Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: Role of metabotropic glutamate receptors 2/3

L. Pozzi, M. Baviera, G. Sacchetti, E. Calcagno, C. Balducci, R. W. Invernizzi, M. Carli

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Abstract

The hypothesis that attention deficits induced by the hypofunction of N-methyl d-aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S133CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by % correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 μM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S133CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S133CREB in the frontal cortex but was without effect on the decrease in p-S133CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.

Original languageEnglish
Pages (from-to)336-348
Number of pages13
JournalNeuroscience
Volume176
DOIs
Publication statusPublished - Mar 10 2011

Fingerprint

Cyclic AMP Response Element-Binding Protein
Prefrontal Cortex
Glutamic Acid
Phosphorylation
LY 379268
Impulsive Behavior
Putamen
Frontal Lobe
Serine
Microdialysis
Nucleus Accumbens
Response Elements
Cyclic AMP
Reaction Time
Carrier Proteins
Western Blotting
metabotropic glutamate receptor 3
metabotropic glutamate receptor 2
aspartic acid receptor
3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid

Keywords

  • 5-choice serial reaction time task
  • Attention
  • Glutamate release
  • LY379268
  • NMDA receptor antagonist
  • P-SCREB

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: Role of metabotropic glutamate receptors 2/3",
abstract = "The hypothesis that attention deficits induced by the hypofunction of N-methyl d-aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S133CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by {\%} correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 μM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S133CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S133CREB in the frontal cortex but was without effect on the decrease in p-S133CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.",
keywords = "5-choice serial reaction time task, Attention, Glutamate release, LY379268, NMDA receptor antagonist, P-SCREB",
author = "L. Pozzi and M. Baviera and G. Sacchetti and E. Calcagno and C. Balducci and Invernizzi, {R. W.} and M. Carli",
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T1 - Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation

T2 - Role of metabotropic glutamate receptors 2/3

AU - Pozzi, L.

AU - Baviera, M.

AU - Sacchetti, G.

AU - Calcagno, E.

AU - Balducci, C.

AU - Invernizzi, R. W.

AU - Carli, M.

PY - 2011/3/10

Y1 - 2011/3/10

N2 - The hypothesis that attention deficits induced by the hypofunction of N-methyl d-aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S133CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by % correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 μM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S133CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S133CREB in the frontal cortex but was without effect on the decrease in p-S133CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.

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