Using prepulse inhibition to detect functional D3 receptor antagonism: Effects of WC10 and WC44

Martin Weber, Wei Li Chang, John P. Durbin, Paula E. Park, Robert R. Luedtke, Robert H. Mach, Neal R. Swerdlow

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)141-147
Number of pages7
JournalPharmacology Biochemistry and Behavior
Volume93
Issue number2
DOIs
StatePublished - 1 Aug 2009

Fingerprint

Apomorphine
Assays
3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole
Antipsychotic Agents
Rats
Dopamine Agonists
Schizophrenia
Dopamine
Screening
Sensory Gating
Drug Discovery
pramipexole
Prepulse Inhibition

Keywords

  • D3 selective compounds
  • Dopamine
  • Prepulse inhibition
  • Schizophrenia

Cite this

Weber, Martin ; Chang, Wei Li ; Durbin, John P. ; Park, Paula E. ; Luedtke, Robert R. ; Mach, Robert H. ; Swerdlow, Neal R. / Using prepulse inhibition to detect functional D3 receptor antagonism : Effects of WC10 and WC44. In: Pharmacology Biochemistry and Behavior. 2009 ; Vol. 93, No. 2. pp. 141-147.
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Using prepulse inhibition to detect functional D3 receptor antagonism : Effects of WC10 and WC44. / Weber, Martin; Chang, Wei Li; Durbin, John P.; Park, Paula E.; Luedtke, Robert R.; Mach, Robert H.; Swerdlow, Neal R.

In: Pharmacology Biochemistry and Behavior, Vol. 93, No. 2, 01.08.2009, p. 141-147.

Research output: Contribution to journalArticle

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AU - Weber, Martin

AU - Chang, Wei Li

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