Role of Oxytocin in Prolactin Release

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The Emerging Roles ofOxytocin in Rhythmic Prolactin

Release

Richard BertramProgram in Neuroscience

Florida State University


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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


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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.


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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


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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


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Central Blockade of ProlactinReceptors Inhibits the CS-Induced

Prolactin RhythmIcv infusion of prolactin antagonist

Central prolactin feedback is necessary for the rhythm!


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What is the Mechanism for this Rhythm?


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Dopamine is the PhysiologicalInhibitor of Prolactin Release

Arey et al., Proc. Soc. Exp. Biol. Med., 203:60, 1993


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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


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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


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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)


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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


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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


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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


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Improved Rhythm Generator

Rhythm duringone day

Rhythm during10 days

CS simulated by partial inhibition of dopamine neurons


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Oxytocin Injection Can Initiate theProlactin Rhythm

OT injected Egli et al., AJP 290:E566, 2006


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What Role Does Oxytocin Play inthe Prolactin Rhythm?

O t i Sti l t P l ti S ti


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Oxytocin Stimulates Prolactin SecretionFrom Lactotrophs in vitroThrough a

Calcium-Linked Mechanism

Egli et al.,Endocrinology145:3386, 2004

Secretion

Intracellularcalcium


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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


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Model with Oxytocin Interactions

qPRLDAk

OTT

dt

PRLd

d

Op

2

1

OTqPRLk

T

dt

OTd

O

O

2

1


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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)


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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.


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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


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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


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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


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Response to Oxytocin is Greaterfrom Proestrous Cells

Secretion increased Calcium response increased

Tabak et al., Endocrinology, 151:1806, 2010


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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?


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A review of this talk is freely available online in the July Special Issue:

Role of Oxytocin in Prolactin Release

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