Adenosine A2A receptor gene disruption provokes marked changes in melanocortin content and pro-opiomelanocortin gene expression.
A2A receptor knockout (A2AR-/-) mice are more anxious and aggressive, and exhibit reduced exploratory activity than their wild-type littermates (A2AR+/+). Because alpha-melanocyte-stimulating hormone (alpha-MSH) influences anxiety, aggressiveness and motor activity, we investigated the effect of A2AR gene disruption on alpha-MSH content in discrete brain regions and pro-opiomelanocortin (POMC) expression in the hypothalamus and pituitary. No modification in alpha-MSH content was observed in the hypothalamus and medulla oblongata where POMC-expressing perikarya are located. In the arcuate nucleus of the hypothalamus, POMC mRNA levels were not affected by A2AR disruption. Conversely, in A2AR-/- mice, a significant increase in alpha-MSH content was observed in the amygdala and cerebral cortex, two regions that are innervated by POMC terminals. In the pars intermedia of the pituitary, A2AR disruption provoked a significant reduction of POMC mRNA expression associated with a decrease in alpha-MSH content. By contrast, in the anterior lobe of the pituitary, a substantial increase in POMC mRNA and adrenocorticotropin hormone concentrations was observed, and plasma corticosterone concentration was significantly higher in A2AR-/- mice, revealing hyperactivity of their pituitary-adrenocortical axis. Together, these results suggest that adenosine, acting through A2A receptors, may modulate the release of alpha-MSH in the cerebral cortex and amygdala. The data also indicate that A2A receptors are involved in the control of POMC gene expression and biosynthesis of POMC-derived peptides in pituitary melanotrophs and corticotrophs.
Jégou
S
S
European Institute for Peptide Research (IFRMP23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, UA CNRS, University of Rouen, Mont-Saint-Aignan, France. sylvie.jegou@univ-rouen.fr
El Yacoubi
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M
Mounien
L
L
Ledent
C
C
Parmentier
M
M
Costentin
J
J
Vaugeois
J-M
JM
Vaudry
H
H
D000818:Animals; D015870:Gene Expression; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D043705:Receptor, Adenosine A2A / Q000235:genetics*; D000521:alpha-MSH / Q000378:metabolism*
D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin