The Role of Basal Forebrain Orexin-2-Receptors in Attentional Performance in Rattus norvegicus

Changes in homeostatic function, including sleep patterns and energy balance, are often predictive of age-related neurocognitive disorders such as Alzheimer’s and Parkinson’s disease. The basal forebrain has been implicated in both attentional processing and responses to homeostatic cues, suggesting a possible link between the significantly impaired attention task performance of Alzheimer’s and Parkinson’s patients and shifts in their homeostatic regulation. Recent research suggests a possible mechanism: the basal forebrain receives input from hypothalamic neurons that release the excitatory neuropeptides, orexin-A and orexin-B (orexins). Orexins bind with varying affinities to orexin-1- and orexin-2-receptors on cholinergic neurons in the basal forebrain and increase the rate at which they fire action potentials in response to attentional demands and regulation of homeostasis. Degeneration of these cholinergic projections to the cortex is a hallmark of Alzheimer’s and Parkinson’s, but it is currently unknown if impairment is due solely to loss of these projections, or if the decline can be attributed to loss of particular receptors on these neurons. In order to evaluate the necessity of orexin-2-receptors for attentional performance, TCS-OX2-29, an orexin-2-receptor selective, non-peptide antagonist was administered via bilateral infusion into the basal forebrain of Rattus norvegicus prior to completion of an attention task with a distracter present. The findings suggest a dose- and block-dependent decline in correct rejections at the 40 nM TCS-OX2-29 infusion into the basal forebrain on the sustained attention task with distracter compared to saline administration. An exploratory analysis technique revealed possible improvements in relative hits at 2 nM and 20 nM TCS-OX2-29 infusions into the basal forebrain. Combined, these findings suggest that the orexin-2-receptor is involved in attentional performance, and that blocking the orexin-2-receptor with TCS-OX2-29 may, at high doses, result in a decline in correct rejections, while lower doses of 2 nM and 20 nM may be involved in sensitization of the orexin-2-receptor, making it more likely to respond to binding of orexin A and orexin B.