Anxiety is a normal human emotion that everyone experiences at some point. To feel anxious before a situation is normal and it usually ends soon after one is out of the situation that caused it. But for millions of people, the anxiety does not go away, and gets worse over time resulting in psychological or physical sickness. These people have anxiety disorders. The mainstays of treatment are benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). Although clinically useful, chronic use of benzodiazepines leads to tolerance, dependence and sedation. SSRIs require weeks to work and are not without side effects either. Better alternatives over existing anxiety treatments are needed but poor mechanistic understanding of anxiety has impeded discovery of novel interventions. Our project addresses this critical barrier to progress in anxiety research. Our recently published work has suggested causal role of oxidative stress in anxiety-like behavior of rats. In separate studies Regulator of G-Protein Signaling protein (RGS)-2 and two antioxidant enzymes, glutathione reductase (Gsr)-1 and glyoxalase (Glo)-1 have been postulated as modulators of anxiety. Our work suggests a critical convergence of oxidative stress, Glo1, Gsr1 and RGS2 in anxiety. In our preliminary studies, induction of oxidative stress sub-chronically via L-Buthionine-(S,R)-sulfoximine (BSO) treatment reduced RGS2, Glo1 and Gsr1 levels in locus coeruleus (LC), hippocampus and amygdala and increased anxiety-like behavior of rats. On the other hand, acute oxidative stress increased RGS2, Glo1 and Gsr1 levels in these brain areas but did not produce anxiety-like behavior in rats. Furthermore, lentiviral-mediated overexpression of RGS2 in the hippocampus rescued the anxious phenotype of sub-chronically BSO treated rats. And, Glo1 and Gsr1 protein expression increased in response to RGS2 overepxression within the hippocampus. Our preliminary studies in neuronal cell cultures mimic animal studies with respect to differential regulation of RGS2, Glo1 and Gsr1. Acute oxidative stress increased RGS2, Glo1 and Gsr1 mRNA and proteins while sub- chronic treatment decreased their levels. Our hypothesis is that RGS2 via activation of specific signaling cascades plays a central role in modulating antioxidant enzymes, Glo1 and Gsr1, critical to the etiology of anxiety. We will test our hypothesis by pursuing two specific aims.
In aim 1 using a brain-derived cell culture model of acute and sub-chronic oxidative stress, involvement of PKC, p38 and calpain pathways as well as involvement of transcription factors (Nrf2, Sp-1) in an RGS2 dependent regulation of Glo1 and Gsr1 levels will be studied.
In aim 2 utilizing our published rat model of acute and sub-chronic oxidative stress, involvement of PKC, p38 and calpain pathways in an RGS2 dependent modulation of Glo1 and Gsr1 together with the assessment of anxiety-like behavior, would be determined. Mechanistic insights obtained from our proposal would lead to the identification of novel targets for drug design in the treatment of anxiety disorders.

Public Health Relevance

Anxiety disorders affect an estimated 40 million people in the United States. Despite an enormous increase in anxiety disorder research, the mechanisms in the brain that regulate anxiety remain poorly understood. Emerging reports including ours, offer a strong argument for a causal role of oxidative stress in anxiety. This proposal seeks to determine those mechanisms representing a new line of investigation that would reveal unique avenues for treatment of anxiety.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Academic Research Enhancement Awards (AREA) (R15)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Nadler, Laurie S
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University of Houston
Schools of Pharmacy
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Solanki, Naimesh; Salvi, Ankita; Patki, Gaurav et al. (2017) Modulating Oxidative Stress Relieves Stress-Induced Behavioral and Cognitive Impairments in Rats. Int J Neuropsychopharmacol 20:550-561
Salim, Samina (2017) Oxidative Stress and the Central Nervous System. J Pharmacol Exp Ther 360:201-205
Liu, Hesong; Atrooz, Fatin; Salvi, Ankita et al. (2017) Behavioral and cognitive impact of early life stress: Insights from an animal model. Prog Neuropsychopharmacol Biol Psychiatry 78:88-95
Kochi, Camila; Liu, Hesong; Zaidi, Safiyya et al. (2017) Prior treadmill exercise promotes resilience to vicarious trauma in rats. Prog Neuropsychopharmacol Biol Psychiatry 77:216-221
Salvi, Ankita; Patki, Gaurav; Khan, Eisha et al. (2016) Protective Effect of Tempol on Buthionine Sulfoximine-Induced Mitochondrial Impairment in Hippocampal Derived HT22 Cells. Oxid Med Cell Longev 2016:5059043
Solanki, Naimesh; Atrooz, Fatin; Asghar, Saman et al. (2016) Tempol protects sleep-deprivation induced behavioral deficits in aggressive male Long-Evans rats. Neurosci Lett 612:245-250
Solanki, Naimesh; Alkadhi, Isam; Atrooz, Fatin et al. (2015) Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder. Nutr Res 35:65-75
Patki, Gaurav; Atrooz, Fatin; Alkadhi, Isam et al. (2015) High aggression in rats is associated with elevated stress, anxiety-like behavior, and altered catecholamine content in the brain. Neurosci Lett 584:308-13
Patki, Gaurav; Salvi, Ankita; Liu, Hesong et al. (2015) Tempol treatment reduces anxiety-like behaviors induced by multiple anxiogenic drugs in rats. PLoS One 10:e0117498
Patki, Gaurav; Salvi, Ankita; Liu, Hesong et al. (2015) Witnessing traumatic events and post-traumatic stress disorder: Insights from an animal model. Neurosci Lett 600:28-32

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