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Neuroscience Research

Neuroscience Research

Positron Emission Tomography (PET) allows for the measurement of populations of neurotransmitter receptors and regulators of neurotransmission (transporters which uptake neurotransmitters after their release) in human participants. Using Fallypride PET to image D2/3 dopamine receptor and PE2I PET to image dopamine transporter populations across the human brain, work in the Zald Affective Neuroscience Lab (PI: David Zald, PhD) seeks to understand the role of brain dopamine in subjective valuation, motivation, reward, and decision making. Pharmacological challenges that induce dopamine release (d-amphetamine administration) can be used to measure how the Fallypride PET signal changes differentially across individuals; this metric assists us in understanding the role of dopamine signaling in human behavior.
Combining PET data with functional magnetic resonance imaging (fMRI) of human participants while they perform behavioral tasks allows for a more complete understanding of the neurobiology of decision making behavior and the role of the dopamine system in it.

Fallypride pet as a tool to study the dopamine system in humans

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An early (left image) and late (middle) Fallypride PET image displaying the accumulation of the tracer in the striatum (hot colors) with time. From this raw data, we can create binding potential (BP) maps of D2/3 receptor availability across the brain (right image). Looking at differences in these BP measures at baseline and after acute amphetamine (which induces DA release and normally decreases the Fallypride signal) gives us insight into the role of the dopamine system in a variety of human behaviors (personality, choice, addiction risk, etc....).

Research Projects

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Drug High, Like, and Feel ratings vary across individuals.
Timing of the peak in these effects vary.
What explains these individual differences?

Individual differences in subjective responses to dAMPH.

We have data from our lab here at Vanderbilt and via our collaborators Harriet de Wit at the University of Chicago and Abraham Palmer at the University of California, San Diego that healthy, young adults vary in the degree of self-reported “Feel”, “High”, and “Liking” they report after oral d-amphetamie (dAMPH) versus placebo. The timing of peak subjective Feel/High/Liking, when present, varies across individuals. We are currently studying whether variability in dopamine signaling as assessed with 18F-Fallypride PET before and after dAMPH administration can explain these individual differences in self-report subjective effects.
This work has implications for identifying biological markers of potential psychostimulant addiction risk as the speed of delivery of drugs of abuse (and associated fast onset in their effects) are linked to risk for developing dependence. In addition to PET, we plan to assess whether variability in personality traits and genetic markers are associated with the differences we observe in our PET and subjective effect measures.

Journal of Psychopharmacology Article - Temporal differences in damph subjective response
Journal of psychopharmacology Supplemental material
Neuropharmacology Article - Fallypride PET and Subjective Responses to dAMPH
Neuropharmacology supplemental material
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COMT
DAT1
DRD2
Taq1A

Effects on DRD2/3 receptor availability, DAT levels, or dAMPH-induced DA release?
Impact of commonly studied dopamine genetic polymorphisms on Fallypride PET signal(s).

While many researchers have used genetic variants in dopamine signaling-related genes (DRD2, DAT, COMT, etc…) as proxy measures of dopamine signaling, the impact of genetic variation on dopamine PET signal has been limited by the expense of obtaining sufficient power in PET studies. Here in the Affective Neuroscience lab at Vanderbilt, we are in a unique position to investigate the role of these dopamine signaling genes on baseline DRD2/3 binding potential (assessed with Fallypride) and dAMPH-induced DA release in samples of >150 and ~45 (with another ~50 planned to be collected), respectively. Combining this data with a to-be-collected PET measure of baseline DAT levels will allow us a more complete understanding of if and where genetic variation impacts dopamine signaling.
This work will be instrumental in demonstrating the neurobiological and mechanistic specificity (if any) at which these often-studied genetic variants act and potentially identify other variants as good markers of putative dopamine signaling. As genetic tools are becoming more widely used and cost-effective, this work will identify potentially useful tools for assessing dopamine signaling variation in a wide range of settings.

Translational Psychiatry Article - c957T as key determinant of d2/3 receptor availability in putamen and Ventral Striatum
Translational Psychiatry Supplemental Material
Role of sex hormones on dopamine signaling.

While preclinical and some human work suggests that the female hormones estradiol and progesterone modulate affective processing, working memory, and mesocorticolimbic dopamine signaling, to our knowledge no work has focused on whether these hormones affect dAMPH-induced dopamine release. We plan to investigate sex and sex hormone effects on this measure (indexed by Fallypride displacement after oral dAMPH versus placebo).
This work has the potential to allow us to understand variability across sexes and within females that may relate to differential rates of drug addiction and relapse.
Furthermore, enzymatic activity of COMT (a critical regulator of cortical dopamine) varies across the sexes. We are also investigating sex x COMT effects on fMRI measures of brain function during task and rest.

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COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on Brain Function
Lack of consistent sex differences in d-amphetamine-induced dopamine release

CV

Chris_Smith_CV_May_2021.pdf
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Collaborations: Projects, Papers, & People

Polygenic Risk Scores of Psychiatric Disorders: Role of General Factor of Psychopathology
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Lea Davis, Vanderbilt Genetics Institute
Benjamin Lahey, University of Chicago
General Factor of Psychopathology
Dopamine D2/3 Receptor Availability and Aging
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Gregory Samanez-Larkin, Duke University
Kendra Seaman, Duke University
JCBFM, Partial Volume Correction Effects on Age, D2/3 Receptor Availability
PREPRINT: Differential regional decline in dopamine receptor availability across adulthood
Data Visualization
Dopamine and the Discounting of Time, Effort, and Probability
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Gregory Samanez-Larkin, Duke University
Jaime Castrellon, Duke University
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Differences in dopamine associated with reward discounting in clinical groups but not healthy adults
Role of Dopamine in Impulsive and Compulsive Behaviors in Parkinson's Disease Patients on Dopamine Agonists
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Daniel Claassen, Vanderbilt University Medical Center
Journal of Neuroscience, D2/3 receptor expression in Parkinson's disease patients with & without ICB
Partial Volume Correction in FLB 457 and Fallypride PET Data
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Gregory Samanez-Larkin, Duke University
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JCBFM, Partial Volume Correction Effects on Age, D2/3 Receptor Availability
Individual Differences in Subjective Responses to d-amphetamine
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HARRIET DE wIT, uNIVERSITY OF CHICAGO
Abraham palmer, university of California San diego
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Journal of Psychopharmacology, Temporal Differences in Subjective Effects of Oral d-Amphetamine
Genetics and Epigenetics of Dopamine Related Genes
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Theresa Swift-scanlan, Virginia Commonwealth University School of nursing
Andrew smolen, University of Colorado at boulder
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BMC Medical Genomics, Interrogation of CpG Island Methylation in the Gene Encoding COMT
JOCN, Genetic Polymorphisms Regulating Dopamine Signaling in the Frontal Cortex Interact to Affect Working Memory
FMT PET (Dopamine Synthesis Measure)
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Bill Jagust, University of california berkeley (Linh dang, former graduate student collected data)
Linh dang, Google (Former postdoctoral fellow In Zald aFFeCtive neuroscience lab)
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Journal of Neurophysiology FMT PET, Delay Discounting Paper
Delay Discounting Task in FMT PET Subjects
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Deanna Wallace, University of California San Francisco
Esther aarts, Donders institute in the netherlands with roshan cools

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