Panic disorder is a severe anxiety disorders characterized by significant disability. Rats in which GABA inhibition is chronically disrupted in the dorsomedial hypothalamus/perifornical (DMH/PeF) region, exhibit heightened anxiety and panic-like responses, defined as increases in heart rate (HR), mean arterial pressure (BP), respiratory rate (RR), and anxiety as measured by the social interaction (SI) test, following exposure to subthreshold cues such as 0.5 M sodium lactate and 7.5% CO2, agents known to provoke panic attacks in subjects suffering from panic disorder. During the last funding period, we have extensively characterized the afferent pathways for the lactate stimulus, demonstrated some of the regulatory mechanisms within the DMH, and identified the efferent targets of the DMH that are implicated in the panic-like response. The goal of this competitive renewal (MH 52619) is to further elucidate the pathways and neurotransmitters involved in the different components of panic response using pharmacological, functional neuroanatomical, and molecular studies. Overall Hypothesis of the work is that disruption of GABA inhibition in the DMH/PeF region of rats induces a 'panic-prone'state, as a result of pathological activation of a select group of glutamate/peptidergic projection neurons, most prominently orexin/dynorphin A (ORX/DYN) positive cells. This results in aberrant stimulation of a number of efferent targets from the DMH. During this funding period, we will study the pathways involved in activating the bed nucleus of the stria terminalis (BNST) to result in anxiety-like responses and specific brain stem projection targets such as the nucleus tractus solitarius (NTS) in causing inhibition of parasympathetic and activation of sympathetic pathways to increase HR and BP following lactate infusions in these panic-prone rats. We will test these hypotheses with experiments using neuronal immunohistochemical studies;systemic injections of ORX and other peptide receptor antagonists;targeted lesioning of the ORX neurons in the DMH/PeF;measuring the changes in pre-proORX (ppORX), proDynorphin (pDYN) and other peptide mRNA expressions using RTPCR;and acute ppORX and/or pDYN gene knockdown with siRNA, within the DMH. We will study the efferent sites with infusions of pharmacological agents, gene silencing using siRNA as well as neuroanatomical techniques. Finally, we will study the role of local versus extrinsic GABA neurons by GAD-67/65 gene silencing in the DMH/PeF region.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH052619-12
Application #
7792355
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Winsky, Lois M
Project Start
1996-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$321,938
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bonaventure, Pascal; Dugovic, Christine; Shireman, Brock et al. (2017) Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation. Front Pharmacol 8:357
Federici, Lauren M; Roth, Sarah Dorsey; Krier, Connie et al. (2016) Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women. Menopause 23:1257-1266
Hickman, Debra L; Fitz, Stephanie D; Bernabe, Cristian S et al. (2016) Evaluation of Low versus High Volume per Minute Displacement CO? Methods of Euthanasia in the Induction and Duration of Panic-Associated Behavior and Physiology. Animals (Basel) 6:
Johnson, Philip L; Federici, Lauren M; Fitz, Stephanie D et al. (2015) OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES. Depress Anxiety 32:671-83
Bonaventure, Pascal; Yun, Sujin; Johnson, Philip L et al. (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 352:590-601
Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D et al. (2015) Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. Pharmacol Biochem Behav 138:174-9
Molosh, Andrei I; Johnson, Philip L; Spence, John P et al. (2014) Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 17:1583-90
Koehler, Karl R; Mikosz, Andrew M; Molosh, Andrei I et al. (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500:217-21
Johnson, Philip L; Fitz, Stephanie D; Engleman, Eric A et al. (2013) Group II metabotropic glutamate receptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable rats. J Psychopharmacol 27:152-61
Molosh, Andrei I; Sajdyk, Tammy J; Truitt, William A et al. (2013) NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. Neuropsychopharmacology 38:1352-64

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