - 641. [Abstract] [PDF]

				P. Johnson, C. Lowry, W. Truitt, and A. Shekhar Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic J Psychopharmacol, August 1, 2008; 22(6): 642 - 652. [Abstract] [PDF]

				D. N. Mayorov Brain superoxide as a key regulator of the cardiovascular response to emotional stress in rabbits Exp Physiol, May 1, 2007; 92(3): 471 - 479. [Abstract] [Full Text] [PDF]

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