Russell Brown

Professor

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• brown1@etsu.edu
• 423-439-8523
• VA 1/136

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EDUCATION/PROFESSIONAL EXPERIENCE

BS 1998 University of Oklahoma (Psychology and Chemistry)
MS 1995, PhD 1998 University of Kentucky (Experimental Psychology)
Postdoctoral Fellowship 1998-2000 University of Lethbridge, Lethbridge, Alberta, Canada (in the labs of Drs. Bryan Kolb and Ian Whishaw)

I am a behavioral neuroscientist, with a strong emphasis in psychopharmacology. My research background actually began in the cognitive arena, analyzing underlying mechanisms of behavioral ecological mechanisms in Dr. Lynn Devenport's lab at the University of Oklahoma. This work continued in the laboratories of Dr. Phil Kraemer and Dr. Stephen Scheff at the University of Kentucky studying ontogeny of learning and memory and rodents, timing behavior in avians, as well as pharmacological approaches to improve compensation after traumatic brain injury. I have always had a strong research interest in brain plasticity and its response to experience.

At the end of my graduate school career, we began to analyze the effects of nicotine on cognitive function and in a rodent model of traumatic brain injury. I carried on this work in the laboratories of Drs. Bryan Kolb and Ian Whishaw at the University of Lethbridge, expanding my interests into the effects of nicotine on brain plasticity and compensation after brain injury.

I took a faculty position at East Tennessee State University (ETSU) in August of 2000, and through a collaboration, began pursuing mechanisms of psychostimulant addiction using a model of dopamine D2 receptor supersensitivity that originated in Dr. Rich Kostrzewa's lab in the Department of Pharmacology in Quillen College of Medicine at ETSU. Although Richs interests were more directed towards Parkinsons Disease and neurotoxicity, I realized this model had potential as a model of schizophrenia. From that point on, a major research focus in our lab centered on comorbidity in behavioral disorders, especially substance abuse in schizophrenia using the neonatal quinpirole model.

RESEARCH/TEACHING INTERESTS

1. Substance abuse comorbidity in behavioral disorders
2. Sex differences in the response to psychostimulants
3. The consequences of drug treatment on neural plasticity

 
1. Substance abuse comorbidity in Schizophrenia: In this line of research, our laboratory has analyzed the behavioral and neurochemical consequences of dopamine D2-like supersensitization. The dopamine D2 receptor is increased in its sensitivity through neonatal quinpirole (a dopamine D2/D3 agonist) treatment during the first three weeks of life in a rat. This increase in sensitivity does not result in a change in receptor number, and persists throughout the animals lifetime. Over several years of work, we have found that neonatal quinpirole treatment enhances behavioral sensitization and rewarding effects of nicotine. This is especially important because approximately 80% of schizophrenics smoke cigarettes, and they smoke heavily. Ultimately, this results in a poor quality of life and shortens the average lifespan in a smoking schizophrenic. Our primary interest here is to try to identify behavioral and neurobiological targets for treating smoking in schizophrenia.

2. Investigation of PARP inhibitors in Major Depressive Disorder. More recently, we have begn one of two new research lines in my laboratory. One is a collaboration with Dr. Greg Ordway, a faculty member in our department, analyzing novel pharmacological targets for the treatment of Major Depressive Disorder. Dr. Ordway discovered an elevation of the DNA repair enzyme Poly (ADP-ribose) polymerase (PARP) in the white matter of human brain tissue of individuals that had suffered from major depression. We have been investigating the effects of PARP inhibitors in preclinical rodent models of depression with success. We believe we may have found a novel target for the treatment of depression, and especially focusing this work towards individuals who are treatment-resistant to current antidepressant treatments.

3.  Novel anti-inflammatories for treatment of Alzheimer’s Disease. A third line of research is in collaboration with P2D Bioscience, Inc. (Cincinnati, OH) and Dr. Prasad Gabbita. We have been investigating the effects of several anti-neuroinflammatory drugs, given through the diet, to the 3xTg Alzheimer’s Disease model in the mouse. We have also had a considerable amount of success on this work, and hope to continue to do more research in the future.

LABORATORY PERSONNEL

Graduate Students:

Loren Peeters (BA, Tusculum College, 2019). Loren is a fourth-year graduate student, analyzing behavioral changes and mechanisms of plasticity in response to nicotine as well as therapeuetic targets in the F1 generation animals that are the offspring of 'founders' neonatally treated with quinpirole (or saline).

Anthony Cuozzo (BS, Florida State University, 2021). Anthony is a first-year graduate student, also working with the F1 generation model of drug abuse vulnerability and underlying mechanisms related to both substance abuse and psychosis. 

Kira Ivanich (Federal Work Study; Independent study). Kira is an undergraduate student that has been focusing on our Alzheimer's Disease project, and is currently analyzing microglial changes across brain areas in three different mouse models of AD. 

