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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
Spinal Ejaculation Generator
Supraspinal Sites
Sensory cuespreceding
ejaculation
Neural Control of EjaculationNeural Control of Ejaculation
Pelvic Organs
Spinal Ejaculation Generator
Supraspinal Sites
Sensory cuespreceding
ejaculation
Descending excitatory andinhibitory signals
Motor/Autonomic
Neural Control of EjaculationNeural Control of Ejaculation
Pelvic Organs
Spinal Ejaculation Generator
Supraspinal Sites
Sensory cuespreceding
ejaculation
Descending excitatory andinhibitory signals
Motor/Autonomic
Sensory signalsrelated toejaculation
Sensory signalsrelated toejaculation
Neural Control of EjaculationNeural Control of Ejaculation
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
SupraspinalSupraspinal control of ejaculationcontrol of ejaculation
Giuliano and Clement, 2005
Cerebral Cortex
ThalamusSPFp
PonsnPGi
HypothalamusMPOAPVN
MidbrainPAG
MeApd BNSTpm
PNpd
Sensory input fromgenital area
SupraspinalSupraspinal control of ejaculationcontrol of ejaculation
Giuliano and Clement, 2005
Cerebral Cortex
ThalamusSPFp
PonsnPGi
HypothalamusMPOAPVN
MidbrainPAG
MeApd BNSTpm
PNpd
Sensory input fromgenital area
Motor outputs to spinal nucleicommanding ejaculation
SupraspinalSupraspinal control of ejaculationcontrol of ejaculation
Giuliano and Clement, 2005
Cerebral Cortex
ThalamusSPFp
PonsnPGi
HypothalamusMPOAPVN
MidbrainPAG
MeApd BNSTpm
PNpd
Sensory input fromgenital area
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))
SupraspinalSupraspinal control of ejaculationcontrol of ejaculation
Giuliano and Clement, 2005
Cerebral Cortex
ThalamusSPFp
PonsnPGi
HypothalamusMPOAPVN
MidbrainPAG
MeApd BNSTpm
PNpd
Sensory input fromgenital area
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!