title: rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts.
abstract: Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow's et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.
authors.affiliation: Department of Psychiatry & McKnight Brain Institute, University of Florida, College of Medicine , Gainesville, FL , USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Blum
authors.forename: Yijun
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Marlene
authors.initials: M
authors.lastname: Oscar-Berman
authors.forename: Andrew
authors.initials: A
authors.lastname: Smolen
authors.forename: Marcelo
authors.initials: M
authors.lastname: Febo
authors.forename: David
authors.initials: D
authors.lastname: Han
authors.forename: Thomas
authors.initials: T
authors.lastname: Simpatico
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Cronjé
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Demetrovics
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gold
mesh_terms: D000328:Adult; D000465:Algorithms; D001921:Brain / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D002395:Catecholamines / Q000627:therapeutic use*; D018592:Cross-Over Studies; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D059907:Functional Neuroimaging; D060005:Genotyping Techniques; D006556:Heroin Dependence / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008995:Monoamine Oxidase / Q000627:therapeutic use*; D015260:Neprilysin / Q000627:therapeutic use*; D009434:Neural Pathways / Q000187:drug effects* / Q000503:physiopathology; D010865:Pilot Projects; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D002395:Catecholamines; D018491:Dopamine Agonists; C000601005:KB220Z; D008995:Monoamine Oxidase; D015260:Neprilysin
keywords: Abstinent heroin addicts; KB220Z; brain reward circuitry; dopamine; fMRI