ACTIVE RESEARCH FUNDING

ACTIVE RESEARCH FUNDING:

1 R15 DA04926-01 
Brown, Russell W. (PI) 04/01/19-03/31/23 (No cost extension awarded)  
“The role of adenosine A(2A) receptor activation on the behavioral and plasticity response to nicotine in a rodent model of schizophrenia.” This project is designed to analyze the role of adenosine A(2A) receptor as a target for reducing the rewarding aspects of nicotine in a rodent model of schizophrenia developed in our laboratory.  
Role: Principal Investigator 

1R15 MH119628         
Chandley, Michelle J. (PI) 05/01/19-04/30/23 (No cost extension awarded)  
“Neuroinflammatory mediators of glutamatergic and gabaergic neuropathology in the anterior cingulate cortex of Autism Spectrum Disorder.” This project is designed to analyze neuropathology in both human post-mortem brain tissue and in an animal model of autism. Our role is to help with social interaction behavioral testing.  
Role: Co-Investigator 

1R44 AG069622 
P2D Bioscience, Inc. (PI) 10/01/22-09/30/24 
“A first-in-class orally bioavailable small molecule dual inhibitor targeting NLRP3 and the dopamine transporter to treat AD.” In this project, we will behaviorally test three different mouse of models of Alzheimer’s Disease as well as analyze neurobiological mechanisms of these effects analyzing neural plasticity proteins both in vivo and in cell culture.  
Role: Principal Investigator of subaward 

BLRD I01 BX005367-01  
Gass, Justin T. (PI) 01/01/22 – 12/31/26
“mGlu5 modulation prevents and attenuates deficits in a model of PTSD/AUD comorbidity.” In this project, we will be involved with brain tissue assays of brain-derived neurotrophic factor (BDNF) as well as several pro- and anti-inflammatory cytokines.  
Role: Co-Investigator 

Subaward to NIH SBIR SB1: 5R44 AG051302-03
Gabbita, S. Prasad (PI) 08/01/18 – 07/31/20
“Application of novel anti-inflammatory drugs towards Alzheimer’s Disease.”
This project is designed to analyze novel TNF-alpha modulators towards alleviating behavioral and neurobiological deficits in the 3xTg Alzheimer’s Disease model in the mouse.
Role: Co-Investigator

1R15 AG055107.
Zhu, Meng-Yang (PI)  10/01/18-09/30/21
“Restoration of noradrengergic and dopaminergic functions in the brain of aged rats.”
This project is designed to analyze genetic alterations in the noradrenergic system and its effects on stress-related behaviors. Our laboratory’s role is in stress behavioral testing.
Role: Co-Investigator

SELECTED PUBLICATIONS

Brown RW, Varnum CG, Wills LJ, Peeters LD, Gass JT. Modulation of mGlu5 improves sensorimotor gating deficits in rats neonatally treated with quinpirole through changes in dopamine D2 signaling. Pharmacol Biochem Behav. 2021 Dec;211:173292. doi: 10.1016/j.pbb.2021.173292. Epub 2021 Oct 25. PubMed PMID: 34710401; PubMed Central PMCID: PMC9176413.

Gill WD, Burgess KC, Vied C, Brown RW. Transgenerational evidence of increases in dopamine D2 receptor sensitivity in rodents: Impact on sensorimotor gating, the behavioral response to nicotine and BDNF. J Psychopharmacol. 2021 Oct;35(10):1188-1203. doi: 10.1177/02698811211033927. Epub 2021 Jul 22. PubMed PMID: 34291671; PubMed Central PMCID: PMC9169618.

Shelton HW, Gabbita SP, Gill WD, Burgess KC, Whicker WS, Brown RW. The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia. Behav Brain Res. 2021 May 21;406:113229. doi: 10.1016/j.bbr.2021.113229. Epub 2021 Mar 5. PubMed PMID: 33684425.

Peeters LD, Brown RW. Dopamine Receptor Supersnsitivity and Schizohprenia. In: Kostrzewa RM, editor. Handbook of Neurotoxicity 2nd ed. New York City: Springer; 2021. p.224-230. 224-230p.

Zeng F, Fan Y, Brown RW, Drew Gill W, Price JB, Jones TC, Zhu MY. Effects of Manipulation of Noradrenergic Activities on the Expression of Dopaminergic Phenotypes in Aged Rat Brains. ASN Neuro. 2021 Jan-Dec;13:17590914211055064. doi: 10.1177/17590914211055064. PubMed PMID: 34812056; PubMed Central PMCID: PMC8613899.

Brown RW, Bhide PG, Gill WD, Peeters LD. The adenosine A(2A) receptor agonist CGS 21680 alleviates auditory sensorimotor gating deficits and increases in accumbal CREB in rats neonatally treated with quinpirole. Psychopharmacology (Berl). 2020 Dec;237(12):3519-3527. doi: 10.1007/s00213-020-05631-8. Epub 2020 Aug 8. PubMed PMID: 32772144; PubMed Central PMCID: PMC7686116.

Kostrzewa RM, Wydra K, Filip M, Crawford CA, McDougall SA, Brown RW, Borroto-Escuela DO, Fuxe K, Gainetdinov RR. Dopamine D2 Receptor Supersensitivity as a Spectrum of Neurotoxicity and Status in Psychiatric Disorders. J Pharmacol Exp Ther. 2018 Sep;366(3):519-526. doi: 10.1124/jpet.118.247981.

Ordway GA, Szebeni A, Hernandez LJ, Crawford JD, Szebeni K, Chandley MJ, Burgess KC, Miller C, Bakkalbasi E, Brown RW. Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models. Int J Neuropsychopharmacol. 2017 Dec 1;20(12):994-1004. doi: 10.1093/ijnp/pyx068. PubMed PMID: 29016792; PubMed Central PMCID: PMC5716178.