| Title | The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study With [11C]-(+)-PHNO. | | Author(s) | Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, Rusjan P, Houle S, Wilson AA, Kapur S | | Institution | PO Box 053, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, England. | | Source | Arch Gen Psychiatry 2009 Jun; 66(6):606-15. | | MeSH | Adult
Antipsychotic Agents
Basal Ganglia
Benzodiazepines
Benzothiazoles
Binding, Competitive
Carbon Radioisotopes
Caudate Nucleus
Clozapine
Dopamine Agonists
Dopamine Antagonists
Double-Blind Method
Female
Globus Pallidus
Humans
Image Processing, Computer-Assisted
Male
Middle Aged
Oxazines
Positron-Emission Tomography
Putamen
Raclopride
Receptors, Dopamine D2
Receptors, Dopamine D3
Risperidone
Schizophrenia
| | Abstract | CONTEXT: Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes.
OBJECTIVES: To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions.
DESIGN: Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients.
SETTING: Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
PARTICIPANTS: Twenty-three patients with schizophrenia and 23 healthy controls.
MAIN OUTCOME MEASURES: Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride.
RESULTS: The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole.
CONCLUSIONS: Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia. | | Language | eng | | Pub Type(s) | Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19487625 |
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