SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine

Philipp Singer, Weining Zhang, Kay Yan Benjamin Yee

Research output: Journal article publicationJournal articleAcademic researchpeer-review

6 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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.
Original languageEnglish
Pages (from-to)309-317
Number of pages9
JournalPsychopharmacology
Volume230
Issue number2
DOIs
Publication statusPublished - 1 Nov 2013
Externally publishedYes

Keywords

  • Dopamine
  • Glutamate
  • Glycine transporter 1
  • Positive symptoms
  • Schizophrenia
  • Sensorimotor gating

ASJC Scopus subject areas

  • Pharmacology

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