title: SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine.
abstract: BACKGROUND
  Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-D-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity.
  
  
  OBJECTIVE
  Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex.
  
  
  METHODS
  Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI.
  
  
  RESULTS
  When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg--a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg--that was insufficient to enhance PPI when administered alone--SSR504734 even exacerbated the deleterious effect of apomorphine on PPI.
  
  
  CONCLUSIONS
  The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition.
authors.affiliation: Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, Schwerzenbach, 8603, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Singer
authors.forename: Weining
authors.initials: W
authors.lastname: Zhang
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate; D013216:Reflex, Startle / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects
chemical_list: C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D001549:Benzamides; D018491:Dopamine Agonists; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D000661:Amphetamine; D001058:Apomorphine; D005998:Glycine; D004298:Dopamine