Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.
Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo.
Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 92037-0804, USA.
Martin
M
Weber
Wei-Li
WL
Chang
John P
JP
Durbin
Paula E
PE
Park
Robert R
RR
Luedtke
Robert H
RH
Mach
Neal R
NR
Swerdlow
D000818:Animals; D014150:Antipsychotic Agents; D001058:Apomorphine / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D000077487:Pramipexole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D052160:Benzothiazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C543148:WC10 compound; C543147:WC44 compound; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D000077487:Pramipexole; D001058:Apomorphine