Effects of infusions of antisense oligodeoxynucleotides for glutamic acid decarboxylase into the nucleus accumbens on sustained attention performance in the rat

Benzodiazepine receptor (BZR) ligands have been shown to impair sustained attention performance following infusion into the basal forebrain in the rat, and the attentional effects of these compounds have been attributed to their ability to manipulate cortical acetylcholine efflux through modulation of {dollar}gamma{dollar}-aminobutyric acid (GABA) transmission. Furthermore, it has been proposed that the GABAergic neurons mediating these effects arise from the nucleus accumbens, but this has yet to be determined. Therefore, in an attempt to decrease the amount of GABA released from these neurons, antisense oligodeoxynucleotides (ODNs) for the two isoforms of glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, were infused into the nucleus accumbens in the first experiment. Infusions of the scrambled sequence ODNs or ODNs for the GAD67 isoform did not affect performance in a sustained attention paradigm designed for rats. However, infusions of the ODNs for GAD65 selectively impaired the animals' ability to detect the visual signals. Multiple infusions of ODNs for both forms of GAD resulted in a similar deficit in signal detection along with an increase in the number of false positive signal detections (false alarms). The second experiment attempted to determine whether the effects on sustained attention performance of the GAD ODN infusions resulted from a decrease in GABA release within the basal forebrain by injecting the BZR agonist chlordiazepoxide (CDP) into the basal forebrain following infusion of the ODNs for GAD into the nucleus accumbens. It was predicted that if the attentional effects of the ODNs were due to decreases in GABA release within the basal forebrain that those impairments would be attenuated by administration of CDP into that area. However, it was observed that infusion of CDP into the basal forebrain further disrupted the animals' ability to detect the signals and alleviated the increase in the number of false alarms following the combined ODN treatment. Therefore, this experiment did not provide unequivocal evidence that the attentional effects of the GAD ODN infusions into the nucleus accumbens were mediated within the basal forebrain. Further investigation is necessary to disclose the mechanisms responsible for the effects of the ODNs.