olanzapine and naxagolide

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.. 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.. 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.. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Twenty-three patients with schizophrenia and 23 healthy controls.. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride.. 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.. 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.

Topics: 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; Olanzapine; Oxazines; Positron-Emission Tomography; Pramipexole; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia