The proposed study will investigate the role of dopamine (DA) in time perception and euphoria using functional magnetic resonance imaging (fMRI). Previous research in animals and humans has identified the important role that the neurotransmitter DA plays both in interval timing and in the reinforcing properties of addictive drugs. Dopaminergic drugs are also known to influence the speed of the internal clock which is used to perform interval timing tasks, with DA agonists (e.g., d-amphetamine: AMPH) causing increases in clock speed while DA antagonists (e.g., haloperidol: HALO) cause decreases in clock speed. While these behavioral findings are well established in animals, the only human data addressing dopamine's effects on interval timing was gathered from patients with Parkinson's disease on and off their apomorphine + L-dihydroxyphenylalanine (L-DOPA) replacement therapy. For the current proposal, twenty healthy adult subjects (males and females) will be studied for their behavioral sensitivity to HALO and AMPH and assessed on quantitative and qualitative behavioral measures (i.e., temporal discrimination and subjective effects of the drugs themselves and mood). Six subjects who show robust responses to the drugs will participate in an imaging experiment of similar design using fMRI. Subjective assessments of each drug's effects (intensity and euphoria) will be administered at specific time points between imaging runs, and longer questionnaires on mood (POMS) and drug effects (ARCI) will be given at the beginning and end of each session. Subjects will be tested on two separate occasions for each study, once after taking HALO and once after taking AMPH. The major goals of this proposal are 1) To extend recent findings on activation of frontal-striatal loops in human interval timing. 2) To explore the neural effects of dopamine agonists and antagonists on interval timing and mood. 3) To correlate the subjective effects of dopaminergic drugs on interval timing and mood with tomographic physiological data. These preliminary studies will serve as part of a broader research program meant to understand in both normal subjects and patient populations the neural and pharmacological bases of temporal processing in the seconds-to- minutes range, and how interval timing is integrated into and influences ongoing human behavior. Consequently, these studies will contribute to our understanding of the quantitative and qualitative effects of dopaminergic drugs (e.g., alteration in time perception and euphoria) that may contribute to drug abuse and dependence.
