Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men.
BACKGROUND
In animals, repeated exposure to stimulant drugs leads to an enhanced drug-induced psychomotor response and increased dopamine release. This phenomenon, known as sensitization, may confer vulnerability to drug addiction or drug-induced psychosis in humans. A similar phenomenon, referred to as endogenous sensitization, is also believed to play a role in the emergence of positive symptoms in patients with schizophrenia.


OBJECTIVE
To determine whether behavioral and neurochemical sensitization occur in healthy individuals after limited exposure to amphetamine in the laboratory.


METHODS
Open-label, 1-year follow-up of repeated amphetamine administration in healthy volunteers.


METHODS
Department of Psychiatry, McGill University, and McConnell Brain Imaging Center, Montreal Neurological Institute.


METHODS
Ten healthy men (mean +/- SD age, 25.8 +/- 1.8 years).


METHODS
Three single doses of amphetamine (dextroamphetamine sulfate, 0.3 mg/kg by mouth) were administered on days 1, 3, and 5.


METHODS
Using positron emission tomography and [11C]raclopride, we measured dopamine release in response to amphetamine on the first exposure (day 1) and 14 days and 1 year after the third exposure.


RESULTS
The initial dose of amphetamine caused dopamine release in the ventral striatum (a reduction in [11C]raclopride binding). Consistent with a sensitization-like phenomenon, 14 and 365 days after the third dose of amphetamine there was a greater psychomotor response and increased dopamine release (a greater reduction in [11C]raclopride binding), relative to the initial dose, in the ventral striatum, progressively extending to the dorsal caudate and putamen. A high novelty-seeking personality trait and self-rating assessments indicating impulsivity predicted proneness to sensitization.


CONCLUSIONS
Sensitization to stimulants can be achieved in healthy men in the laboratory. This phenomenon is associated with increased dopamine release and persists for at least 1 year.
Boileau
Isabelle
I
McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, Quebec, Canada.
Dagher
Alain
A
Leyton
Marco
M
Gunn
Roger N
RN
Baker
Glen B
GB
Diksic
Mirko
M
Benkelfat
Chawki
C
D000284:Administration, Oral; D000328:Adult; D000339:Affect / Q000187:drug effects / Q000502:physiology; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D016739:Behavior, Addictive / Q000378:metabolism / Q000523:psychology; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D007175:Impulsive Behavior / Q000378:metabolism / Q000523:psychology; D008137:Longitudinal Studies; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D049268:Positron-Emission Tomography / Q000706:statistics & numerical data*; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism* / Q000493:pharmacokinetics; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism
D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D020891:Raclopride; D003913:Dextroamphetamine; D004298:Dopamine