Different brain regions’ interactions have been implicated in relevant neurological diseases, such as major
depressive disorder (MDD), anxiety disorders, age-dependent cognitive decline, Alzheimer’s disease (AD) and
addiction. We aim to explore the role of the medial prefrontal cortex (mPFC) in the Neuropeptide Y (NPY) and
Galanin (GAL) interaction since we have demonstrated specific NPY and GAL interactions in brain areas related
to these brain diseases. We performed GALR2 and Y1R agonists intranasal infusion and analyzed the mPFC
activation through c-Fos expression. To assess the associated cellular mechanism we studied the formation of
Y1R-GALR2 heteroreceptor complexes with in situ proximity ligation assay (PLA) and the expression of the brain-
derived neurotrophic factor (BDNF). Moreover, the functional outcome of the NPY and GAL interaction on the
mPFC was evaluated in the novel object preference task. We demonstrated that the intranasal administration of
both agonists decrease the medial prefrontal cortex activation as shown with the c-Fos expression. These effects
were mediated by the decreased formation of Y1R-GALR2 heteroreceptor complexes without affecting the BDNF
expression. The functional outcome of this interaction was related to an impaired performance on the novel
object preference task. Our data may suggest the translational development of new heterobivalent agonist
pharmacophores acting on Y1R–GALR2 heterocomplexes in the medial prefrontal cortex for the novel therapy on
neurodegenerative and psychiatric diseases.
Data Sharing and Data Accessibility: The data that support the findings of this study are openly available in
Institutional repository of the University of Malaga (RIUMA) and from the corresponding author upon reasonable
request.
