control of ejaculation: what the rat's brain tells the clinician

Control of Control of EjaculationEjaculation

What the RatWhat the Rat’’s Brain Tells the s Brain Tells the ClinicianClinician

Elaine M. Hull & Juan M. DominguezElaine M. Hull & Juan M. DominguezFlorida State UniversityFlorida State University

What is ejaculation?What is ejaculation?

2 phases:2 phases:EmissionEmissionExpulsionExpulsion

Seminal emissionSeminal emissionSperm + fluids from Sperm + fluids from seminal vesicle, seminal vesicle, prostate, & Cowperprostate, & Cowper’’s s gland gland urethra (in urethra (in prostate)prostate)Parasympathetic NS Parasympathetic NS

secretionsecretionSympathetic Sympathetic movementmovement

Expulsion, orgasmExpulsion, orgasmBulbospongiosusBulbospongiosus, , ischiocavernosusischiocavernosus, & , & pelvic floor muscles pelvic floor muscles contract, bladder neck contract, bladder neck closes.closes.Orgasm: cerebral Orgasm: cerebral process; does not process; does not require expulsion of require expulsion of semensemen

Gray’s anatomy

How is ejaculation How is ejaculation coordinated and coordinated and

controlled?controlled?

Pelvic Organs

Spinal Ejaculation Generator

Supraspinal Sites

Neural Control of EjaculationNeural Control of Ejaculation

Pelvic Organs


Supraspinal Sites

Sensory cuespreceding

ejaculation


Pelvic Organs


Supraspinal Sites


ejaculation

Descending excitatory andinhibitory signals

Motor/Autonomic


Pelvic Organs


Supraspinal Sites


ejaculation

Descending excitatory andinhibitory signals

Motor/Autonomic

Sensory signalsrelated toejaculation

Sensory signalsrelated toejaculation


A spinal ejaculation generatorA spinal ejaculation generatorLumbar Lumbar spinothalamicspinothalamic ((LStLSt) neurons) neurons

Truitt et al., 2003

LStLSt neuronsneurons(A)(A) GalaninGalanin--containing containing

neurons are neurons are FosFos--irir after after 2 ejaculations,2 ejaculations,

(B)(B) but not after only but not after only intromissions.intromissions.

(C)(C) They are They are FosFos--irir after 8after 8--OHOH--DPAT + I DPAT + I ejaculation.ejaculation.

(D)(D) No No FosFos--irir in a female in a female after she received 1 after she received 1 ejaculation.ejaculation.

Truitt et al., 2003

LStLSt neuronsneuronsPercentage of Percentage of galaningalanincells that were cells that were FosFos--irirafter Home Cage, after Home Cage, Anestrous Female, Anestrous Female, Mounts, M+I, 1 Mounts, M+I, 1 EjacEjac., ., 2 2 EjacsEjacs

Truitt et al., 2003

LStLSt neuronsneurons

Destruction of Destruction of LStLStneurons by neurons by saporinsaporinconjugated to SSP conjugated to SSP abolished abolished ejacejac., but ., but mount & intro were mount & intro were normal.normal.(SSP: analog of SP, (SSP: analog of SP, agonist at NK1 agonist at NK1 receptors. Most receptors. Most LStLStcells have NK1 rec.)cells have NK1 rec.)

Truitt et al., 2003

LStLSt SummarySummary

LStLSt neurons are selectively activated by neurons are selectively activated by ejaculation and are necessary for ejaculation and are necessary for ejaculation.ejaculation.Receipt of ejaculation by a female does Receipt of ejaculation by a female does not activate not activate galaningalanin--containing neurons in containing neurons in the same area.the same area.

SupraspinalSupraspinal control of ejaculationcontrol of ejaculation

Giuliano and Clement, 2005

Cerebral Cortex

ThalamusSPFp

PonsnPGi

HypothalamusMPOAPVN

MidbrainPAG

MeApd BNSTpm

PNpd

Sensory input fromgenital area



Cerebral Cortex

ThalamusSPFp

PonsnPGi

HypothalamusMPOAPVN

MidbrainPAG

MeApd BNSTpm

PNpd


Motor outputs to spinal nucleicommanding ejaculation

Roles of MPOA DopamineRoles of MPOA Dopamine

Dominguez and Hull, 2005

Dopamine is released in MPOA Dopamine is released in MPOA before and during matingbefore and during mating

DA increase from BL DA increase from BL was correlated with was correlated with ability to ejaculateability to ejaculate

Hull et al., 1995

Role of MPOA glutamateRole of MPOA glutamateGlut. increased during Glut. increased during mating andmating andPeaked with Peaked with ejacejac..PostPost--ejacejac. decrease . decrease correlated with PEIcorrelated with PEIReverseReverse--dialysis of dialysis of uptake inhibitors uptake inhibitors increased increased ejacsejacs., ., decreased EL, PEI.decreased EL, PEI.

Dominguez et al., 2006

Stimulate MPOA Stimulate MPOA BS firingBS firingPAG lesions abolish the effectPAG lesions abolish the effect

Marson, 2004

Summary of MPOA effectsSummary of MPOA effectsHigh doses of D2 agonists High doses of D2 agonists seminal emission seminal emission ex copula.ex copula.High doses of D2 agonists High doses of D2 agonists ejaculation ejaculation in in copula.copula.Electrical stimulation Electrical stimulation BS firing. BS firing. Lesions of PAG block that effect.Lesions of PAG block that effect.

Role of the PVNRole of the PVNReviewed in Reviewed in ArgiolasArgiolas & & MelisMelis, 2004, 2004

D2 agonists, glutamate, NO in PVN D2 agonists, glutamate, NO in PVN ex ex copulacopula erection & seminal emissionerection & seminal emissionPVN lesions decrease amount of semen in PVN lesions decrease amount of semen in ejaculate.ejaculate.OxytocinOxytocin fibers fibers lumbosacrallumbosacral cord, as cord, as well as hippocampus, other brain areaswell as hippocampus, other brain areasOxytocinOxytocin systemic circulation via PPsystemic circulation via PP

(reviewed in (reviewed in ArgiolasArgiolas & & MelisMelis, 2004), 2004)

Role of the PVNRole of the PVN

Argiolas and Melis, 2004

Role of the PVNRole of the PVN

Argiolas and Melis, 2004

Ca2+

(+)

(-)

NOS

DopamineOxytocin

Excitatory Amino Acids

OpioidsGABA

NO

(+)

(-)

Oxytocin

Hippocampus

Pons

Med. Oblongata

Spinal Cord

Role of Role of nPGinPGi

Lesions of nucleus Lesions of nucleus paragigantocellularisparagigantocellularis in in medulla: as effective as spinal medulla: as effective as spinal trantran--section section at releasing the at releasing the urethrogenitalurethrogenital reflex reflex (model of orgasm) (model of orgasm) ((MarsonMarson et al., et al., ‘‘92).92).

nPGinPGi sends 5sends 5--HT axons to lower spinal HT axons to lower spinal cord; 5cord; 5--HT lesions HT lesions disinhibitdisinhibit UG reflex UG reflex

((MarsonMarson & McKenna, 1992, 1994).& McKenna, 1992, 1994).

An ejaculation circuitAn ejaculation circuitSelective activation (Selective activation (FosFos--irir) by ejaculation:) by ejaculation:SubparafascicularSubparafascicular nucleus of thalamus nucleus of thalamus ((SPFpSPFp))PosteromedialPosteromedial bed nucleus of bed nucleus of striastria terminalisterminalis((BNSTpmBNSTpm))PosterodorsalPosterodorsal medial medial amygdalaamygdala ((MeApdMeApd))PosterodorsalPosterodorsal preopticpreoptic nucleus (nucleus (PNpdPNpd))



Cerebral Cortex

ThalamusSPFp

PonsnPGi

HypothalamusMPOAPVN

MidbrainPAG

MeApd BNSTpm

PNpd


Motor outputs to spinal nucleicommanding ejaculation

So, what DOES the ratSo, what DOES the rat’’s s brain tell the clinician?brain tell the clinician?

So, what DOES the ratSo, what DOES the rat’’s s brain tell the clinician?brain tell the clinician?

Premature ejaculationPremature ejaculationDelayed or absent ejaculationDelayed or absent ejaculation

“Can’t you at least wait till I’ve laid the eggs?”

Role of Role of norepinephrinenorepinephrine (NE)(NE)

Sympathetic NS transmitter Sympathetic NS transmitter seminal seminal emission & ejaculation; also in CNS.emission & ejaculation; also in CNS.DoseDose--dependent effects of NE drugsdependent effects of NE drugsαα2 2 autoautoreceptorsreceptors decrease NE releasedecrease NE releaseαα2 antagonists (e.g., 2 antagonists (e.g., yohimbineyohimbine) increase NE ) increase NE release, facilitate copulation in ratsrelease, facilitate copulation in rats

But too much NE But too much NE inhibits erectioninhibits erection

Role of dopamine (DA)Role of dopamine (DA)

Rats: Rats: Dopamine agonists facilitate copulation Dopamine agonists facilitate copulation and reflexesand reflexesD2 agonists D2 agonists ejaculationejaculation

Humans:Humans:DA agonists have been used for erectile DA agonists have been used for erectile dysfunction, but not for dysfunction, but not for ejacejac. disorder.. disorder.DA antagonists (DA antagonists (antipsychoticsantipsychotics) block ) block ejacejac..

Role of serotonin (5Role of serotonin (5--HT) in ratsHT) in ratsNeurotoxicNeurotoxic lesions facilitate copulationlesions facilitate copulation55--HT is released in LH at ejaculationHT is released in LH at ejaculation

SSRI in LH delayed onset of copulationSSRI in LH delayed onset of copulation55--HT in LH decreased DA in HT in LH decreased DA in NucNuc. . AccumbAccumb..Mechanism for PEI quiescenceMechanism for PEI quiescence

55--HT1A agonist (8HT1A agonist (8--OHOH--DPAT) DPAT) ejacejac..55--HT1B agonist inhibits ejaculationHT1B agonist inhibits ejaculation55--HT2C agonist HT2C agonist erection, inhibit erection, inhibit ejacejac..

Effects of Effects of SSRIsSSRIs in ratsin rats

Chronic Prozac inhibited ejaculationChronic Prozac inhibited ejaculationSystemic Systemic oxytocinoxytocin restored it restored it (Cantor et al., (Cantor et al., ’’99).99).

88--OHOH--DPAT (5DPAT (5--HT1A agonist) also restoredHT1A agonist) also restored it it ((FaulringFaulring et al., 2002, et al., 2002, SfNSfN).).

88--OHOH--DPAT DPAT ejacejac..How does it work?How does it work?

AutoreceptorAutoreceptor on 5on 5--HT somasHT somasPostsynaptic receptorPostsynaptic receptorUptake inhibitor?Uptake inhibitor?

DPAT increased both DA and 5DPAT increased both DA and 5--HT in MPOAHT in MPOAEffects not blocked by 5Effects not blocked by 5--HT1A antagonistHT1A antagonist

Lorrain et al., 1998

Rat: DPAT in MPOARat: DPAT in MPOA

Matuszewich et al., 1999

88--OHOH--DPAT DPAT burst firing of rat burst firing of rat bulbospongiosusbulbospongiosus musclemuscle

Clement et al., 2006

88--OHOH--DPAT DPAT burst firing of rat burst firing of rat bulbospongiosusbulbospongiosus musclemuscle

Clement et al., 2006 JPETClement et al., 2006 JPETD2 antagonists blocked D2 antagonists blocked DPATDPAT’’ss effect.effect.A 5A 5--HT1A antagonist did not.HT1A antagonist did not.D2 agonist D2 agonist more clusters of firingmore clusters of firingthan did DPATthan did DPAT

Therefore, at least Therefore, at least some of some of DPATDPAT’’ss

effects are mediated effects are mediated by D2 receptorsby D2 receptors

Effects of Effects of SSRIsSSRIs in in humanshumans

Most Most SSRIsSSRIs delay or block ejaculationdelay or block ejaculationNo No ejacejac. delay by some . delay by some SSRIsSSRIs

NefazodoneNefazodone: blocks 5: blocks 5--HT2 receptors HT2 receptors MirtazapineMirtazapine: blocks 5: blocks 5--HT2 & HT2 & αα22autoautoreceptorsreceptorsBupropionBupropion: inhibits reuptake of DA & NE, also : inhibits reuptake of DA & NE, also 55--HT1A agonistHT1A agonist

How about the little blue pill?How about the little blue pill?

Effects of nitric oxide (NO) in Effects of nitric oxide (NO) in ratsrats

NO NO GC GC cGMPcGMP transmitter release: transmitter release: DA in MPOA, DA in MPOA, oxytocinoxytocin from PVN.from PVN.NO NO GC GC cGMPcGMP vasodilationvasodilation, , erectionerection

Parasympathetic, antiParasympathetic, anti--sympatheticsympatheticNOS antagonist increases seminal emissionNOS antagonist increases seminal emission

Effects of NO in menEffects of NO in men

PhosphodiesterasePhosphodiesterase 5 (PDE 5) catalyzes the 5 (PDE 5) catalyzes the degradation of degradation of cGMPcGMP..SildenafilSildenafil (Viagra), (Viagra), vardenafilvardenafil ((LevitraLevitra), ), tadalafiltadalafil((CialisCialis) inhibit PDE 5 ) inhibit PDE 5 increase erection increase erection (parasympathetic effect)(parasympathetic effect)But, they also delay/inhibit ejaculationBut, they also delay/inhibit ejaculation

Dilates smooth muscle in vas deferens & Dilates smooth muscle in vas deferens & seminal vesicles: canseminal vesicles: can’’t squeeze fluidst squeeze fluidsUsed to treat premature Used to treat premature ejacejac. .

SummarySummary

MPOA & PVN MPOA & PVN ejacejac..D2 receptors, NO, glutamateD2 receptors, NO, glutamateOxytocinOxytocin from PVNfrom PVN

NO NO erection, inhibits ejaculationerection, inhibits ejaculation55--HT inhibits HT inhibits ejacejac., via 1B, 2C receptors., via 1B, 2C receptors

55--HT1A HT1A ejacejac., partly via D2 receptors., partly via D2 receptors

SummarySummary

SSRIsSSRIs inhibit desire, erection, & inhibit desire, erection, & ejacejac..Less inhibition from Less inhibition from SSRIsSSRIs that also inhibit that also inhibit DA & NE reuptake &/or are 5DA & NE reuptake &/or are 5--HT2 or HT2 or αα2 2 antagonists.antagonists.SSRIsSSRIs and NOS inhibitors used to treat and NOS inhibitors used to treat premature ejaculation, but can be TOO premature ejaculation, but can be TOO effective.effective.

Thanks!Thanks!

My lab, especially Dr. Juan DominguezMy lab, especially Dr. Juan DominguezThe rats and patients who provided the The rats and patients who provided the informationinformationNIMH grants R01 MH 40826, K02 01714NIMH grants R01 MH 40826, K02 01714You for your attention!You for your attention!

control of ejaculation: what the rat's brain tells the clinician

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