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

Marcelo Febo,Rajendra D Badgaiyan,Mark S Gold,Pablo D Perez,Luis M Colon-Perez,Craig F Ferris,Praveen Kulkarni,John Giordano,Panayotis K Thanos,David Baron,Kenneth Blum

doi:10.1371/journal.pone.0174774

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 substance-related 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.

Highlights

Addiction to psychoactive drugs poses a significant threat to the health, social and economic fabric of families, communities, and nations
Representative image registration for anatomical and functional scans is shown in S1 Fig. Functional connectivity between the left and right ventral and dorsal striatum were assessed to determine the presence of functional homotopic connectivity in placebo control rats, S2 Fig. Homotopic connectivity in the striatum, as previously reported, and in the nucleus accumbens (NAc), was confirmed, S2 Fig. The presence of movement in images was examined, and animals with excess motion artifact were removed shown in S3 Fig. Measured respiratory rates and body temperatures remained stable before and after administering KB220Z, with breathing typically between 50–70 breaths per minute
It has become increasingly apparent that drug addiction involves adaptations in the genetic and epigenetic landscape of brain reward circuitry and its associated limbic and cognitive regions [37–40]

Summary

Introduction

Addiction to psychoactive drugs poses a significant threat to the health, social and economic fabric of families, communities, and nations. 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. 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 S1 Table [2]. The limited success of treating psychoactive substance abuse with current modalities leaves open the need to develop new therapies [3–6]

Methods

Results

Conclusion