role of oxytocin in prolactin release
TRANSCRIPT
-
7/31/2019 Role of Oxytocin in Prolactin Release
1/31
The Emerging Roles ofOxytocin in Rhythmic Prolactin
Release
Richard BertramProgram in Neuroscience
Florida State University
-
7/31/2019 Role of Oxytocin in Prolactin Release
2/31
Collaborators
Florida State University University of California,Marc E. Freeman San DiegoJol Tabak DeNise McKeeArturo Gonzales-IglesiasCleyde V. HelenaRuth Cristancho-Gordo
ETH, Zurich Georgia Institute of TechnologyMarcel Egli Natalia Toporikova
Financial support: NIH grants DK43200 and DA19356
Universidad de So PauloMaristela O. Poletini
-
7/31/2019 Role of Oxytocin in Prolactin Release
3/31
-
7/31/2019 Role of Oxytocin in Prolactin Release
4/31
Circadian Prolactin Rhythm in Female
Rats
PSP Pseudopregnancy, rhythm induced by mating
OVX ovaries removed, rhythm induced by artificialcervical stimulation (CS). Our in vivo work is
typically done with OVX rats.
-
7/31/2019 Role of Oxytocin in Prolactin Release
5/31
Central Injection of Prolactin Itself CanTrigger the Prolactin Rhythm
Helena et al., Endocrinology, 150:3245, 2009
oPRL ovine prolactin
Systemic administration of prolactin also works, but the required
concentration is much higher
OVX rats
Intracerebroventricular (icv) injection of ovine prolactin
-
7/31/2019 Role of Oxytocin in Prolactin Release
6/31
Central Blockade of ProlactinReceptors Inhibits the CS-Induced
Prolactin Rhythm
S179D Prolactin receptor antagonist
Helena et al., Endocrinology, 150:3245, 2009
Icv infusion of prolactin antagonist
-
7/31/2019 Role of Oxytocin in Prolactin Release
7/31
Central Blockade of ProlactinReceptors Inhibits the CS-Induced
Prolactin RhythmIcv infusion of prolactin antagonist
Central prolactin feedback is necessary for the rhythm!
-
7/31/2019 Role of Oxytocin in Prolactin Release
8/31
What is the Mechanism for this Rhythm?
-
7/31/2019 Role of Oxytocin in Prolactin Release
9/31
Dopamine is the PhysiologicalInhibitor of Prolactin Release
Arey et al., Proc. Soc. Exp. Biol. Med., 203:60, 1993
-
7/31/2019 Role of Oxytocin in Prolactin Release
10/31
Dopamine From 3 Sources
Tuberoinfundibular (TIDA):
Dorsomedial ARN Median eminence
Tuberohypophysial (THDA):
Rostral ARN Neural and intermediate lobes
Periventricular hypophysial (PHDA):
PeVN Intermediate lobe
P l i S i l
-
7/31/2019 Role of Oxytocin in Prolactin Release
11/31
Prolactin StimulatesNeuroendocrine Dopamine
Secretion
DeMaria et al., Brain Res. 837:236, 1999
DOPAC the major metabolite of dopamine
oPRL
ovine prolactin
In medianeminence
Also true forneural andintermediate
lobes
Systemic ovineprolactin injection
H h i Th D i
-
7/31/2019 Role of Oxytocin in Prolactin Release
12/31
Hypothesis: The Dopamine-Prolactin Circuit Produces the
Rhythm
This can happen only if the positive feedback ofprolactin onto dopamine neurons is delayed. Thereis evidence for such a delay(Ma et al., Endocrinology, 146:93, 2005;
DeMaria et al., Brain Res., 837:236, 1999)
-
7/31/2019 Role of Oxytocin in Prolactin Release
13/31
Our Approach: Build a Math Model
qPRLDAk
T
dt
PRLd
d
p
2
1
DAqPRLkTdt
DAdpd
2
3 hours
Bertram et al.,AJP, 290:E573, 2006
-
7/31/2019 Role of Oxytocin in Prolactin Release
14/31
Prediction: Dopamine Levels Should Be Outof Phase with Prolactin Levels
Dopamine secretion intothe median eminence andthe neural lobe peaksat noon, between the
prolactin surges
McKee et al., Endocrinology, 148:4649, 2007
-
7/31/2019 Role of Oxytocin in Prolactin Release
15/31
Input from the SuprachiasmaticNucleus
Neurons of the suprachiasmatic nucleus (SCN) thatproject to the arcuate nucleus and release vasoactiveintestinal polypeptide (VIP) are most active early in themorning. They areinhibitory to DA neurons.
