Abstract
Rationale: Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors. Objective: The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Methods: Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Results: Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. Conclusions: These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 31-39 |
| Number of pages | 9 |
| Journal | Psychopharmacology |
| Volume | 225 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2013 |
| Externally published | Yes |
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Keywords
- Attention
- GABA
- Glutamate
- Glutamic acid decarboxylase
- Schizophrenia
ASJC Scopus subject areas
- Pharmacology
Cite this
The influence of NMDA and GABAA receptors and glutamic acid decarboxylase (GAD) activity on attention. / Pehrson, Alan L.; Bondi, Corina O.; Totah, Nelson K B; Moghaddam, Bita.
In: Psychopharmacology, Vol. 225, No. 1, 01.2013, p. 31-39.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The influence of NMDA and GABAA receptors and glutamic acid decarboxylase (GAD) activity on attention
AU - Pehrson, Alan L.
AU - Bondi, Corina O.
AU - Totah, Nelson K B
AU - Moghaddam, Bita
PY - 2013/1
Y1 - 2013/1
N2 - Rationale: Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors. Objective: The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Methods: Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Results: Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. Conclusions: These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.
AB - Rationale: Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors. Objective: The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Methods: Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Results: Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. Conclusions: These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.
KW - Attention
KW - GABA
KW - Glutamate
KW - Glutamic acid decarboxylase
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84872319087&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872319087&partnerID=8YFLogxK
U2 - 10.1007/s00213-012-2792-z
DO - 10.1007/s00213-012-2792-z
M3 - Article
C2 - 22797703
AN - SCOPUS:84872319087
VL - 225
SP - 31
EP - 39
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
IS - 1
ER -