title: Down-regulation of serotonin and dopamine transporter genes in individual rats expressing a gambling-prone profile: A possible role for epigenetic mechanisms.
abstract: Gambling Disorder (GD) is characterized by excessive gambling despite adverse consequences on individual functioning. In spite of some positive findings, it is difficult to draw any conclusion on the genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like those that engage epigenetics) may explain gene alterations in this addictive disease. Wistar male rats underwent an operant task for the evaluation of individual propensity to gamble. Few rats, after having learnt to prefer nose-poking for a large over a small food reward, were sacrificed to obtain a baseline profile of gene expression at both central and peripheral levels. In the remaining rats, probability of occurrence of large-reward delivery decreased progressively to very low levels. Thus, rats were faced with temptation to "gamble", i.e. to nose-poke for a binge reward, whose delivery was omitted the majority of times. After 3weeks of testing, rats showing a clear-cut profile of either gambling proneness or aversion were selected and sacrificed after the last session. A selective down-regulation of i) serotonin transporter in prefrontal cortex, ii) tyrosine hydroxylase in ventral striatum, iii) dopamine transporter in lymphocytes was evidenced in "gambler" vs "non-gambler" rats. The exposure to such operant task (compared to home-cage alone) modulated ventrostriatal but not prefrontal genes. A consistent increase of DNA methylation, in one specific CpG site at serotonin transporter gene, was evident in prefrontal cortex of "gambler" rats. Elucidation of epigenetic changes occurring during GD progression may pave the way to the development of new therapeutic strategies through specific modulation of epigenetic factors.
authors: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors: Francesca
authors: F
authors: Zoratto
authors: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors: Emilia
authors: E
authors: Romano
authors: Department of Medical Surgical Sciences & Biotechnology, "Sapienza" University of Rome, Rome, Italy.
authors: Esterina
authors: E
authors: Pascale
authors: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
authors: Mariangela
authors: M
authors: Pucci
authors: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
authors: Anastasia
authors: A
authors: Falconi
authors: Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Policlinico, Milan, Italy; Bipolar Disorders Clinic, Stanford University, Stanford, CA, USA.
authors: Bernardo
authors: B
authors: Dell'Osso
authors: School of Medicine and Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; European Center for Brain Research, Santa Lucia Foundation, Rome, Italy.
authors: Mauro
authors: M
authors: Maccarrone
authors: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors: Giovanni
authors: G
authors: Laviola
authors: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. Electronic address: cdaddario@unite.it.
authors: Claudio
authors: C
authors: D'Addario
authors: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. Electronic address: walter.adriani@iss.it.
authors: Walter
authors: W
authors: Adriani
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003216:Conditioning, Operant; D019175:DNA Methylation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005715:Gambling / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D010551:Personality; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D016601:RNA-Binding Proteins; C482440:Sert1 protein, rat; D014446:Tyrosine 3-Monooxygenase
keywords: PBMCs; animal model; dopamine; epigenomics; gambling; lymphocytes; prefrontal cortex; serotonin