DAVIPrDAqPRLkT
dt
DAdvpd
2
-
7/31/2019 Role of Oxytocin in Prolactin Release
16/31
Improved Rhythm Generator
Rhythm duringone day
Rhythm during10 days
CS simulated by partial inhibition of dopamine neurons
-
7/31/2019 Role of Oxytocin in Prolactin Release
17/31
Oxytocin Injection Can Initiate theProlactin Rhythm
OT injected Egli et al., AJP 290:E566, 2006
-
7/31/2019 Role of Oxytocin in Prolactin Release
18/31
What Role Does Oxytocin Play inthe Prolactin Rhythm?
O t i Sti l t P l ti S ti
-
7/31/2019 Role of Oxytocin in Prolactin Release
19/31
Oxytocin Stimulates Prolactin SecretionFrom Lactotrophs in vitroThrough a
Calcium-Linked Mechanism
Egli et al.,Endocrinology145:3386, 2004
Secretion
Intracellularcalcium
-
7/31/2019 Role of Oxytocin in Prolactin Release
20/31
-
7/31/2019 Role of Oxytocin in Prolactin Release
21/31
Prolactin Feeds Back Onto and InhibitsOxytocin Neurons of the Supraoptic Nucleus
(SON) and Perhaps the ParaventricularNucleus (PVN)
Kokay et al., AJP 290:R1216, 2006
Electrical firing rate
with extracellularrecording fromthe SON
CCK stimulating agent
-
7/31/2019 Role of Oxytocin in Prolactin Release
22/31
Model with Oxytocin Interactions
qPRLDAk
OTT
dt
PRLd
d
Op
2
1
OTqPRLk
T
dt
OTd
O
O
2
1
-
7/31/2019 Role of Oxytocin in Prolactin Release
23/31
Simulation and Prediction
Prediction:The PRL rhythm willreturn when the OT antagonistleaves the system. That is, OTat the lactotroph is requiredfor the expression of the rhythm,but not for triggering the rhythm.
Simulation
PRL
Time (days)
As predicted, the prolactinrhythm comes back oncethe antagonist clears thesystem (day 2 no rhythm;day 3 rhythm present)
(McKee et al., Endocrinology, 148:4649, 2007)
-
7/31/2019 Role of Oxytocin in Prolactin Release
24/31
Conclusions: Part 1
2. The prolactin rhythm can be induced bymating, or in OVX animals, by cervical stimulation,central or peripheral prolactin injection, orperipheral oxytocin injection.
1. The prolactin rhythm is likely due to interactionsbetween dopamine neurons and lactotrophs.
3. Oxytocin at the lactotroph is necessary for theexpression of the CS-induced rhythm, but is notpart of the triggering mechanism.
-
7/31/2019 Role of Oxytocin in Prolactin Release
25/31
-
7/31/2019 Role of Oxytocin in Prolactin Release
26/31
12 24 12 24 12 24 12 240 12 24 12 24 12 24 12 240.0
0.2
0.4
0.6
0.8
Diestrus-1Diestrus-2 EstrusProestrus
Dopa
mine(ng/mgpro
tein)
The Amount of Dopamine Arriving inthe Anterior Lobe Decreases Coincident
with the Rise of Prolactin During the
Estrous Cycle
-
7/31/2019 Role of Oxytocin in Prolactin Release
27/31
Does Oxytocin Contribute to theProestrous Surge?
1. Plasma oxytocin concentration increases in response to estradioladministration (Yamaguchi et al., Endocrinol. Jpn., 26:197, 1979)
2. The concentration of oxytocin in pituitary portal blood peakson the afternoon of proestrus (Sarkar and Gibbs, Neuroendocrinology,48:214, 1988)
So a role for oxytocin seems plausible
-
7/31/2019 Role of Oxytocin in Prolactin Release
28/31
Does the Oxytocin Sensitivity ofLactotrophs Vary During the Cycle?
Our experiments:
Remove anterior pituitaries from cycling rats on the morning
of diestrus-1 or afternoon of proestrus
Disperse cells. Use mixed population for prolactin secretionmeasurements, enrich for lactotrophs for calcium measurements
Apply oxytocin to the pituitary cells
-
7/31/2019 Role of Oxytocin in Prolactin Release
29/31
Response to Oxytocin is Greaterfrom Proestrous Cells
Secretion increased Calcium response increased
Tabak et al., Endocrinology, 151:1806, 2010
-
7/31/2019 Role of Oxytocin in Prolactin Release
30/31
Conclusions: Part 2
1. Sensitivity of lactotrophs to oxytocin is increased duringthe afternoon of proestrus. This corresponds to the time ofthe peak in plasma oxytocin levels, and the prolactin surge.
2. Both the size of the individual calcium responses and thenumber of cells responding to oxytocin are upregulatedon the afternoon of proestrus.
Open Question: What is the mechanism of the upregulationof the oxytocin response?
-
7/31/2019 Role of Oxytocin in Prolactin Release
31/31
A review of this talk is freely available online in the July Special Issue: