This study investigates the role of nicotine (NIC: the prototypic agonist at nicotinic acetylcholine receptors) and mecamylamine (MEC: a nicotinic antagonist) in interval timing and mood using functional magnetic resonance imaging (fMRI). About 25% of Americans meet criteria for NIC dependence, which represents an important health issue because of the association of cigarette smoking with lung cancer, emphysema, and other serious disorders. The proportion of patients with schizophrenia who smoke is greater than 80% by some estimates. The mechanisms of NIC dependence are poorly understood at present, however the addictive properties of many drugs are thought to be mediated by the mesolimbic dopamine (DA) system. NIC receptors are located on DA cell bodies in both the mesolimbic and the nigrostriatal DA systems, the latter of which plays important roles both in motor activity and in the speed of the internal clock used in interval timing tasks. The current proposal seeks to identify the physiological mechanisms underlying timing and mood effects of NIC and MEC, focusing on the drugs' indirect effects on these two DA systems. For the proposed experiment, twelve each male and female healthy, adult, non-smoking subjects will be studied for their behavioral sensitivity to NIC and MEC in different testing sessions and assessed on quantitative and qualitative behavioral measures (i.e., temporal discrimination, mood, and subjective drug effects). Six male and six female subjects who show robust responses will participate in an imaging experiment of similar design using fMRI. Subjective assessments of each drug's effects (intensity and euphoria) will be given at specific time points between imaging runs. Longer questionnaires on mood (Profile of Mood States, POMS), psychological symptoms (Symptom Checklist with 90 items, Revised; SCL-90-R), and drug effects (Addiction Research Center Inventory, ARCI) will be given at the beginning and end of each session. The major goals of this proposal are: 1) To further characterize the functional role played by frontal-striatal loops in human interval timing. 2) To explore the neural effects of NIC and MEC on interval timing and mood. 3) To correlate the subjective effects of NIC and MEC on interval timing and mood with tomographic physiological data. The proposed studies are part of a broader research program meant to understand the neural and pharmacological bases of temporal processing in the seconds-to-minutes range and will contribute to our understanding of the quantitative and qualitative effects of NIC (e.g., alterations in time perception and mood) that may contribute to tobacco dependence. These studies will provide a solid foundation for extending the findings from normal human subjects to understanding aspects of the functional neuropathology in schizophrenic patients.
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