Increased acetylcholine and glutamate efflux in the prefrontal cortex following intranasal orexin‐A (hypocretin‐1)

Abstract

Orexin/hypocretin neurons of the lateral hypothalamus and perifornical area are integrators of physiological function. Previous work from our laboratory and others has shown the importance of orexin transmission in cognition. Age-related reductions in markers of orexin function further suggest that this neuropeptide may be a useful target for the treatment of age-related cognitive dysfunction. Intranasal administration of orexin-A (OxA) has shown promise as a therapeutic option for cognitive dysfunction. However, the neurochemical mechanisms of intranasal OxA administration are not fully understood. Here, we use immunohistochemistry and in vivo microdialysis to define the effects of acute intranasal OxA administration on: (i) activation of neuronal populations in the cortex, basal forebrain, and brainstem and (ii) acetylcholine (ACh) and glutamate efflux in the prefrontal cortex (PFC) of Fischer 344/Brown Norway F1 rats. Acute intranasal administration of OxA significantly increased c-Fos expression, a marker for neuronal activation, in the PFC and in subpopulations of basal forebrain cholinergic neurons. Subsequently, we investigated the effects of acute intranasal OxA on neurotransmitter efflux in the PFC and found that intranasal OxA significantly increased both ACh and glutamate efflux in this region. These findings were independent from any changes in c-Fos expression in orexin neurons, suggesting that these effects are not resultant from direct activation of orexin neurons. In total, these data indicate that intranasal OxA may enhance cognition through activation of distinct neuronal populations in the cortex and basal forebrain and through increased neurotransmission of ACh and glutamate in the PFC.

Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

“…Orexin neurons send widespread projections to the cortex that modulate various aspects of cognition, especially those related to attentional function. Correspondingly, intranasal [Ala 11 ,D-Leu 15 ]-OxB and intranasal OxA (Calva et al, 2017) increased c-Fos expression in the agranular insular cortex, a brain region that facilitates interoceptive attention to an organism's physiological status (Avery et al, 2017;Craig and Craig, 2002;Hassanpour et al, 2017). Orexin's actions in the insular cortex may help promote appropriate behavioral responses to homeostatic challenges, consistent with orexin's role as a physiological integrator.…”

“…2) show that significant differences in c-Fos expression are localized to specific brain regions. Specifically, in the cortex of young animals, intranasal OxA significantly increased c-Fos expression in the piriform, agranular insular, prelimbic, and ventral orbital cortices (Calva et al, 2017). Significant increases in cortical c-Fos expression after intranasal [Ala 11 ,D-Leu 15 ]-OxB were limited to the piriform and agranular insular cortices.…”

“…Orexin neurons also densely innervate the PFC where they modulate neurotransmission related to attentional processing (Fadel et al, 2005;Huang et al, 2006;Vittoz and Berridge, 2006;Zajo et al, 2016). Our prior intranasal studies indicate that intranasal OxA increases glutamatergic and cholinergic neurotransmission within the PFC of young rats (Calva et al, 2017), suggesting that intranasal OxA enhances attentional processing in the PFC. Though we observed a strong trend for increased c-Fos expression in the prelimbic PFC after intranasal [Ala 11 ,D-Leu 15 ]-OxB administration, our overall observations indicate that orexin-mediated enhancement of attentional function may primarily occur via the OX 1 receptor.…”

“…While these studies provide a powerful framework for the therapeutic potential of intranasal OxA, studies investigating the mechanisms responsible for these behavioral observations remain limited. Accordingly, we have recently performed neurochemical and anatomical studies using intranasal OxA in young rats to assess these mechanisms (Calva et al, 2017). These studies will be examined further in the proceeding results and discussion sections by comparing the effects of intranasal OxA administration on neuronal activation between young and aged animals.…”

“…neurons-Our previous work in young animals utilized intranasal administration of the OxA peptide (Calva et al, 2017); therefore, the receptor mechanisms by which intranasal orexin administration may activate basal cholinergic neurons remains unresolved. Accordingly, we examined the effects of intranasal [Ala 11 ,D-Leu 15 ]-OxB administration, a selective OX 2 receptor agonist, on c-Fos expression within cholinergic (ChAT+) neurons of the basal forebrain ( Fig.…”