title: Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain.
abstract: Dopamine D3 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 D3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D3 receptors by measuring receptor occupancy via ex-vivo [3H]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 D3 expression. Rats were treated subcutaneously with haloperidol (0.04 mg/kg), clozapine (20 mg/kg) and olanzapine (0.63 mg/kg), the selective D2 antagonist L-741626 (2.5 mg/kg) and the selective D3 antagonist SB-277011-A (10 mg/kg). Doses were based on levels of D2 occupancy considered clinically relevant (60-80%). When measuring D3 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 D1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in Fos-LI, highlighting the D1 agonist property of clozapine. In conclusion, it appears that drugs occupying >50% D3 receptors produce robust increases in ICjM Fos-LI. This study may help to identify the appropriate D3 receptor antagonists that have the potential to be tested in the clinic.
authors: Neuroscience Department, Janssen Research & Development, A division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors: Nima
authors: N
authors: Davoodi
authors: Neuroscience Department, Janssen Research & Development, A division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors: Paula
authors: P
authors: te Riele
authors: Neuroscience Department, Janssen Research & Development, A division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium. Electronic address: xlangloi@its.jnj.com.
authors: Xavier
authors: X
authors: Langlois
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001569:Benzodiazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020670:Islands of Calleja / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D000077152:Olanzapine; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011859:Radiography; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013764:Tetrahydronaphthalenes
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007211:Indoles; D009570:Nitriles; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D013764:Tetrahydronaphthalenes; D001569:Benzodiazepines; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin
keywords: D(2); D(3); Major islands of Calleja; Receptor occupancy; c-fos