Abstract
Delivery of neuropeptide Y (NPY) to the brain by intranasal infusion soon after traumatic stress has shown therapeutic potential, and prevented development of many behavioral and neuroendocrine impairments in the single prolonged stress (SPS) animal model of PTSD. Therefore, we examined whether the Y1R preferring agonist [Leu31Pro34]NPY is sufficient to prevent development of SPS induced depressive-like behavioral changes, and hypothalamic gene expression as obtained with intranasal NPY intervention. Male Sprague-Dawely rats were given intranasal infusion of either NPY (150 μg/rat), a low (68 μg /rat), or high (132 μg/rat) dose of [Leu31Pro34]NPY or vehicle immediately following the last SPS stressor, left undisturbed for 1 week and then tested for depressive-like behavior together with naïve unstressed controls. Vehicle treated animals had elevated immobility forced swim test (FST) and reduced sucrose preference, which were not observed in animals given NPY or the higher dose of [Leu31Pro34]NPY. This dose of [Leu31Pro34]NPY, like NPY, also prevented the SPS-elicited induction of CRF mRNA in the mediobasal hypothalamus. However, [Leu31Pro34]NPY did not prevent, but rather enhanced, the SPS-triggered induction of GR and FKBP5 mRNA levels in the mediobasal hypothalamus. Thus, [Leu31Pro34]NPY may be as effective as NPY and displays therapeutic potential for preventing development of depressive-like behaviors and dysregulation of the CRF/HPA system in PTSD. However, due to its different effects compared to NPY on GR and FKBP5 a broader agonist, such as NPY, may be more desirable.
Highlights
Considerable evidence indicates that in the CNS neuropeptide Y (NPY) can attenuate the response to stress, and has therapeutic potential for PTSD as well as for depression
We examined the ability of two doses of the Y1R preferring agonist [Leu31Pro34]NPY to change despair or depressive-like behavior in forced swim test (FST) of rats subjected to single prolonged stress (SPS) stressors (Figure 2)
The results of this study suggest an important role for the Y1R in protection from development of the depression-like symptoms following the exposure to severe stress
Summary
Considerable evidence indicates that in the CNS neuropeptide Y (NPY) can attenuate the response to stress, and has therapeutic potential for PTSD as well as for depression (reviewed in Heilig, 2004; Morales-Medina et al, 2010; Wu et al, 2011; Sah and Geracioti, 2013; Enman et al, 2015; Reichmann and Holzer, 2016; Sabban et al, 2016; Schmeltzer et al, 2016). NPY1 Receptor Agonists and Traumatic Stress exposure to traumatic stress can prevent the development of many PTSD associated behavioral and neuroendocrine impairments. Intranasal infusion of NPY after exposure to traumatic stress in the single prolonged stress (SPS) protocol, rodent model of PTSD, averted the elevation of anxiety, depressive-like behavior and hyperarousal observed in vehicle treated animals a week or more afterwards. Intervention with intranasal NPY provided resistance against prolonged activation of the hypothalamic pituitary adrenal (HPA) axis, and molecular changes in multiple brain regions, including the mediobasal hypothalamus (Serova et al, 2013; Laukova et al, 2014; Sabban et al, 2015a, 2016). NPY can lead to changes ERK or CREB signaling resulting in alterations in gene expression (reviewed in Brothers and Wahlestedt, 2010; Sah and Geracioti, 2013)
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