Psihomotorički stimulansi, poput kokaina i metamfetamina utječu na neuronsku mrežu mijenjajući dopaminergičnu i serotonergičnu transmisiju uzrokujući neuroadaptivne promjene moždanih funkcija koje rezultiraju promijenjenim motoričkim sposobnostima. Istraživanja na vinskoj mušici - Drosophili melanogaster pokazuju da opetovana administracija volatiliziranog kokaina izaziva progresivno povećanje lokomotornog odgovora definirano kao lokomotorna senzitizacija. Ponovljenom administracijom, kokain aktivira dopaminsku transmisiju, no posljedice akutne ili ponovljenih administracija volatiliziranog metamfetamina kod Drosophile još nije poznat. Iako postoji nekoliko metoda za mjerenje lokomotorne senzitizacije u Drosophili, niti jedna nije u potpunosti zadovoljila sve uvjete za kvantitativno, reproducibilno, objektivno i visokoprotočno mjerenje. U ovom diplomskom radu razvili smo i validirali novu visokoprotočnu platformu koja će objektivno i reproducibilno inducirati i na individualnoj razini kvantificirati lokomotornu senzitizaciju Drosophile melanogaster na kokain i metamfetamin. Definirali smo razlike u mehanizmu djelovanja kokaina i metamfetamina te ulogu cirkadijalnih gena i gena dopaminskog sustava u regulaciji razvoja lokomotorne senzitizacije u odgovoru na te psihostimulanse. Naši rezultati potvrđuju kako važnu ulogu u regulaciji lokomotorne senzitizacije na kokain imaju Clock, period i cycle geni, te potencijalno VMAT u dopaminskim i Clock pozitivnim neuronima. Lokomotorna senzitizacija na metamfetamin ovisi o različitim genima od senzitizacije na kokain - Clkjrk te potencijalno D1 receptoru i VMAT u dopaminskim neuronima. Dakle, regulacija senzitizacije na kokain i metamfetamin se razlikuje u genetskim mehanizmima. Utvrdili smo da su za razvoj senzitizacije na oba psihostimulansa važni dopaminski transporteri - DAT te VMAT u period pozitivnim neuronima. Drosophila melanogaster kao modelni organizam u ispitivanju razvoja lokomotorne senzitizacije doprinijet će genetskom probiru i identifikaciji potencijalno ključnih gena koji sudjeluju u regulaciji razvoja bihevioralne senzitizacije na psihostimulanse što će u budućnosti pomoći razumijevanju molekularnih mehanizama u podlozi razvoja ovisnosti.

Psychomotor stimulants, such as cocaine and methamphetamine, affect the neuronal network by altering dopaminergic and serotonergic transmission causing neuroadaptive brain function changes resulting in modulation in motor abilities. Research work in Drosophila melanogaster shows that repeated administration of volatilized cocaine leads to a progressive increase in locomotor response defined as locomotor sensitization. With repeated administration cocaine activates dopamine transmission leading to locomotor sensitization, but consequences of acute and repeated administrations of volatilized methamphetamine in Drosophila are not known. Although there are several methods for measuring locomotor sensitization, none fulfills all the criteria being quantitative, reproducible, objective and high-throughput. In this thesis we have developed and validated a new high-throughput platform that objectively and reproducibly induces locomotor sensitization to cocaine and methamphetamine at population and individual level in Drosophila melanogaster. We defined the differences in the action of cocaine and methamphetamine and the role for circadian genes and the dopaminergic system in regulating the development of locomotor sensitization in response to these psychostimulants. Our results confirm important role for Clock, period and cycle genes in regulating locomotor sensitization on cocaine, and likely VMAT in dopaminergic and Clock positive neurons. Locomotor sensitization to methamphetamine depends on different set of genes than sensitization to cocaine, mainly Clock and likely D1 receptor and VMAT in dopaminergic neurons. Thus, regulation of sensitization to cocaine and methamphetamine differs in genetic mechanisms. We have found that dopamine transporter DAT and VMAT in per positive neurons are important for the development of sensitization to both psychostimulants. Drosophila melanogaster as a model organism for the study of locomotor sensitization will contribute to the genetic screening and identification of potentially critical genes involved in the regulation of behavioral sensitization to psychostimulants, which in the future will help in understanding molecular mechanisms underlying addiction.