title: The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study With [11C]-(+)-PHNO.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  
  
  METHODS
  Twenty-three patients with schizophrenia and 23 healthy controls.
  
  
  METHODS
  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.
authors.affiliation: PO Box 053, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, England.
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
authors.forename: David
authors.initials: D
authors.lastname: Mamo
authors.forename: C M
authors.initials: CM
authors.lastname: Shammi
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.forename: Heidi
authors.initials: H
authors.lastname: Marcon
authors.forename: Penny
authors.initials: P
authors.lastname: Barsoum
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000187:drug effects; D001569:Benzodiazepines / Q000627:therapeutic use*; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000187:drug effects; D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects; D003024:Clozapine / Q000627:therapeutic use*; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004311:Double-Blind Method; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010078:Oxazines; D049268:Positron-Emission Tomography; D000077487:Pramipexole; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3 / Q000187:drug effects*; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000000981:diagnostic imaging* / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D001569:Benzodiazepines; C042631:naxagolide; D020891:Raclopride; D000077487:Pramipexole; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine