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Home , Bremelanotide, Sexual desire

10/9/2018

The neurochemistry of sexual and sexual pleasure

James G. Pfaus, PhD, IF

Center for Studies in Behavioral Neurobiology Department of Psychology, Concordia University Montréal, QC, Canada

2018 Meeting of the North American Society Presidential symposium “Sexual desire: Wired for wild” 3 October 2018

Acknowledgements –Jim Pfaus

Grants: Canadian Institutes for Research (CIHR), Fonds de la recherche en santé du Québec (FRSQ), and the Natural Sciences and Engineering Research Council (NSERC).

Contracts/Ad Boards/Honoraria: Acadia Pharmaceuticals, Emotional Brain LLC; Palatin Technologies/AMAG Pharmaceuticals.

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Masters and Johnson’s (1966) EPOR Model, after Moll (1908)

Male Female

Voluptuous acme

Equable voluptuous sensations Albert Moll (1862‐1939) The Onset

Tumescence drive Detumescence drive

and as modified by Kaplan (1974) and Georgiadis et al. (2012)

William Masters and Virginia E. Johnson (1915‐2001) (1925‐2013) Helen Singer Kaplan (1929‐1995)

Janniko Georgiadis (1973‐ )

Female Sexual Response Cycle Phases

RESTING EXCITEMENT

ORGASMIC PLATEAU

Salonia A, Giraldi A, Chivers ML, Georgiadis JR, Levin R, Maravilla KR, McCarthy MM.: Physiology of women's sexual function: basic knowledge and new findings. J Sex Med. 2010;7:2637‐60.

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Female Sexual Response Cycle Faces

RESTING EXCITEMENT

ORGASMIC PLATEAU

Salonia A, Giraldi A, Chivers ML, Georgiadis JR, Levin R, Maravilla KR, McCarthy MM.: Physiology of women's sexual function: basic knowledge and new findings. J Sex Med. 2010;7:2637‐60.

Definitions • Sexual Increased genital blood flow; heart rate; sweating, pupil dilation

• Sexual Desire/Interest Wanting or craving sexual activity; behaviors aimed at acquiring sex partners or sexual reward

• Sexual Reward Pleasure; ; intimacy; bonding; control; other rewards

• Sexual Inhibition Satiety; primary aversion; secondary avoidance

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(At least) two types of sexual systems

1.Reflexive (autonomic activation; genital reflexes and sensations, innate copulatory behaviors); involves hypothalamus, brainstem, spinal cord.

2. Incentive (Pavlovian associations between sexual stimuli and reward or punishment, and operant associations between behavior and reward or punishment); involves limbic and cortical structures that interact with certain hypothalamic nuclei.

Georgiadis, Kringelbach, Pfaus (2012) Nature Rev Urol, 9, 486‐498

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Basson’s Model of Desire

Numerous Sexual Incentives for Receptiveness Sex

Rewards: Innate Sexual Sexual and Desire Sexual Stimuli Non-Sexual (hormonally driven)

Sexual Responsive Arousal Desire (experientially driven)

Basson (2002) J Sex Mar Ther 28, 1‐10.

after Perelman (2006) J Sex Med, 3, 1004-1012

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INHIBITION (Reward/Satiety, Stress, or Aversion)

Opioids- 5-HT- CBs-

NE/OT+ X NE/OT+

DA/MCs+ DA/MCs+ X

X

Pfaus, Scepkowski, 2005, Curr Sex Health Rep, 2, 95‐100

Female sexual desire

Precopulatory sexual solicitations in female rats and macaques are predictive of sexual interest and desire in women, and are driven by similar hormonal and neurochemical mechanisms

• Facilitative effects of and •Dopamine and activation of solicitations and desire • Inhibition of 5‐HT2A receptors activates solicitations and desire over time. • Combination of and PDE‐5Is increase solicitations and responsive desire in both rats and women.

Gelez H et al., JSM,2013:10:1231‐1239 Pfaus JG, Guiliano F., Gelez, H. JSM, 2007;4 (suppl. 4) 269‐279 Pfaus JG, Jones SL, Flanagan‐Cato LM, Blaustein, JD. Chapter 50, Physiology of Reproduction, 2015 New York:Elsevier Snoeren EMS et al., JSM 2011,8:989‐1001

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Excitatory Systems of the Brain + + Dopamine (DA) Noradrenaline (NA)

ENDOCRINE, AUTONOMIC Cell bodies in locus coeruleus REGULATION, Projections to hypothalamic, limbic, and cortical regions; descending projections to , ATTENTION, cerebellum and spinal cord. DESIRE, REWARD MOVEMENT AROUSAL Pfaus (2009) J Sex Med, 6, 1506‐1533.

Neural excitatory systems

Zona incerta

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Dopamine release in the mPOA is a general neural switch that controls sympathetic and parasympathetic blood flow in the presence of sexual cues.

Pfaus (2009). J Sex Med, 6, 1506‐1533.

Response to visual erotica (non‐clinical samples)

mPOA mPOA

Arnow et al. (2009) Neuroscience, 158, 484‐502; Arnow et al. (2002), Brain, 125, 1014‐1023

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mPOA D1 activation is critical for sexual desire and modulating sympathetic outflow

SEXUAL SENSORY STIMULI Cortial and limbic systems

mPOA

CLITORIS OR PENILE CORPUS

GENITALS

OR PENIS

Flaccid Erect

Round ligament Suspensory of the uterus ligament Bladder Bladder Pubic bone Erect shaft Blood-filled Suspensory Hood ligament Closed valve cavern Empty cavern inside artery Pudendal vein Leg Pudendal vein Pudendal artery Pudendal artery Leg Glans Shaft

Hood Glans

Paraurethral Paraurethral duct duct Inner lip Perineal Perineal sponge Outer lip Inner lip sponge Outer lip Urethral Clitoral opening Urethral Closed valve opening Urethral to the vagina opening inside vein sponge Bulb Vulvovaginal Urethral Clitoral opening Vulvovaginal Bulb gland sponge to the vagina gland

Sympathetic activation causes blood to accumulate in the spongiosum of the clitoris and labia, increasing the diameter of the glans clitoris, and exposing more tactile sensory nerve endings in both clitoris and labia.

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Sensory Input

mPOA Mesolimbic Nigrostriatal

Genital Appetitive Somatomotor Responses Behaviors Patterns

Hull, Lorrain, Du, Matuszewich, Lumley, Putnam, Moses (1999) Behav Brain Res, 105, 105‐116

Excitatory Systems of the Brain ++

DESIRE, AROUSAL AROUSAL, BONDING

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Melanocortins and Sex

• POMC , including ACTH, and α‐MSH, have pronounced effects on the sexual behavior of female and male rats

• α‐MSH facilitates lordosis in ‐primed females and in gonadally‐intact males

• α‐MSH levels in anterior hypothalamus increased by estrogen, suggesting that it may be one of several intermediaries of estrogen action

Melanocortins in the brain

• Cells originate in the arcuate nucleus of the hypothalamus and nucleus of the solitary tract. • Axons innervate other hypothalamic regions, limbic regions midbrain, brainstem, and spinal cord. • Melanocortin receptors exist in these regions, along with organs in the periphery.

Arcuate nucleus POMC neurons POMC projections Melanocortin receptors

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Bremelanotide: (formerly PT-141) Ac-Nle-Asp-His-DPhe-Arg-Trp-Lys-OH

α-MSH: Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val . Binds to MC3R and MC4R in brain . Induces in healthy men . Induces erections in healthy rats . Induces erections in men with mild-to-moderate erectile dysfunction and in men who do not respond well to PDE-5 inhibitors . Rapid effect in rats (within 5 to 20 min) . Facilitates solicitations selectively in female rats

Effects of bremelanotide in female rats

Dose of BMT (μg/kg) mPOA DA release after BMT D1

D2

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Effects of bremelanotide in female rats

Conditioning

Odor Final Test Conditioned Partner Preference test

Females received 5 trials each with scented males in a paced condition (partition), and unscented males in a nonpaced condition Unscented Scented male male (no partition). (Scented) (Unscented) (nonpreferred) (preferred) On the final test, females were Injected with BMT (200 μg/kg, sc) or SAL and given a choice No evidence that BMT disrupted conditioned of two males, one scented (preferred) and one unscented (nonpreferred) in an open field. partner preference. It increased solicitations only for the preferred partner.

mPOA

saline

bremelanotide (100 µg/kg) bremelanotide (200 µg/kg)

Pfaus, Giuliano, Gelez, 2007, J Sex Med, 4 (suppl 4), 269-279

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Neuronal activation induced by bremelanotide

Brain Region Activity Significance mPOA +++ Solicitation (Proceptivity) VTA +++ Incentive Salience Attention NAc +++/++ Incentive Salience shell/core Attention PIR +++ Conditioned Arousal BLA +++ Reward-Related Learning VMH - Lordosis

Pfaus, Giuliano, Gelez (2007). J Sex Med, 4 (suppl 4), 269-279

Action of melanocortins in the mPOA

Resting (unstimulated) DA release Stimulated DA release

MC4R MC4R MC4R MC4R

α‐MSH/BMT

D1 dopamine D1 dopamine receptor receptor

Decreased release Increased release of dopamine of dopamine

Graham et al. (2015). Eur J Neurosci, 42, 3138‐3148

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GABA projections from the mPOA to the VTA activate mesolimbic dopamine through disinhibition. mPFC

GLU

Serotonin mPOA Cannabinoids

NAc

Mesolimbic activation of appetitive responses

Opioids/Opiates Graham et al. (2015). Eur J Neurosci, 42, 3138‐3148

Inhibitory Systems of the Brain -- Opioids Serotonin (5-HT)

Nucleus Paragigantocellularis (POMC) systems: (nPGi)

Cell bodies found in periarcuate regions Cell bodies in Raphe nuclei of hypothalamus and brainstem. Ascending projections to hypothalamic, limbic, and cortical regions; Diffuse projections to hypothalamic, Descending projections to spinal cord limbic, cortical, midbrain, and brainstem regions. SATIETY REWARD/PLEASURE

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GLU+

Mu opioid receptors (MORs) exist in all regions of the sexual reward/bonding circuit. β‐END+

Opioids sensitize β‐END‐ DA release; naloxone inhibits conditioned Opioids inhibit appetitive responses ; naloxone facilitates Van Furth, Van Ree, (1995) copulation under stress; Pitchers et al. (2014) MORs internalize after multiple ejaculations. Hughes, Everitt, Herbert (1990) Coolen et al. (2007)

Opioids sensitize mesolimbic dopamine neurons and dopamine release in terminal regions mPFC

GLU

Serotonin mPOA Cannabinoids

NAc

Mesolimbic activation of appetitive responses

Opioids/Opiates

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We can block the rewarding effect of in both males and females with either an opioid antagonist (naloxone) or induced by the presentation of a sexually nonreceptive partner, or one that is inaccessible.

Systemic naloxone blocks partner preference in males

Saline Naloxone

● Saline or Naloxone (4 mg/kg) administered sc before each of 9 conditioning trials. Saline given to both groups prior to the final open field test.

● Males with naloxone experience did not develop CEP, and in fact displayed an apparent avoidance of familiar females paired with the naloxone state.

Ismail, Girard‐Bériault, Nakanishi, Pfaus, 2009, Behav Neurosci, 123, 992‐999

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Systemic naloxone blocks partner preference in females

9 conditioning trials with SAL or NAL (4 mg/kg) followed by an open-field test. All females injected with SAL prior to ..the final open-field test.

NO NAL ON THE FINAL TEST…

Coria‐Avila et al. (2008) Behav Neurosci, 122, 385‐395

Lordosis Magnitude 3 SolicitationsSolicitations Lordosis Magnitude 3

10 50

8 40

6 30 *

4 * 20 mean number mean number 2 10

0 0 SAL NAL SAL NAL

Hops andand Darts Darts Intromissions

25 50

20 40 15 * 30 * 10 20 mean number 5 mean number 10

0 0 SAL NAL SAL NAL DefensiveDefensive BehaivorsResponses Ejaculations

2 * 4

1.5 3

1 2 *

0.5 1 mean number mean number

0 0 SAL NAL SAL NAL

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Prefrontal Cortex Controls “Executive Functions”

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Inhibitory outflow from the prefrontal cortex

Inhibitory outflow regulated by 5-HT

mPOA/AH

Serotonin’s activation of descending glutamate neurons from the PFC activate inhibitory GABA interneurons in the VTA to shut down mPFC mesolimbic dopamine.

GLU

Serotonin mPOA Cannabinoids

NAc

Mesolimbic activation of appetitive responses

Opioids/Opiates

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Putative mechanism of action of (Addyi®)

Flibanserin serotonin receptor activity at the synapse

Agonist at 5‐HT1A autoreceptors (reduces serotonin release)

Antagonist at 5‐HT2A receptors (blocks serotonin action)

Reduction in serotonin disinhibits… leading to:

Increased sexual desire Decreased sexual distress Modest increase in sexually satisfying events

Effects of flibanserin (Addyi®) in female rats

Mixed 5-HT1a / 2a antagonist

OVX, sexually experienced females given 21 days of oral flibanserin treatment (0, 15, 45 mg/kg, b.i.d.).

Sexual testing occurred at 7-day intervals in bilevel chambers.

Low EB priming (5 μg) given 48 hr prior to each test (to prevent estrogen sensitization).

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Effects of flibanserin in female rats

SolicitationsSolicitations HopsHops and and Darts Darts

15 * 35 * 30 25 10 0 0 20 15 15 15 5 45 10 45

Mean number Mean number 5 0 0 Day 7 Day14 Day 21 Day 7 Day14 Day 21 Days of Treatment Days of Treatment

FemaleFemale Defensive Defensive Responses Responses IntromissionsIntromissions ReceivedReceived

20 20 * 15 15 0 0 10 15 10 15 45 45 5 5 Mean number * Mean number 0 0 Day 7 Day14 Day 21 Day 7 Day14 Day 21 Days of Treatment Days of Treatment Chronic flibanserin induced sexual desire typical of females primed with EB+P

Gelez, Greggain‐Mohr, Pfaus, Allers, Giuliano (2013), J Sex Med, 10, 1231‐1239

5-HT NE DA

mPFC

NAc

mPOA

Allers et al. (2010) J Sex Med, 7, 1757-1767

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Integration of excitation and inhibition

Sexual inhibition (dysfunction)

+ - Drugs or states Drugs or states that activate that inhibit

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Sexual excitation (restoration)

-+ Drugs or states Drugs or states that inhibit that activate

Pleasure activates bonding, attention, and arousal to create attraction and desire

Attraction and Desire

AWARENESS PFC, ACC‐IN, SC

BONDING, ATTENTION, AROUSAL OT DA VP mPOA, PVN, SON, VP, NAc VTA, Hipp, MEApd

NE

PLEASURE Opioids ARC

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Cupid and Psyche by Jacques‐Louis David (1817)

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HSDD Can occur in women (or men) with or without concomitant decreases in physiological and subjective .

Etiologies: 1. Hypofunctional excitation 2. Hyperfunctional inhibition 3. Both

Arnow et al. (2009) Neuroscience, 158, 484‐502

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Treatments and potential treatments

Experiential: Traditional sex therapy Mindfulness

Hormonal/ Pharmacotherapeutic: Estradiol + Testosterone Flibanserin (Addyi®) Bremelanotide Librido (T+) or Libridos (T+) Lorexys (+)

Effects of flibanserin in female

Desire Distress

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Effects of bremelanotide in female humans

Desire Distress

FSFI‐D scores

Adapted from Clayton et al. (2016) Womens Health (Lond), 12, 325‐337.

Treatments for HSDD/FSIAD

Flibanserin (Addyi®), Mindfullness, Sensate Focus Bupropion/Trazodone (Lorexys®) Testosterone/Buspirone (Lybridos®) _

Hypothalamus and +

+

Bremelanotide Testosterone/Sildenafil (Lybrido®)

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