Effects of Sitagliptin on Behavioral

Responses in PTSD Model

Matan Dahan
 What do we already know?
• Neuropeptide Y (NPY), a 36 amino-acid peptide, has a role in the regulation
of various basic physiological functions, such as food intake, metabolic
functions, circadian rhythm, cognition, neuronal excitability, and
addictions and modulation of emotional responses to various stressors.
• The biological actions of NPY are mediated by the activation of at least
five molecularly defined G-coupled receptors family known as the Y1, Y2,
Y4, Y5, and Y6 receptor subtypes (Kopp et al, 2002; Michel et al, 1998).
• In relation to stress, studies largely support a role for the activation of Y1 in
the attenuation of anxiety-like behavior. However, the function of Y2 in
anxiety is allegedly opposite of the Y1 (Enman, 2014)
 What do we already know?
• PTSD patients had significantly lower concentrations of CSF NPY as
compared with the normal comparison subjects (Sah et al, 2009).
• Plasma NPY concentrations were higher in trauma-exposed veterans
without PTSD compared with veterans with PTSD (Yehuda et al, 2006).
• The release of NPY is thought to facilitate the containment of negative
consequences following exposure to stress and has anxiolytic-like
effects (Heilig, 2004).
• Exogenous administered NPY elevated endogenous NPY and rescued
the behavioral effects of PSS (Cohen et al, 2012).
 Dipeptidyl-Peptidase-4 (DPP-4) pathway

X
Insulin

X
Glucagon

X
Gastric
Emptying

X
GLP-1

DPP-4
inhibitor
X
Appetite

DPP-4
enzyme
https://www.youtube.com/@ZeroToFinals
Hubers et al, 2018
Study 1

mg/kg 10
Results
 Study 2

mg/kg 20
Results
 Study 3

1. Animals (N=3) were habituated to the housing

conditions and were handled once daily.
2. Two hours after administration (30 mg/kg),
animals were anesthetized and sacrificed.
3. Brains were quickly removed, post-fixed and
prepared for slicing.
4. Serial coronal sections (10 m) at the level of
the paraventricular nucleus (PVN) were
collected for each animal, using a cryostat
(Leica CM 1850) and mounted on coated
slides.

Matsui et al, 2020

 Results
PSS + DPP4 Inhibitor PSS + Saline

PVTN PVTN
 Results
PSS + DPP4 Inhibitor PSS + Saline

PVN PVN
 Results
PSS + DPP4 Inhibitor PSS + Saline

ARC ARC
 Discussion
Surprisingly in both study 1 and study 2, we did not observe the
expected reduction in anxiety-like behavior in DPP-IV-treated rats.
No significant effect on prevalence rates of PTSD-phenotype was
observed for either dose of DPP-IV as compared to vehicle.

However, study 3 exhibits the wide distribution of NPY in PVTN,

PVN, and ARC in DPP-IV-treated rats compared to the other
groups, strengthening the question why behavioral changes were
not observed contrary to expectations.
 Discussion
• A possible explanation for the unexpected results is the reduced NPY-
Y1 receptor responsiveness to its ligand. There may also be region-
specific or pathway-specific differences in the effects of NPY
overexpression on receptors since the expression level of the different
types of NPY receptors is not homogenous throughout the brain.
• Moreover, the overabundance of NPY could lead to desensitization of
NPY receptors, which is common for GPCRs in the presence of
abundant ligand. This can be caused by reduced receptor surface
expression in the neuron, and/or a decrease in receptor signaling
efficiency.
 ?What now

1d

30 mg/kg Reminder + Open field