Enhanced functional connectivity and volume between cognitive and reward centers of naïve rodent brain produced by pro-dopaminergic agent KB220Z

RESEARCH ARTICLE Enhanced functional connectivity and volume between cognitive and reward centers of naïve rodent brain produced by prodopaminergic agent KB220Z Marcelo Febo1☯*, Kenneth Blum1,2,3,4,5☯*, Rajendra D. Badgaiyan2‡, Pablo D. Perez1☯, Luis M. Colon-Perez1☯, Panayotis K. Thanos6‡, Craig F. Ferris7☯, Praveen Kulkarni7‡, John Giordano3‡, David Baron5‡, Mark S. Gold1,5‡ a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Febo M, Blum K, Badgaiyan RD, Perez PD, Colon-Perez LM, Thanos PK, et al. (2017) Enhanced functional connectivity and volume between cognitive and reward centers of naïve rodent brain produced by pro-dopaminergic agent KB220Z. PLoS ONE 12(4): e0174774. https://doi. org/10.1371/journal.pone.0174774 Editor: Alessandro Gozzi, Istituto Italiano di Tecnologia, ITALY Received: February 1, 2016 Accepted: March 15, 2017 Published: April 26, 2017 Copyright: © 2017 Febo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. 1 Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, United States of America, 2 Department of Psychiatry, Wright State University, Boonshoft School of Medicine, Dayton, Ohio, United States of America, 3 Department of Holistic Medicine, National Institute for Holistic Addiction Studies, North Miami Beach, Florida, United States of America, 4 Division of Applied Clinical Research & Education, Dominion Diagnostics, LLC, North Kingstown, Rhode Island, United States of America, 5 Department of Psychiatry, Keck Medicine University of Southern California, Los Angeles, California, United States of America, 6 Research Institute on Addictions, University at Buffalo, Buffalo, New York, United States of America, 7 Center for Translational Neuroimaging, Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States of America ☯ These authors contributed equally to this work. ‡ These authors also contributed equally to this work. * (KB); (MF) Abstract Dopaminergic reward dysfunction in addictive behaviors is well supported in the literature. There is evidence that alterations in synchronous neural activity between brain regions subserving reward and various cognitive functions may significantly contribute to substancerelated disorders. This study presents the first evidence showing that a pro-dopaminergic nutraceutical (KB220Z) significantly enhances, above placebo, functional connectivity between reward and cognitive brain areas in the rat. These include the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, prelimbic and infralimbic loci. Significant functional connectivity, increased brain connectivity volume recruitment (potentially neuroplasticity), and dopaminergic functionality were found across the brain reward circuitry. Increases in functional connectivity were specific to these regions and were not broadly distributed across the brain. While these initial findings have been observed in drug naïve rodents, this robust, yet selective response implies clinical relevance for addicted individuals at risk for relapse, who show reductions in functional connectivity after protracted withdrawal. Future studies will evaluate KB220Z in animal models of addiction. Funding: The University of Florida Foundation www.uff.ufl.edu/ supported the present research. Marcelo Febo is the recipient of R01DA019946 and R21 DA038009. C.F. Ferris is the recipient of P01HD075750 and U54CA151881. Rajendra D. Badgaiyan is supported by the National Institutes of Health grants www.ncbi.nlm.nih.gov/ PLOS ONE | https://doi.org/10.1371/journal.pone.0174774 April 26, 2017 1 / 27 KB220Z enhanced resting state functional connectivity and volume in naïve rodent brain 1R01NS073884 and 1R21MH073624; Panayotis Thanos is the recipient of R01HD70888-01A1. Kenneth Blum served as Scientific Director of Path Foundation NY is the recipient of a grant from LifeExtension Foundation, Ft. Lauderdale, Florida awarded to Path Foundation NY www. pathfoundationny.org. Kenneth Blum Ph.D. is Chief Scientific Advisor and a paid a consultant for Dominion Diagnostics LLC., listed as one of his affiliates. Dr. Blum is a paid consultant as the neuroscience advisor for The Shores Treatment and Recovery Center not listed as an affiliate here. These funders provided support in the form of salaries for authors [MF RDB, PT, KB], but did not have any additional role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The National Institute for Holistic Addiction Studies provided some initial funding for the current study; the Institute had no input to the design or interpretation of the present study. The contents of the manuscript are solely the responsibility of the authors and do not represent the official views of the funding agencies. Competing interests: Kenneth Blum Ph.D. is Chief Scientific Advisor and has licensed Intellectual Property not related to KB220 variants for commercial advantage to Dominion Diagnostics LLC., listed as one of his affiliates. Dr. Blum is Chief Scientific Officer for and holds stock in RDSolutions System LLC. Nupathways, Victory Nutrition International (VNI) Inc., and RDSolutions System LLC., are licensees of patents related to KB220Z from Dr. Blum’s company Synaptamine Inc., for commercial product development and sale. They had no input into the design, interpretation or any other part of the current study. These commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials. Dr. Blum is the owner of US and foreign patents related to KB220 listed below. The other authors have declared that they have no competing interests. Introduction Addiction to psychoactive drugs poses a significant threat to the health, social and economic fabric of families, communities, and nations. The number of substance users is staggering. The annual U.S. National Survey on Drug Use and Health (NSDUH) estimated that in 2013 about 24.6 million Americans aged 12 or older used illicit drugs in the past month [1]. This problem urgently requires the development novel treatments for addiction and advanced methods to evaluate the efficacy of potential therapeutic agents. Developing treatments based on wellknown biosynthetic pathways that regulate central dopamine systems involved in mediating rewarding experiences is a major challenge. To curtail psychoactive drug abuse and dependence the U.S. Food and Drug Administration (FDA) approved several pharmaceutical agents collectively known as Medication Assisted Treatment (MAT) see (...truncated)