Use of methamphetamine phMRI in humans to investigate the role of dopamine in reward and other functions related to mental illness

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Abstract

This is a thesis submitted by Patrick Horgan on 31/03/2010 for the degree ofMaster of Philosophy in The University of Manchester for the study “Use ofmethamphetamine phMRI in humans to investigate the role of dopamine inreward and other functions related to mental illness”.IntroductionDopamine is a neurochemical that has an important role in brain processessuch as memory, learning and movement. In this study, manipulation ofdopamine receptors by methamphetamine and amisulpride was completed inhealthy volunteers undergoing functional magnetic resonance imaging (fMRI).Amisulpride is a selective dopamine receptor antagonist whereasmethamphetamine increases neuronal dopamine release. The main aim of thestudy was to examine whether effects of methamphetamine on blood oxygenlevel dependent (BOLD) signals in the brain could be attenuated by amisulpride.MethodsThe effects of the drugs were examined using three groups. One group wasgiven oral amisulpride and intravenous (i.v.) methamphetamine (AM). Anothergroup was given oral placebo and i.v. methamphetamine (PM). A third groupwas given oral placebo and i.v. placebo (PP). The effects of methamphetaminewere measured by comparing the PM group with the PP group. The effects ofamisulpride on methamphetamine responses were shown by the AM group. Achallenge pharmacological-fMRI (phMRI) imaging technique was used toexamine for the direct pharmacological effects of the drugs. Another imagingtechnique (modulation phMRI) was used to examine for drug effects onparticipants performing an N-back task, a finger tapping task and a rewardlearning task. Performance measures and reaction times for the tasks wereexamined for effects due to drug group where possible.ResultsAn effect on performance due to methamphetamine for some of the tasks wasdetected but the effect of amisulpride pretreatment was variable. There weredifferent effects of methamphetamine for the reaction time data depending onthe task. Amisulpride pretreatment did not clearly alter these effects. Therewere some demonstrable effects of methamphetamine on BOLD signalchanges for the tasks used. Increased BOLD signal was detected in expectedareas related to activating effects of methamphetamine for the challengephMRI, the finger tapping task and (to a lesser degree) for the N-back task.There was some attenuation of the BOLD signal resulting frommethamphetamine with amisulpride pretreatment for the challenge phMRI, thefinger tapping task and the N-back task. The effects of drug treatment on thereward learning task were weaker; however, this task showed activationssomewhat consistent with the role of dopamine in reward prediction error.ConclusionsThere were some demonstrable effects on BOLD signal changes related tomethamphetamine and attenuation by amisulpride for the challenge phMRI, Nbacktask and finger tapping task. There was some evidence of another type ofdopamine related effect for the reward learning task.

Keyword(s)

amisulpride amphetamine methamphetamine ; phMRI fMRI reward N-back motor memory dopamine

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