7 nicotinic ACh receptor-deficient mice exhibit sustained attention impairments that are reversed by 2 nicotinic ACh receptor activation

Background and PurposeDisruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. ACh in the prefrontal cortex regulates attentive behaviour; however, the role of 7 nicotinic ACh receptor (7nAChR) in attention is contentious. Experimental ApproachIn order to probe attention, we trained both wild-type and 7nAChR knockout mice on a touch screen-based five-choice serial reaction time task (5-CSRT). Following training procedures, we then tested sustained attention using a probe trial experiment. To further differentiate the role of specific nicotinic receptors in attention, we then tested the effects of both 7nAChR and 2nAChR agonists on the performance of both wild-type and knockout mice on the 5-CSRT task. Key ResultsAt low doses, 7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. 7nAChR knockout mice displayed deficits in sustained attention that were not ameliorated by 7nAChR agonists. However, these deficits were completely reversed by the administration of a 2nAChR agonist. Furthermore, administration of a 2nAChR agonist in 7nAChR knockout mice elicited similar biochemical response in the prefrontal cortex as the administration of 7nAChR agonists in wild-type mice. Conclusions and ImplicationsOur experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting 2nAChRs pharmacologically to decrease attentional deficits due to a dysfunction in 7nAChRs.