SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine.
- 2013-06-06
Published in:
- Psychopharmacology. - 2013
Amphetamine
Animals
Apomorphine
Benzamides
Dopamine
Dopamine Agonists
Dose-Response Relationship, Drug
Glycine
Glycine Plasma Membrane Transport Proteins
Male
Mice
Mice, Inbred C57BL
Piperidines
Receptors, N-Methyl-D-Aspartate
Reflex, Startle
Sensory Gating
English
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1007/s00213-013-3160-3
- PMID 23736281
- Persistent URL
- https://sonar.ch/global/documents/36561
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