The role of DNA methylation in the development of cocaine-induced behavioural sensitisation
Date
2013-11-11
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Ravimsõltuvust iseloomustab vastupandamatu tung tarbida psühhotroopseid aineid hoolimata sellega kaasuvatest tõsistest kõrvaltoimetest. Uuringud on näidanud, et ravimsõltuvus kujuneb välja järk-järgult ja sõltuvusega seotud neurobioloogilised muutused võivad jääda püsima ka pärast psühhotroopsete ainete tarvitamise lõppu. Korduv psühhostimulaatori (nt. kokaiini) manustamine põhjustab katseloomadel suurenenud käitumusliku vastuse. Sellist fenomeni nimetatakse psühhomotoorseks ehk käitumuslikuks sensitisatsiooniks ning see modelleerib adiktiivset käitumist ja psühhostimulaatorite psühhootilisi komplikatsioone inimesel. Kuna käitumuslikule sensitisatsioonile on iseloomulikud püsivad muutused katseloomade käitumises, siis arvatakse, et osaliselt on selle põhjuseks lühi- ja pikaajalised geeniekspressiooni muutused, mis omakorda mõjutavad närviimpulsi ülekannet, sünapsite moodustamist ja närviringide funktsioneerimist. Mitmed uuringud viitavad, et epigeneetilised mehhanismid, eriti geeni promootori piirkonna DNA metüülimine, mille korral liidetakse DNA metüültransferaasi (DNMT) vahendusel metüülrühm tsütosiin-guanosiin (CpG) dinukleotiidsele järjestusele, on seotud pikaajaliste geeniekspressiooni muutustega. Käesoleva töö eesmärgiks oli uurida DNA metüülimise rolli kokaiini poolt põhjustatud käitumusliku sensitisatsiooni kujunemises hiirtel ja rottidel. Töö tulemused näitasid, et kokaiini manustamine suurendas dünaamiliselt Dnmt3a ja Dnmt3b ekspressiooni täiskasvanud hiirte naalduvas tuumas (nucleus accumbens) ja hipokampuses; põhjustas valitud markergeenide promootori piirkonnas nii DNA metüülimist kui ka demetüülimist ning DNMT inhibiitori, zebulariini, manustamine normaliseeris hüpermetüülitud geeni transkriptsiooni täiskasvanud hiirte naalduvas tuumas ja pidurdas käitumusliku sensitisatsiooni teket. Samuti leidsime, et keskkonnategurid, nagu metüülrühma doonor S-adenosüülmetioniin (SAM) ja varajases elueas kogetud stress, võivad DNA metüülimise kaudu soodustada psühhostimulaatoritest tingitud ravimsõltuvuse teket nii hiirtel kui ka rottidel.
Drug addiction is a chronic relapsing disorder characterised by a pattern of compulsive drug seeking and taking behaviour despite severe adverse consequences. Prolonged abuse of drugs, such as psychostimulants, may contribute to behavioural abnormalities that can last for months or even years after discontinuing drug consumption. Repeated administration of psychostimulants (such as cocaine) induces an enhanced behavioural response to subsequent drug exposure, a phenomenon known as psychomotor or behavioural sensitisation. Psychostimulant-induced behavioural sensitisation in rodents provides a model for addictive behaviours, such as those associated with craving and relapse, and for the psychotic complications of psychostimulant abuse. Behavioural sensitisation is remarkably persistent phenomenon. In rodents, it can persist from months to years after drug treatment is discontinued. Persistent behavioural sensitisation indicates that drug-induced short- and long-term changes in gene expression may be involved. Accumulating data suggest that epigenetic mechanisms, such as DNA methylation (catalysed by DNA methyltransferases - DNMTs), are critical regulators of persistent gene expression changes and may be related to behavioural disorders. The aim of this study was to investigate the role of DNA methylation in the development of cocaine-induced behavioural sensitisation in mice and rats. Our data demonstrated that cocaine treatment caused a dynamic increase in Dnmt3a and Dnmt3b expression levels in the nucleus accumbens (NAc) and hippocampus of adult mice; induced both DNA methylation/demethylation in the promoter regions of the selected genes; and intracerebroventricular treatment with the DNMT inhibitor zebularine normalised hypermethylated gene transcription in the NAc of adult mice and delayed the development of cocaine-induced behavioural sensitisation. We also found that environmental factors, such as methyl group donor S-adenosylmethionine (SAM) and early life stress, may promote, via DNA methylation, the development of psychostimulant-induced drug addiction in mice and rats.
Drug addiction is a chronic relapsing disorder characterised by a pattern of compulsive drug seeking and taking behaviour despite severe adverse consequences. Prolonged abuse of drugs, such as psychostimulants, may contribute to behavioural abnormalities that can last for months or even years after discontinuing drug consumption. Repeated administration of psychostimulants (such as cocaine) induces an enhanced behavioural response to subsequent drug exposure, a phenomenon known as psychomotor or behavioural sensitisation. Psychostimulant-induced behavioural sensitisation in rodents provides a model for addictive behaviours, such as those associated with craving and relapse, and for the psychotic complications of psychostimulant abuse. Behavioural sensitisation is remarkably persistent phenomenon. In rodents, it can persist from months to years after drug treatment is discontinued. Persistent behavioural sensitisation indicates that drug-induced short- and long-term changes in gene expression may be involved. Accumulating data suggest that epigenetic mechanisms, such as DNA methylation (catalysed by DNA methyltransferases - DNMTs), are critical regulators of persistent gene expression changes and may be related to behavioural disorders. The aim of this study was to investigate the role of DNA methylation in the development of cocaine-induced behavioural sensitisation in mice and rats. Our data demonstrated that cocaine treatment caused a dynamic increase in Dnmt3a and Dnmt3b expression levels in the nucleus accumbens (NAc) and hippocampus of adult mice; induced both DNA methylation/demethylation in the promoter regions of the selected genes; and intracerebroventricular treatment with the DNMT inhibitor zebularine normalised hypermethylated gene transcription in the NAc of adult mice and delayed the development of cocaine-induced behavioural sensitisation. We also found that environmental factors, such as methyl group donor S-adenosylmethionine (SAM) and early life stress, may promote, via DNA methylation, the development of psychostimulant-induced drug addiction in mice and rats.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
sõltuvushäired, psühhostimulaatorid, käitumismuutused, geeniekspressioon, DNA metüülimine, loomkatsed, substance abuse, psychostimulants, behaviour modifications, gene expression, DNA methylation, animal experiments