Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

Disentangling Pre- and Postsynaptic Aspects of Amphetamine-induced Sensitization: a Combined [18F]DOPA / [11C]-(+)-PHNO PET Study

Patients with schizophrenia show enhanced dopamine synthesis capacity and release, an effect that can be evoked in healthy subjects by repeated amphetamine administration. Therefore for the first time the relationship between dopamine synthesis and release will be studied in healthy subjects before and after amphetamine sensitization in order to better understand adaptive mechanisms of the dopamine system.

Study Overview

• Status: Unknown
• Conditions: Schizophrenia; Psychosis; Sensitisation
• Intervention / Treatment: Drug: Dextroamphetamine Sulfate

Detailed Description

Positron emission tomography (PET) studies have consistently shown increased brain dopamine (DA) synthesis and enhanced d-amphetamine-induced DA release in patients with schizophrenia. Repeated administration of d-amphetamine leads to an increased subjective and behavioral drug-response. This effect, termed "sensitization", is paralleled by an increase in dopamine release to levels akin to those observed in schizophrenia. Schizophrenia thus goes along with a state of 'natural sensitization' towards amphetamines. However, while it is known that DA synthesis and release are both enhanced in schizophrenia, it is unknown whether sensitization changes indices of presynaptic DA synthesis in the striatum of healthy subjects. Thus, for the first time, this project will study the effects of repeated d-amphetamine on uptake of the DA precursor [18F]FDOPA and on d-amphetamine-induced changes in binding of the D2/3 receptor agonist radioligand [11C]-(+)PHNO in a within-subject design. Before and after amphetamine sensitization by repeated intermittent administration subjects will receive an [18F]FDOPA and and a [11C]-(+)PHNO PET scan. For the investigation of the influence of functional and structural cortical properties on dopamine synthesis and release, functional and structural magnet resonance imaging will be performed before and after sensitization.

• Study Type: Interventional
• Enrollment (Anticipated): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Ana Weidenauer, MD; Phone Number: 35470 0043140400; Email: ana.weidenauer@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females aged 18-65, in good general health based on history and physical examination
• Psychiatrically healthy as determined by the Mini-International Neuropsychiatric Interview (M.I.N.I.PLUS) (94))
• No relevant abnormalities in laboratory screening including thyroid function tests, blood cell count, serum electrolytes, liver and kidney function, and urinalysis
• No clinically relevant findings in electrocardiography (ECG)
• No clinically relevant findings in vital signs (blood pressure and pulse)
• No regular use of illegal drugs or alcohol abuse based on declared history and confirmed by urine drug screening
• No history of repeated AMPH (AMPH), cocaine or other stimulant drug use

Exclusion Criteria:

• Evidence of present psychiatric or neurological illness according to M.I.N.I.-Plus (any personal or first-degree relative history of: schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, and substance dependence)
• Recreational use of psychostimulant drugs in the past two years; lifetime use of psychostimulants exceeding five exposures
• Medically significant biochemical or hematological abnormality on screening laboratory studies
• Women of childbearing potential: Current pregnancy or breast-feeding
• Clinically relevant abnormalities in the electro-cardiogram (ECG)
• History of myocardial infarction or angina pectoris
• Positive urine drug screen within one week prior to PET study day
• Presence of ferromagnetic metal in the body or heart pacemaker
• Claustrophobia
• Any history of arterial hypertension or paroxysmal hypertensive states
• Established diagnosis of advanced arteriosclerosis
• Established diagnosis of hyperthyroidism
• History of hypersensitivity to sympathomimetics
• History of head trauma resulting in loss of consciousness that required medical intervention
• Lifetime history of substance dependence (except nicotine)
• If participation in this study would exceed the annual radiation dose limits (30 mSv) for human subjects
• Subjects currently participating in research studies
• Suicidal ideation or likelihood of a suicide or homicide attempt

