Prolactin-derived vasoinhibins increase anxiety- and depression-related behaviors.
The hormone prolactin (PRL) regulates neuroendocrine and emotional stress responses. It is found in the hypothalamus, where the protein is partially cleaved to vasoinhibins, a family of N-terminal antiangiogenic PRL fragments ranging from 14 to 18kDa molecular masses, with unknown effects on the stress response. Here, we show that the intracerebroventricular administration of a recombinant vasoinhibin, containing the first 123 amino acids of human PRL that correspond to a 14kDa PRL, exerts anxiogenic and depressive-like effects detected in the elevated plus-maze, the open field, and the forced swimming tests. To investigate whether stressor exposure affects the generation of vasoinhibins in the hypothalamus, the concentrations of PRL mRNA, PRL, and vasoinhibins were evaluated in hypothalamic extracts of virgin female rats immobilized for 30min at different time points after stress onset. The hypothalamic levels of PRL mRNA and protein were higher at 60min but declined at 360min to levels seen in non-stressed animals. The elevation of hypothalamic PRL did not correlate with the stress-induced increase in circulating PRL levels, nor was it modified by blocking adenohypophyseal PRL secretion with bromocriptine. A vasoinhibin having an electrophoretic migration rate corresponding to 17kDa was detected in the hypothalamus. Despite the elevation in hypothalamic PRL, the levels of this hypothalamic vasoinhibin were similar in stressed and non-stressed rats. Stress reduced the rate of cleavage of PRL to this vasoinhibin as shown by the incubation of recombinant PRL with hypothalamic extracts from stressed rats. These results suggest that vasoinhibins are potent anxiogenic and depressive factors and that stress increases PRL levels in the hypothalamus partly by reducing its conversion to vasoinhibins. The reciprocal interplay between PRL and vasoinhibins may represent an effective mechanism to regulate anxiety and depression.
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Miriam
M
Zamorano
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Maria G
MG
Ledesma-Colunga
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Norma
N
Adán
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Camila
C
Vera-Massieu
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Maria
M
Lemini
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Isabel
I
Méndez
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Bibiana
B
Moreno-Carranza
Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany.
Inga D
ID
Neumann
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Stéphanie
S
Thebault
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico.
Gonzalo
G
Martínez de la Escalera
Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social (IMSS), Morelia, Mexico.
Luz
L
Torner
Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro, Mexico. Electronic address: clapp@unam.mx.
Carmen
C
Clapp
D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000494:pharmacology*; D003863:Depression / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D018797:Cell Cycle Proteins; C493181:VASH1 protein, human; D011388:Prolactin
16K prolactin; Anxiety; Depression; Hypothalamus; Prolactin; Proteolytic cleavage; Stress; Vasoinhibins