The influence of NMDA and GABA_A receptors and glutamic acid decarboxylase (GAD) activity on attention

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 GABA_A receptors. Objective: The present study used a rodent model to compare the inhibition of NMDA and GABA_A 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 GABA_A 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 GABA_A 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.