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy subjects; Measurement of Dextroamphetamine Sulfate-induced dopamine release and synthesis before and after amphetamine sensitization.	Drug: Dextroamphetamine Sulfate; Repeated oral administration of dexamphetamine 0.4mg/KG bodyweight four times.; Other Names: [11C]-(+)-PHNO PET, [18F]FDOPA PET

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[18F]FDOPA Ki values	Relative change in regional [18F]FDOPA Ki values after AMPH sensitization	Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[11C]-(+)-PHNO BPND values	Relative change in regional [11C]-(+)-PHNO BPND values after AMPH administration before and after sensitization	Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4
Subjective ratings of amphetamine effects (Drug Effects Questionnaire)	Subjective ratings will be assessed via questionnaire (Drug Effects Questionnaire) four times throughout the study.	Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Subjective ratings of amphetamine effects (Subjective States Questionnaire)	Subjective ratings will be assessed via questionnaire (Subjective States Questionnaire) four times throughout the study.	Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Cognitive measures	Working memory, reward processing and impulsivity will be assessed via a computerized test battery four times throughout the study	At baseline, on each of the two sensitization visits after amphetamine administration and 2 weeks after amphetamine sensitization before FDOPA scanning, total timeframe 4 weeks, Time points: Week 1 Week 2 Week 4
Impulsiveness	The personality traits impulsiveness will be assessed once during study participation by the questionnaire Barrat Impulsiveness Scale (BIS).	Baseline, Week 1
Personality-related markers	Personality traits like novelty seeking will be assessed once during study participation using the Temperament and Character Inventory (TCI).	Baseline, Week 1
Peripheral markers of sensitization	Plasma concentration of the dopamine metabolite HVA, glucose and insulin metabolism related parameters (glucose, glucagon, insulin, c-peptide, somatostatin), plasma cocaine and AMPH-regulated transcript (CART) levels will be measured at each PET study day.	Baseline FDOPA scan, baseline PHNO + amphetamine scan, post-sensitization PHNO+ amphetamine scan, post-sensitization FDOPA scan, Time points: Week 1 Week 2 Week 4
Salivary cortisol	Salivary cortisol will be assessed using Salivettes ®.	Salivary cortisol will be assessed each time amphetamine is administered: At baseline and 30, 60, 90, 145 and 210 minutes after i.v. or oral amphetamine administration.
Fractional anisotropy (diffusion-weighted tensor imaging) of white matter	Fractional anisotropy of white matter will be measured by means of magnet resonance imaging.	Before and after amphetamine sensitization, Week 1, Week 5
Gray matter volume	Gray matter volume will be measured by means of magnet resonance imaging. T1 and PD sequences will be recorded.	Before and after amphetamine sensitization, Week 1, Week 5
Functional connectivity	Functional connectivity between brain regions will be measured by means of magnet resonance imaging during a resting state of the subject.	Before and after amphetamine sensitization, Week 1, Week 5

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Ana Weidenauer, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Weidenauer A, Bauer M, Sauerzopf U, Bartova L, Praschak-Rieder N, Sitte HH, Kasper S, Willeit M. Making Sense of: Sensitization in Schizophrenia. Int J Neuropsychopharmacol. 2016 Dec 31;20(1):1-10. doi: 10.1093/ijnp/pyw081. Print 2017 Jan.
• Sauerzopf U, Sacco R, Novarino G, Niello M, Weidenauer A, Praschak-Rieder N, Sitte H, Willeit M. Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence. Eur J Neurosci. 2017 Jan;45(1):45-57. doi: 10.1111/ejn.13418. Epub 2016 Oct 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Anticipated): August 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: July 8, 2017
• First Submitted That Met QC Criteria: July 14, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Actual): April 19, 2018
• Last Update Submitted That Met QC Criteria: April 18, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Schizophrenia; Psychosis; Positron Emission Tomography; Magnetic Resonance Imaging; Dopamine; Amphetamine; [18F]FDOPA; [11C]-(+)-PHNO
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Dextroamphetamine
• Other Study ID Numbers: 16969

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No