科研之友
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摘要
Dopamine D-3 receptors are a major target for drug discovery programs related to psychiatric disorders such as schizophrenia. The ability of a compound to occupy significant levels of D-3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D-3 receptors by measuring receptor occupancy via ex-vivo [H-3]7-OH-DPAT autoradiography, and further validating this outcome via analysis of Fos-like immunoreactivity (Fos-LI) in the rat major islands of Calleja (ICjM), a brain structure with high D-3 expression. Rats were treated subcutaneously with haloperidol (0.04 mg/kg), clozapine (20 mg/kg) and olanzapine (0.63 mg/kg), the selective D-2 antagonist L-741626 (2.5 mg/kg) and the selective D-3 antagonist SB-277011-A (10 mg/kg). Doses were based on levels of D-2 occupancy considered clinically relevant (60-80%). When measuring D-3 occupancy, clozapine and SB-277011-A displayed meaningful levels of occupancy (60% and 77%, respectively), haloperidol and olanzapine showed limited occupancy (16% and 27%, respectively), whereas L-741626 showed no occupancy. There were no significant changes in ICjM Fos-LI after L-741626 and haloperidol treatment, minor but significant increases after olanzapine treatment, whereas highly significant increases were seen with SB-277011-A and clozapine. Additionally, pre-treating clozapine with the D-1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in Fos-LI, highlighting the D-1 agonist property of clozapine in conclusion, it appears that drugs occupying > 50% D-3 receptors produce robust increases in ICjM Fos-LI. This study may help to identify the appropriate D-3 receptor antagonists that have the potential to be tested in the clinic.
- 出版日期2014-10-5
