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.

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.

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