TY - JOUR
T1 - Using prepulse inhibition to detect functional D3 receptor antagonism
T2 - Effects of WC10 and WC44
AU - Weber, Martin
AU - Chang, Wei Li
AU - Durbin, John P.
AU - Park, Paula E.
AU - Luedtke, Robert R.
AU - Mach, Robert H.
AU - Swerdlow, Neal R.
N1 - Funding Information:
The authors gratefully acknowledge M. Bongiovanni for assistance in manuscript preparation, and M. Breier, D. Ko, N. Thangaraj and D. Marzan for technical assistance. Research was supported by the National Alliance for Research on Schizophrenia and Depression, the Tourette Syndrome Association, and VISN22 MIRECC (MW), DA23957 (RL). MH59803 (NRS) and MH68366 (NRS). In the past 3 years, NRS received support from Allergan Pharmaceuticals (research funding, consultancy funding) and Sanofi/Aventis (consultancy).
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - D3 selective compounds
KW - Dopamine
KW - Prepulse inhibition
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=67649249801&partnerID=8YFLogxK
U2 - 10.1016/j.pbb.2009.04.022
DO - 10.1016/j.pbb.2009.04.022
M3 - Article
C2 - 19426754
AN - SCOPUS:67649249801
SN - 0091-3057
VL - 93
SP - 141
EP - 147
JO - Pharmacology, Biochemistry and Behavior
JF - Pharmacology, Biochemistry and Behavior
IS - 2
ER -