The circumventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder

Patients with panic disorder experience panic attacks after intravenous sodium lactate infusions by an as yet unexplained mechanism. Lactate elicits a panic-like response in rats with chronic dysfunction of GABA neurotransmission in the dorsomedial hypothalamus (DMH). The circumventricular organs, organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), are potential sites that could detect increases in plasma lactate levels and activate the DMH. To test this, we obtained baseline heart rate (HR) and blood pressure (BP) responses to lactate infusions in rats fit with femoral arterial and venous catheters. Next, unilateral chronic injection cannulae connected to an Alzet infusion pump filled with the GABA synthesis inhibitor L-allylglycine (L-AG) were implanted into the DMH. Another chronic injection cannula was implanted into the region of the OVLT, SFO, or an adjacent control site, the median preoptic area (MePOA). These rats were tested once again with lactate infusions after injection of either artificial cerebrospinal fluid (ACSF) or tetrodotoxin (TTX) into the CVO sites. Injecting TTX into the OVLT completely blocked the lactate-induced response, whereas TTX injections into the SFO or MePOA did not. Also, direct injections of lactate (100 or 500 nl) into the OVLT elicited robust anxiety-like responses in these rats. These results suggest that the OVLT may be the primary site that detects lactate infusions, activating an anxiety-like response in a compromised DMH, and provide the first neuroanatomical basis for lactate response in panic disorder

Indiana Clinical and Translational Sciences Institute Metrics

poster abstractThe Indiana Clinical and Translational Sciences Institute (Indiana CTSI) activities are designed to contribute to the achievement of NIH Strategic Goals for the Clinical and Translational Sciences Award program. The Indiana CTSI uses a Logic Model-based system of metrics to provide data to the NIH regarding Indiana CTSI accomplishments. The metrics address achievement of Specific Aims, number of investigators benefitting from Indiana CTSI resources, publications generated from Indiana CTSI-supported activities, and the awarding of pilot grant funds to support the acquisition of findings and data that may support applications for external funding. This poster shows the growth in Indiana CTSI accomplishments over the first three years of the CTSA grant. Conclusions: The Indiana CTSI has increased its contribution to the NIH strategic goals to advance the conduct of clinical and translational sciences through support of investigators, the contribution of new knowledge, and support for pilot grant activity

Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks

Panic disorder (PD) is a severe anxiety disorder that is characterized by recurrent panic attacks (PA), which can be unexpected (uPA, i.e., no clear identifiable trigger) or expected (ePA). Panic typically involves an abrupt feeling of catastrophic fear or distress accompanied by physiological symptoms such as palpitations, racing heart, thermal sensations, and sweating. Recurrent uPA and ePA can also lead to agoraphobia, where subjects with PD avoid situations that were associated with PA. Here we will review recent developments in our understanding of PD, which includes discussions on: symptoms and signs associated with uPA and ePAs; Diagnosis of PD and the new DSM-V; biological etiology such as heritability and gene×environment and gene×hormonal development interactions; comparisons between laboratory and naturally occurring uPAs and ePAs; neurochemical systems that are associated with clinical PAs (e.g. gene associations; targets for triggering or treating PAs), adaptive fear and panic response concepts in the context of new NIH RDoc approach; and finally strengths and weaknesses of translational animal models of adaptive and pathological panic states

Using Social Network Analysis Tools to Visualize and Analyze Collaboration in Use of CTSA Resources and Publications

poster abstractTo garner baseline data to determine whether or not the Indiana Clinical and Translational Sciences Institute (Indiana CTSI) was achieving collaboration across disciplines and institutions, the Indiana CTIS Tracking and Evaluation (T&E) Program compiled data regarding the utilization of resources across different Indiana CTSI programs and Project Development Teams (PDT) and data for the authors, departments, and institutional affiliations of Indiana CTSI peer reviewed publications. The Indiana CTSI T&E used a social networking tool, NodeXL, and data garnered to create a visualization of utilization of resources and publications co-authorship. The analysis showed the mean number of contacts with different resources per investigator was 1.37; every targeted program and PDT was shown to be linked to another. For publications analysis, 64 papers were identified with a total of 195 authors from the four Indiana CTSI member institutions. Sixty-nine of the authors were ICTSI investigators. However, 126 authors were non Indiana CTSI investigators although residing at partner institutions. Most surprising was that 140 authors were from 58 non-Indiana CTSI institutions. Conclusion: Baseline data indicates interdisciplinary and inter-institutional collaboration is already taking place

Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects