1506

REVIEWS

Pathways of Sexual Desire jsm_1309 1506..1533

James G. Pfaus, PhD

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

DOI: 10.1111/j.1743-6109.2009.01309.x

ABSTRACT

Introduction. Sexual desire is controlled by brain systems involved in sexual excitation and inhibition. Hypoactive
sexual desire disorder (HSDD) may result from hypofunctional excitation, hyperfunctional inhibition, or some mix
of the two.
Aim. This study aimed to identify neurochemical and neuroanatomical systems involved in sexual excitation and
inhibition, their role during normal, and hypoactive sexual expressions.
Methods. A comprehensive review of the human and animal literature is made, and a theory surrounding the ways
that HSDD can be manifested and treated is presented.
Main Outcome Measures. Drug effects and neural systems derived largely from rat studies that are involved in the
stimulation of sexual desire (excitatory system) vs. the stimulation of sexual reward, sedation, and satiety (inhibitory
system).
Results. Brain dopamine systems (incertohypothalamic and mesolimbic) that link the hypothalamus and limbic
system appear to form the core of the excitatory system. This system also includes melanocortins, oxytocin, and
norepinephrine. Brain opioid, endocannabinoid, and serotonin systems are activated during periods of sexual
inhibition, and blunt the ability of excitatory systems to be activated.
Conclusions. Drugs that stimulate the activation of hypothalamic dopamine or that blunt endocannabinoid or
serotonin release and/or postsynaptic binding may be effective in stimulating sexual desire in animals and humans.
The characterization of how those drugs work will help generate a rational approach to drug development in the
treatment of HSDD. Pfaus JG. Pathways of sexual desire. J Sex Med 2009;6:1506–1533.
Key Words. Sexual Desire; Hypoactive Sexual Desire Disorder; Neuropharmacology; Treatment; Libido

Introduction cians and motivational theorists alike view desire

as distinct from arousal in both animals and

S exual desire seems a straightforward concept,

yet there is no agreed-upon definition of what
it is or how it manifests itself. In the Diagnostsic
humans. This is apparent in the DSM’s categori-
zation of arousal disorders distinct from desire dis-
orders, a distinction that generally reflects blood
and Statistical Manual of the American Psychiatric flow to the genitals and erectile tissues vs. a “psy-
Association-Edition IV-Text Revision (DSM-IV- chological” sexual interest in which individuals
TR), the diagnosis of hypoactive sexual desire “want” sex (as defined by Robinson and Berridge
disorder (HSDD) is given when “desire for and [2]). In practice, however, desire may well be
fantasy about sexual activity are chronically or informed or even confirmed by the presence of
recurrently deficient or absent” [1]. By converse autonomic and central responses that define
logic, then, sexual desire is the presence of desire arousal, and there is a growing body of evidence
for and fantasy about sexual activity. This defini- that people regard desire and arousal as parts
tion appears coherent but is circular. Many clini- of one another, despite being given distinct

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Pathways of Sexual Desire 1507

definitions (e.g., [3,4]). When an individual Common Structure of Sexual Behavior

expresses sexual desire behaviorally, it follows
that attention and behavior focus on obtaining All behaviors have a beginning, a middle, and an
some form of positive sexual reinforcement. This end, and all organisms that engage in sexual behav-
can occur alone in fantasies or together with ior share a common set of principles and end
others in goal-directed social and sexual beha- points that define the behavior, along with particu-
viors. Thus, in addition to subjective appraisals lar neural mechanisms that make it successful [6].
of desire, the concept encompasses the effort, We must be able to respond to hormonal and
including risk, that individuals engage in to neurochemical changes that signal our own sexual
obtain sexual rewards, the excitement displayed arousal and desire. This ability underlies our
in anticipation of such rewards, and the strength moment-to-moment level of attention to sexual
of the incentive value ascribed to a particular cues [7,8] and defines a large part of the internal
sexual stimulus. state that is commonly referred to as “sex drive.”
All animals, including humans, manifest sexual The rest requires a complex mix of instinct, learn-
desire behaviorally. Desire can be inferred from ing, and feedback, a neural organization that
increased motor output in anticipation of copula- allows us to initiate and terminate interactions
tion or other sexual behaviors or from the amount with external sexual incentives. We must be able to
of work performed for the opportunity to copulate identify external stimuli that predict where poten-
or to obtain primary or secondary (conditioned) tial sex partners can be found, to seek out, solicit,
sexual rewards associated with these behaviors. court, or otherwise work to obtain sex partners,
Animals, including humans, also choose between distinguish external cues and behavioral patterns
two or more sexual incentives based on the of potential sex partners from those that are not
strength of the incentive cues and the their own sexually receptive, and to pursue sex partners once
internal drive state. What characterizes those sexual contact has been made. Neural mechanisms
behaviors is that they occur before copulation. that allow sexual responding to become habitual or
Solicitation, courtship, operant responses, condi- automated with practice exist, and such processes
tioned locomotion in anticipation of sex, time may underlie the ability of sexually experienced
spent near a place associated with sexual rewards, animals to be less affected by treatments that
and the choices made between two or more incen- disrupt sexual responding in sexually naive
tives can all be considered analogies of sexual animals. Similarly, neural mechanisms that allow
desire. The strength of the behavior can be the stimulation received during sexual contact to
observed as increasing or decreasing or can be be perceived as rewarding exist. Such reward con-
tested by increasing the criterion level of respond- tributes to the formation of preferences for salient
ing that animals must attain before they are given stimuli associated with positive sexual reinforce-
access to rewards. Simply put, animals with more ment and leads to a state of sexual satiety in which
“desire” will display more robust behavior than inhibitory neural systems are activated. Those
animals with less desire. Desire can also be inhibitory systems blunt the reactivation of desire,
inferred from certain behaviors that occur during arousal, and sexual behavior for a period of time
copulation, for example, the amount of solicitation that depends critically on the intensity of the
a female rat will perform toward a particular male reward/satiety state, the context in which sexual
rat or the degree of chasing behavior a male rat arousal occurs, and the expectancy of the indi-
will perform to catch a pacing female rat. A vidual. In the “normal” human sexual response,
growing body of evidence indicates that these this pattern flows from desire and excitement at
aspects of sexual behavior are controlled by a the prospect of sexual interaction, to its initiation,
common set of brain regions and altered in a rela- to a rising “plateau” in which sexual responding is
tively selective fashion by certain drugs that are maintained or intensified on its way to an orgasm,
known to alter desire in humans [5,6]. This, in and finally to resolution or refractoriness after an
turn, allows researchers to construct a neurochem- orgasm (as in Kaplan [9] and Masters and Johnson
istry and neuroanatomy of sexual desire that have [10]). Many aspects of sexual desire are manifested
predictive validity for humans and other animals. before the opportunity to engage in sexual be-
The elucidation of neurochemical pathways that havior becomes apparent. Thus, although some
control sexual desire thus generates a vehicle for appetitive responses made prior to copulation are
the construction of rational approaches to phar- not specific to sexual behavior (e.g., bar pressing in
macotherapy to treat desire disorders. rats or flower giving in people), they can be

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1508 Pfaus

considered “sexual” if they occur in anticipation of sexual responding. As noted above, it is easy to see
a sexual reward. how appetitive behaviors such as bar pressing and
flower giving are analogous. The question that
Homologies and Analogies arises is how we equate the consummatory behav-
Because a substantial portion of knowledge con- iors between laboratory animals and humans.
cerning the neurochemistry of sexual behavior has However, unlike humans, rats do not engage in a
been derived from laboratory animals like rats, it is copulatory “lock” in which the partners stay
important to understand how their behavior is together until an ejaculation or an orgasm(s) is
similar to our own. Despite being many bred for reached. Rather, rats make brief copulatory
many generations in laboratory settings, rats main- contact, largely directed by the female (reviewed in
tain individual differences akin to wild rats in Pfaus et al. [6]). Females solicit copulation from
sexual response [11], including differences in the males and then run away, forcing the males to
ability to display both excitatory and inhibitory chase them. After a runaway, a female rat holds an
conditioning of sexual responses paired with sexual estrogen-dependent stationary posture called “lor-
reward and nonreward, respectively [6,12,13]. dosis,” which is intensified when a male palpates
Indeed, Waldinger and colleagues [14–16] have the flanks as he mounts. After mounting with
demonstrated individual differences in male rat penile intromission into the vagina and pelvic
ejaculatory latencies that have allowed them to thrusting that stimulates the clitoris, the male dis-
classify male rats as “premature” or “delayed” mounts, and the female runs away. She then reini-
ejaculators using a similar statistical criterion as tiates contact with the male and runs away again,
that for humans and generated a more rational whereupon he chases her until she stops to hold
approach to preclinical studies of pharmaco- another lordosis posture, allowing him to mount
therapy [14–16]. and intromit again. This cycle occurs several times
To understand how animal sexual behavior is until the male ejaculates. The female regulates his
homologous or analogous to our own, it has been behavior by soliciting his mounts and by control-
useful heuristically to separate both animal and ling the temporal pattern in which they occur. Her
human sexual activities into so-called “appetitive” control of the initiation and rate of copulation is
and “consummatory” phases that roughly charac- called “pacing” [18], and pacing is the critical
terize behaviors animals engaged in prior to or factor for sexual rewards in the female rat [22,25],
during copulation, respectively [17]. Appetitive just as ejaculation is the critical factor for sexual
human sexual behaviors include solicitations, flir- rewards in the male rat [13,21,26]. In both cases, a
tations, fantasy prior to sexual interactions, and the sexual reward reinforces behaviors and cues that
work or strategies employed to negotiate a suc- come before it, making it possible to pair neutral
cessful sexual interaction. Such behaviors have cues such as odors with sexual reward states, so
unambiguous animal homologies and analogies that desire toward those cues (e.g., increased
[6]. Female rats, for example, control the initiation solicitations by females toward males bearing the
and rate of copulation through a complex act of conditioned cue, ejaculatory preference by males
solicitation and runaway [6,11,18]. Solicitations for females bearing the conditioned cue, or condi-
can be distal or proximal (e.g., behaviors that tioned place preference) can be studied directly.
Beach [19] referred to as proceptive hops and darts Although there is no human counterpart for the
around the male), all of which compel the male to multiple intromission pattern of male rats or the
chase and mount the female. Sexual desire can also lordosis posture of female rats, copulation in rats
be inferred from male chasing behavior, which can yield clues about motivational and reward
reflects the willingness to work to obtain a mount states that are altered by pharmacological agents.
or penile intromission with the female. Appetitive For example, rats that ejaculate with few or no
behaviors in particular have become important preceding intromissions (as occurs after injections
preclinical models for sexual “desire” in animals of the drug 8-OH-DPAT, a serotonergic drug that
because they reflect the willingness of an animal to binds to presynaptic autoreceptors and blocks
initiate and engage in a sexual interaction [20]. serotonin release) are said to have a facilitated
Like humans, rats show a high degree of behav- ejaculation but not a facilitated sexual motivation
ioral flexibility during the appetitive phase and can or desire. In fact, such rats do not show a
learn to associate a variety of neutral stimuli like copulatory-conditioned place preference (see
odors with sexual rewards [12,13,21–26]. In turn, below), indicating that ejaculation that comes too
those stimuli act as primes to stimulate desire and quickly is not rewarding. Conversely, chronic

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treatment of male rats with the selective serotonin retical model of dual control of male erectile
reuptake inhibitor (SSRI) fluoxetine induces a response in which the net expression of sexual
progressive delay in the ejaculation latency and behavior is based on the influence of excitatory and
reduces the number of ejaculations that male rats inhibitory mechanisms in the brain [28]. Perel-
can achieve in a timed test, along with decreases in man’s “Sexual Tipping Point®” (STP) model
measures of sexual desire that are not secondary to expanded those concepts further by postulating a
decreases in motor ability. Even the lordosis set point or threshold for the expression of all
posture can reflect the state of sexual desire in sexual functions or dysfunctions for any individual
female rats. Female rats that have associated sexual that varied dynamically within and between any
rewards with a male bearing a neutral odor cue not given sexual experience(s) (Figure 1, modified
only solicit males bearing the odor selectively but from Perelman [29]). The STP model encom-
also display higher-magnitude lordosis postures passes the dynamic balancing of excitatory and
with such males [12,22]. In both male and female inhibitory influences on both the body and mind
rats, the opioid receptor antagonist naloxone while simultaneously referring to any combination
blocks the development of appetitive sexual be- of desire, arousal, orgasm, or resolution response
haviors, high-intensity lordoses, and conditioned in men and women. All dual control models stress
place and partner preferences. Thus, by using a the adaptive nature of excitatory and inhibitory
rich combination of unconditioned appetitive processes. For example, the adaptive nature of
responses and conditioned copulatory behaviors, a sexual excitement would drive individuals to seek
rational psychopharmacology of sexual desire can out sex partners for reproductive or reward pur-
be constructed by using “models” of sexual desire poses. The adaptive nature of sexual inhibition
in rats or other species that are homologous or would guard against situations that threaten the
analogous to human sexual desire. individual, including chronically stressful life
events. Bancroft and Janssen viewed sexual excite-
ment or inhibition as an individual tendency: “For
Structure of Inhibited Desire
the majority, the presence of a fairly typical level of
The DSM’s description of HSDD [1] as a desire inhibition proneness is adaptive, helping to keep
that is chronically or recurrently deficient or the individual out of trouble. Those whose pro-
absent, taking into account factors that affect pensity for central inhibition of sexual response is
sexual functioning, such as age and the context of too high have increased vulnerability to sexual dys-
the person’s life, assumes that its absence occurs in function. For those whose inhibitory propensity is
situations that would be appropriate for its expres- too low, an increased likelihood of engaging in
sion (the diagnosis should not, for example, be high risk sexual behavior may result.” (p. 571).
given to someone who loses desire for sex with an Indeed, the study of sexual inhibition is critical if
abusive partner). To the extent that the desire has we are to understand how certain events or drugs
a beginning and an end during the normal flow of like alcohol or cocaine may induce sexual disinhi-
sexual behavior (or indeed, during any motivated bition and the propensity to engage in risky sexual
behavior), the neural mechanisms underlying its behaviors [30,31].
activation and/or inhibition are likely altered in Responsiveness to inhibition is easy to catego-
HSDD. This could occur because of hypofunc- rize behaviorally. Individuals either will or will not
tional excitation and/or hyperfunctional inhibition do something. The presence of inhibition can be
that leads to a net decrease in ideations or behav- inferred if an individual wanted to do something
iors indicative of desire. but did not, owing to an obvious unconditional
The notion of separate but interactive neural threat or a conditioned cultural proscription
systems for behavioral excitation and inhibition against the activity (complete with the possibility
goes back to the work of early neurophysiologists of getting caught). This last point, however, raises
like Sechenov, Sherrington, and Pavlov and more some interesting issues regarding the arousing
modern psychologists like Gray, who applied the nature of stimuli that normally induce inhibition.
idea to the study of fear and anxiety [27]. It has Central excitation and inhibition both activate the
important implications for motivation in general autonomic nervous system. In simple terms, life-
because it posits that behavior can commence threatening stimuli activate the sympathetic arm,
either because of direct excitation or through a increasing blood flow and oxygen uptake to
process of disinhibition. Bancroft and Janssen muscles and organs that need it and turning off
advanced this concept further by proposing a theo- blood flow to the genitals. However, in response to

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1510 Pfaus

conditioned and unconditioned sexual incentives

(Figure 2).

Steroid Hormones
It is generally accepted that steroid hormone
actions in the mediobasal hypothalamus and
limbic system prime the brain to be selectively
responsive to sexual incentives [5,34,35]. Such
priming involves molecular actions that result
from the binding of androgens, estrogens, and
progestins to specific hormone receptor complexes
and that lead to the synthesis of different neu-
rotransmitters and transmitter receptors. This
Figure 1 Dual control model of sexual responding that inte-
creates a neurochemical state in which sexual
grates different biopsychosocial influences on sexual func-
tion around a Sexual Tipping Point® hypothesized by stimuli are attended to selectively and are more
Perelman [29] to balance the net effect of sexual excitation likely to induce sexual responding [5,6,33]. Evi-
and inhibition. The interplay between mechanisms of exci- dence for this comes from studies showing that
tation and inhibition generates an individual’s level of sexual natural or surgically induced states of hypogo-
responsiveness at any given time, and sexual tipping points
nadism in animals and humans are typically asso-
are thought to exist throughout the phases of the sexual
response cycle. ciated with a decreased responsivity to sexual
stimuli [36–42] and a loss of appetitive sexual
behavior. Indeed, many individuals presenting
with decreased sexual desire have concomitant
sexual stimuli, both arms of the autonomic nervous endocrine dysregulation, including decreased
system are activated, with the sympathetic system
increasing blood flow from the heart and the para-
sympathetic system increasing blood flow to the
genitals. A small degree of stress or threat in
humans (e.g., something “naughty” or mildly
painful) can be arousing, especially for individuals
with low levels of arousability. Translated to a
sexual situation, such arousal could be directed
into sexual activity, perhaps to the point in some
individuals that it becomes a necessary antecedent.
Anger, fear, or even short-lived terror can be a
prelude to sex specifically because it stirs passion
or arousal that leads to an “excitation transfer” into
sexual excitement under the right circumstances
[32]. However, stimuli that evoke excitation and
inhibition may be different for different individu-
als, such that what inhibits one person may actu- Figure 2 Mechanisms of sexual excitation. Sexual excita-
ally excite another. tion involves the activation of neurotransmitters such as
noradrenaline (NE) and oxytocin (OT), which stimulate
sexual arousal, and dopamine (DA) and melanocortins
(MCs), which stimulate attention and desire, within regions of
Mechanisms of Sexual Excitation the hypothalamus and limbic system, in response to sexual
cues and stimulation. The activation of those neurochemical
Steroid hormones activate mechanisms of sexual systems blunts the influence of inhibitory mechanisms, such
excitation by directing the synthesis of enzymes as endogenous opioids, which are released in the cortex,
and receptors for several interactive neurochemi- limbic system, hypothalamus, and midbrain during an
cal systems [5,33]. Those include dopamine (DA), orgasm or sexual reward; endocannabinoids (ECBs), which
norepinephrine (NE), melanocortin (MC), and mediate sedation; and serotonin (5-HT), which is released in
those regions to induce refractoriness and sexual satiety.
oxytocin (OT) systems acting in hypothalamic and Sexual excitation can be primed internally by steroid
limbic regions of the brain to stimulate sexual hormone actions or externally by sexual incentives or drugs
arousal, attention, and behaviors directed at both that activate excitatory neurochemical systems.

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Pathways of Sexual Desire 1511

plasma testosterone and hyperprolactinemia [43]. is thought to reflect deep emotional processing of
In castrated male rats, appetitive and consumma- stimulus valence (e.g., “good” vs. “bad”). Thus, the
tory sexual responding is restored by exogenous positive increase in LPC to sexual stimuli suggests
replacement with testosterone or by placement a greater valence of those stimuli during the ovu-
of testosterone or estradiol in regions of the latory phase. Another study used BOLD contrast
mediobasal hypothalamus, most notably the images taken by functional magnetic resonance
medial preoptic area (mPOA) or in midbrain imaging to compare brain activation of premeno-
regions such as the ventral tegmental area (VTA) pausal women in midluteal or menstrual phases of
[44–46]. Conversely, gonadally intact male rats the cycle in response to erotic video clips with that
that copulate to several ejaculations become sexu- in response to neutral video clips [62]. Increased
ally exhausted [47,48] and will not display normal activation by the erotic clips was observed in the
patterns of copulation for days afterward. Such anterior cingulate cortex (ACC), left insula, and
males have reduced androgen receptor levels in orbitofrontal cortices during the midluteal phase
certain hypothalamic regions such as the mPOA, relative to the menstrual phase. The ability of
and limbic regions such as the nucleus accumbens erotic visual stimuli to activate limbic and cortical
(NAcc) [49]. In castrated female rats, appetitive structures is reduced after menopause but can be
and consummatory sexual responding is restored restored to premenopausal levels following com-
by the sequential replacement with estradiol and bined estradiol and testosterone treatment [63], as
progesterone [35,50], or estradiol and testosterone can sexual desire and subsequent sexual activity in
[51]. postmenopausal women who experience its loss
Sexual desire, genital arousal, and the emotional [64–66].
response to sexual stimuli also change across the
ovulatory cycle in females. In humans, for Neurochemical and Neuroanatomical Systems
example, a number of women report that their Insights into the neurochemistry of sexual desire
sexual desire rises steadily in the week prior to can be gleaned from a variety of anecdotal and
ovulation, and peaks around the time of ovulation, historical accounts of substances that “enhance
only to be followed by a precipitous decline over libido.” However, such enhancement can mean
the subsequent week [52–54]. Similar findings anything from the stimulation of erection in indi-
have been reported in approaches and solicitations viduals with some degree of erectile difficulty (e.g.,
made around the time of the midcycle estradiol yohimbine) to a stimulation of desire in individuals
peak in female rhesus macaques [55] and in female with “low” desire (e.g., apomorphine) to a disin-
rats on the evening of Proestrus [18,19]. Changes hibitory effect on individuals with “normal” but
in cognitive ability as a function of the ovulatory perhaps suppressed desire (e.g., alcohol). The use
cycle have been known for decades [56–59], and of animal models has advanced the study of both
increases in subjective sexual arousal and desire the neurochemistry and neuroanatomy of sexual
induced by an erotic video are reported to be behavior considerably, and specific neurochemical
greater during the follicular than luteal phase [60]. substrates in different brain regions have been
Krug et al. examined changes in cortical event- studied in detail.
related potentials (ERPs) in premenopausal
women during the ovulatory, midfollicular, and Dopamine
menstrual phases of the cycle in response to pic- The major systems for sexual excitement center
tures depicting different activities, including sexu- around mesolimbic, nigrostriatal, and hypotha-
ally explicit situations [61]. Electrodes were placed lamic DA (Figure 3), which control general atten-
across the midline of the skull, and ERPs were tion to incentive stimuli (especially stimuli of
sampled from frontal, midparietal, and occipital learned significance), concomitant responses made
poles. During the ovulatory phase, the amplitude toward those stimuli, and autonomic outflow that
of the late positive component (LPC) that peaks controls sympathetic activation in some tissues
550–600 msec after the presentation of a stimulus (such as the heart) and parasympathetic activation
was larger in response to sexual stimuli than that of of genital blood flow, respectively [67]. Cell bodies
the LPCs evoked by the other stimuli (people, of the mesolimbic DA system arise in the VTA and
babies, or body care products). This did not occur project diffusely to different limbic and cortical
during the other phases of the cycle or when the structures, including several amygdala nuclei,
task required structural processing (determining NAcc, olfactory tubercle and piriform cortex,
the number of parallel lines on a screen). The LPC lateral septum, and the ACC. The mesocortical

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1512 Pfaus

Figure 3 Brain dopamine (DA) sys-

tems. Three major systems contribute
to sexual arousal and desire, including
the diencephalic incertohypothalamic
DA system, with terminals in the
mPOA of the anterior hypothalamus,
the mesolimbic and mesocortical DA
system, with terminals in the NAcc
(and other limbic regions) and mPFC,
respectively, and the nigrostriatal
system, with terminals in the striatum
(caudate and putamen). These sys-
tems control attention and incentive
motivation and link sexual stimuli to
autonomic outflow. The tuberoinfun-
dibular DA system controls hormone
release from the anterior pituitary
gland. VTA = ventral tegmental area;
mPFC = medial prefrontal cortex;
SN = substantia nigra; mPOA =
medial preoptic area; NAcc = nucleus
accumbens.

arm projects DA fibers largely to the medial pre- women, as have drugs that act indirectly to
frontal cortex (mPFC), a region implicated in increased DA transmission selectively in the
executive control and inhibition [68]. Cell bodies mPOA [20,67,75].
of the nigrostriatal system arise in the substantia A well-documented side-effect of the treatment
nigra and project to the caudate and putamen, of Parkinson’s disease with 3,4-dihydroxy-L-
known collectively as the striatum. DA projections phenylalanine (L-DOPA) is enhanced libido [76].
to the mPOA arise from the zona incerta under the Subsequent work showed that L-DOPA stimu-
thalamus [69]. Those latter projections are inde- lated both appetitive and consummatory sexual
pendent of the systems in the midbrain, although behaviors in sexually sluggish or castrated male
output from the mPOA to the VTA links them rats [77,78] and that those effects were blocked by
together such that DA release patterns in the the DA receptor antagonist pimozide. It is now
mPOA and NAcc of male rats during copulation generally acknowledged that DA agonists stimu-
are virtually identical [70]. Lesions of the mPOA late sexual excitement and arousal in both rats and
disrupt certain appetitive behaviors, such as solici- humans, especially in circumstances where the
tation in female rats or sexually rewarded maze expression of these appetitive behaviors is endog-
learning in male rats, and abolish the initiation of enously low. Although the general DA receptor
copulation in male rats and the timing of pacing agonist apomorphine stimulates penile erection in
and lordosis in female rats [71,72]. Lesions of the normally functioning male rats and men with erec-
NAcc disrupt the ability of distal sexual cues to tile dysfunction [79,80], it has not been reported to
elicit sexual arousal in male rats [23,73] and disrupt affect measures of sexual desire in normally func-
approach behavior in female rats [74]. Finally, tional rats. However, the D2-selective agonist
general noradrenergic tone in the forebrain is quinelorane activated copulation in sexually inac-
important for the control of arousal and in the tive male rats and reduced the ejaculatory thresh-
autonomic nervous system for the control of old in males who copulated [81]. Conversely, DA
genital blood flow. Accordingly, these systems can antagonists, which are used clinically as major
be viewed as excitatory “targets” in the develop- tranquilizers and antipsychotic drugs, disrupt
ment of pharmacologically based therapies to treat appetitive sexual behaviors and delay the initiation
HSDD. Notably, direct-acting general DA ago- of copulation in normally functioning male rats
nists have been studied in this regard in men and [82–84] and abolish appetitive sexual behaviors in

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Pathways of Sexual Desire 1513

castrated female rats primed fully with estradiol necessary for their development and/or mainte-
and progesterone [85]. Estradiol facilitates DA nance, or following lesions of certain steroid-
release, and testosterone potentiates the synthesis concentrating brain regions, for example,
of nitric oxide that controls DA release in rats basolateral amygdala. They can also be reduced
[86–88]. Thus, steroid hormones appear to set the after a devaluation of the reward offered by the
stage for increased DA synthesis and release incentive the male is working for (e.g., switching
during periods in which sexual responding might from receptive female to no female, an extinction
be enhanced. procedure) or following infusions of DA antago-
Like humans, male and female rats display nists to the NAcc [36]. Restoration of bar pressing
increased motor output in anticipation of sexual in male rats with lesions of the basolateral
rewards (e.g., increased wheel running or level amygdala can be made following infusions of
changing in bilevel chambers). These measures of amphetamine to the NAcc, indicating that
anticipatory excitement can be increased by treat- mesolimbic DA release is critical for the expres-
ments that increase the incentive salience of the sion of that behavior and suggesting that the
sex partner (e.g., ovariectomized female rats given extensive glutamate projections from basolateral
hormone replacement with estradiol benzoate amygdala to the NAcc modulate DA release. DA
alone, rendering them moderately sexually recep- antagonists administered systemically to male rats
tive, vs. estradiol benzoate and progesterone, reduce running speed in a runway that leads to a
rendering them fully sexually receptive and pro- goal box containing a sexually receptive female,
ceptive), and by DA agonist drugs or other psy- and microinjections to the mPOA disrupt maze
chomotor stimulant drugs (e.g., low doses of learning for sexual reinforcement in male rats. It is
amphetamine or cocaine). These measures can be likely that different DA terminal regions play a
reduced by systemic treatment with DA antago- role in different types of unconditioned and con-
nists or by direct microinjection of a DA antago- ditioned sexual activities. Female rats will bar-
nist into the mPOA or NAcc. press for access to gonadally intact, sexually active
All animals will work to obtain sexual rewards, males, and access to intromissions from a male that
and such behavior can be viewed as analogous to was made contingent on poking a lever with the
desire. Sexual rewards may come in the form of nose increased the incidents of nose poking in
primary reinforcers (e.g., orgasm in humans, ejacu- sexually receptive female rats. However, contin-
lation in male rats, or the ability to regulate or gent access to male odors alone did not support
“pace” copulation in female rats) or secondary increases in behavior, indicating that the copula-
reinforcers, such as stimuli associated with sexual tory stimulation was rewarding. As noted above,
gratification (e.g., certain facial features, clothes, or paradigms that allow females to control or “pace”
smells in humans; certain odors or place cues in rats the rate of copulation result in sexual rewards. Any
[89]). In male rats, these behaviors have included imposition of an operant prior to copulatory
performance in obstruction boxes, straight-alley stimulation, therefore, allows females to pace
running, maze learning, crossing of electrified copulation at their own preferred rate. Although
grids, nose pokes, and other attempts to “get to” a copulation in general increases DA release in the
potential sex partner behind a wire-mesh screen, mPOA, NAcc, and striatum of male and female
digging through sand, bar pressing for a sex partner, rats, such operant “pacing” of copulation increases
or responding for cues associated with the arrival of DA release more in the striatum than unpaced
a sex partner. Indeed, to gain access to receptive copulation does. Consistent with this, lesions of
females, male guinea pigs will learn to run an alley, the striatum reduce the efficiency of females to
male pigeons will learn to peck keys, and male pace the copulatory interactions, whereas lesions
stickleback fish will learn to swim through rings of the NAcc result in females that avoided sexual
(reviewed in Pfaus et al. [6,89]). contact.
Some appetitive instrumental sexual responses Hull and colleagues have argued that the desire/
are expressed easily, without much prior experi- ejaculation (D1/D2) receptor ratio in the mPOA
ence (e.g., nose pokes, digging, obstruction box of male rats is critical for the stimulation of sexual
performance, crossing electrified grids), whereas arousal and D1 and D2 through integrated control
others require some degree of training (maze of behavior and autonomic processes [67,75]. This
learning, bar pressing) [6,36,89]. Those behaviors makes the coordinated activation of mPOA and
can be reduced following castration, indicating NAcc critical in the stimulation of sexual excite-
that gonadal steroid actions in the brain are ment. Interestingly, ejaculation decreases DA

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1514 Pfaus

release precipitously in the mPOA and NAcc, but rine transmission supports an optimal level of
not in striatum, of male rats [70]. This decline lasts behavior but in which a high amount of transmis-
through the absolute refractory period and is fol- sion disrupts behavior by producing a generalized
lowed by a progressive increase during the relative fear response [93]. Norepinephrine binds to two
refractory period, when arousing stimuli can acti- classes of receptor, classically termed “a” and “b,”
vate copulation in male rats [90]. Interestingly, in respectively, and differentiated according to
males that copulate to sexual exhaustion, DA in whether the receptor stimulates (b) or inhibits (a)
the NAcc reduces to precopulatory baseline levels the stimulation of the second messenger adenylate
[91]. Removal and reintroduction of the familiar cyclase [94]. The a receptors are further classified
female do not increase DA release, but placement into a1 and a2 subtypes, which are found either
of a new receptive female in with the male results postsynaptically or presynaptically, respectively.
in a small increase. However, this increase is not of Thus, actions of norepinephrine at a1 receptors
sufficient magnitude to induce a full copulatory result in a postsynaptic effect, whereas actions at
response. presynaptic a2 receptors serve as a short-loop
inhibitory feedback mechanism that reduces nore-
Norepinephrine pinephrine release. Drugs such as clonidine that
Central noradrenergic systems play a vital role in act as a2 agonists reduce norepinephrine release
general arousal and in the control of autonomic and lead to less sympathetic tone and sedation,
outflow. Cell bodies arise in the locus coeruleus at whereas drugs such as yohimbine that act as a2
the border of the midbrain and brain stem and antagoinsts block the ability of endogenous nore-
project to virtually all forebrain regions, including pinephrine to induce inhibitory feedback and thus
the hypothalamus, limbic and motor systems, and result in sustained noradrenergic tone.
cortex (Figure 4) [92]. Norepinephrine release in Estradiol increases norepinephrine synthesis in
different regions of the brain controls different the brains of female rats [95], and norepinephrine
aspects of motivation with an “inverted U-shaped transmission in the ventromedial hypothalamus
curve,” in which an optimal level of norepineph- potentiates lordosis in female rats [33,96]. Estra-
diol also suppresses a1 noradrenergic receptor
densities in the mPOA of female rats [97],
although infusions of an a1 antagonist to the
mPOA have little effect on castrated females
primed with estradiol and progesterone [98].
Although systemic administration of the a2
agonist clonidine to sexually inactive, castrated
male rats does not stimulate copulation [99], it
decreases the proportion of gonadally intact, sexu-
ally active male rats that achieve ejaculation [100].
In women, clonidine reduces the vaginal response
to erotic stimuli [101]. Administration of the a2
antagonist yohimbine stimulates penile erection in
male rats and men via autonomic activation [102]
and can reverse the sexual inhibition that follows
sexual exhaustion in male rats [103]. Yohimbine
increased the rate of mounting in male rats [104]
except at high doses where it inhibited mounting
altogether. Conversely, lesions of noradrenergic
cells in the locus ceruleus increase the postejacu-
latory refractory period of male rats, and adminis-
Figure 4 Brain norepinephrine system. This system arises tration of norepinephrine synthesis inhibitors like
in the locus coeruleus (LC) and projects caudally to the sodium diethyldithiocarbamate increases the
cerebellum and brain stem and rostrally to the hypotha- mount and intromission latencies, suggesting a
lamic, limbic, motor, and cortical systems in the forebrain. decrement in sexual desire [105]. Such a decre-
This system controls a variety of arousal mechanisms
through response selection and autonomic activation. ment could be explained by sluggish arousal
mPOA = medial preoptic area; NAcc = nucleus accumbens; induced by diminished norepinephrine transmis-
mPFC = medial prefrontal cortex. sion. It is likely that decreased noradrenergic tone

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Pathways of Sexual Desire 1515

could easily account for decreases in sexual desire sexual arousal and desire in humans and rats fol-
owing to insufficient general arousal. This may lowing intranasal, intravenous, and subcutaneous
play a role in the manifestation of decreased sexual administration. Both MT-II and bremelanotide
desire in generally hypoarousable individuals. stimulate erection in sexually functional men and
rats, and in men with erectile dysfunction [112–
Melanocortins 114]. Bremelanotide also stimulates appetitive
Neuropeptides derived from Pro- level changing in male rats (unpublished obser-
opiomelanocortin (POMC) include b-endorphin, vations). In women [114,115] and female rats
adrenocorticotrophic hormone (ACTH), and [116,117], MT-II and bremelanotide increase
a-melanocyte stimulating hormone (a-MSH). measures of sexual desire, including solicitations
The latter two bind to different melanocortin and hops and darts in rats and subjective measures
receptors (MCRs) of which at least five types exist of desire in women. The effectiveness of systemic
[106]. Of those, the MC3 and MC4 subtypes exist MT-II and bremelanotide to stimulate sexual
in hypothalamic and limbic regions of the mam- desire in female rats has been replicated following
malian brain [107]. Cell bodies of this system arise infusions to the lateral ventricles of the brain
in the arcuate and periarcuate nuclei near the base (indicating a central mechanism of action) and
of the third ventricle in the hypothalamus and following infusions directly to the mPOA [20].
project axons diffusely to the hypothalamus, limbic Interestingly, systemic administration of bremel-
system, midbrain, and brain stem (Figure 5) anotide stimulates DA release selectively in the
[108,109]. Estradiol increases a-MSH levels in the mPOA, and its effect on solicitations is blocked by
mediobasal hypothalamus of female rats [110,111], coadministration of a selective MC4 antagonist or
suggesting that a-MSH release may be one of D1 antagonist [20]. This suggests that MCs act
several intermediaries of estrogen action. presynaptically to increase DA release in the
Recently, two MC agonists, melanotan-II (MT- mPOA and that such release acts on D1 receptors
II) and its metabolite bremelanotide (formerly there to facilitate sexual desire. It is not yet known
PT-141), have been reported to stimulate both whether this mechanism also controls the induc-
tion of penile erection and increases the level
changes in male rats.

Oxytocin
OT is a neuropeptide that has been identified as a
“bonding hormone” in both sexual and parental
behavior [118,119]. OT cell bodies are found in
the paraventricular (PVN) and supraoptic (SON)
nuclei of the hypothalamus. Large, magnocellular
neurons in those regions project to the posterior
pituitary whereas small, parvocellular neurons
project diffusely hroughout the hypothalamus and
limbic system (Figure 6). Infusions of OT to the
mPOA or ventromedial hypothalamus facilitates
lordosis behavior in female rats [120,121], whereas
infusions to the PVN of male rats stimulates penile
erection [122]. Systemic administration of OT
facilitates ejaculation in male rats treated chroni-
cally with the SSRI fluoxetine [14,123] and facili-
tates the acquisition of a sexually conditioned
partner preference in male rats (unpublished
Figure 5 Brain melanocortin system. This system arises in observations). Conversely, infusion of an OT
the arcuate nucleus of the hypothalamus (Arc) and projects receptor antagonist blocks bonding. Sexual incen-
rostrally to hypothalamic and limbic forebrain regions. This tives activate OT release in the brain of male rats
system potentiates sexual desire through an interaction with [124], and neutral odors associated with sexual
DA release in the mPOA. DA = dopamine; mPOA = medial
preoptic area; NAcc = nucleus accumbens; mPFC = medial rewards activate parvocellular OT neurons selec-
prefrontal cortex; VTA = ventral tegmental area; MeA = tively in the PVN of male rats [125]. Interestingly,
medial amygdala; PIR = piriform cortex. stimulation of D2 receptors in the PVN stimulates

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1516 Pfaus

amount of sexual inhibition keeps individuals from

engaging in risky or inappropriate sexual behav-
iors, which a lack of inhibition would promote (as
occurs in individuals with KluverBucy Syndrome,
dementia, or frontotemporal cortical and amy-
gdala damage sustained after head trauma)
[93,129–132]. Conversely, too much central inhi-
bition was viewed as increasing the risk of sexual
dysfunction, including inhibited arousal, desire,
and/or a diminished capacity to achieve sexual
gratification. Excessive inhibition may thus lead to
a numbing of intimacy and disruption of bonding
between partners, to the point that sexual activity,
if it is engaged in at all, becomes a routine of
“going through the motions” rather than an
enriching and rewarding experience.
The concept of inhibition is further related to
that of “executive function,” in which the indi-
Figure 6 Brain oxytocin (OT) system. Cells arise in two vidual has to choose among several possibilities
hypothalamic regions: the paraventricular nucleus (PVN) and create hierarchies based on expectancies,
and the supraoptic nucleus (SON). Large (magnocellular) planned actions, and calculations. Cognitive psy-
neurons in those regions project to the posterior pituitary
chologists view executive functions as the role of
gland, where OT is released directly into the bloodstream.
Smaller (parvocellular) neurons project to other regions of the prefrontal cortex [133,134], which must inhibit
the hypothalamus and the limbic system. This system is a complex and ongoing interplay of motor tenden-
involved in the stimulation of genital blood flow during cies to arrive at planned and sustained actions.
sexual arousal and in linking sexual rewards to bonding. People or rats with disrupted prefrontal function,
AC = anterior cingulate gyrus; mPOA = medial preoptic
area; NAcc = nucleus accumbens; mPFC = medial
prefrontal cortex; VTA = ventral tegmental area; MeA =
medial amygdala; PIR = piriform cortex.

OT release and increases extracellular DA levels

in the NAcc [126], suggesting another mechanism
by which hypothalamic DA can integrate with
mesolimbic DA through an OT intermediary. It is
also notable that the PVN receives a substantial
neural projection from the mPOA [127], raising
the possibility that the activation of the mPOA can
lead in sequence to the activation of the PVN.

Mechanisms of Sexual Inhibition

Figure 7 Mechanisms of sexual inhibition. Brain opioid,
Relative to sexual excitation, far less is understood endocannabinoid, and serotonin systems blunt the action of
about mechanisms of sexual inhibition. It is excitatory mechanisms. This occurs normally at the end of
assumed that sexual inhibition is an adaptive the sexual response cycle during a period of “sexual satiety”
response that serves both reproductive and social or refractoriness (e.g., after one or many orgasms).
However, it can also occur if the endogenous inhibitory
end points, for example, to keep individuals out of mechanism(s) is (are) tonically activated by situational vari-
trouble or to allow a sufficient amount of sexual ables such as stress or by drugs that augment their actions
reward to induce a restorative state of sexual (e.g., SSRIs). They can also be overly activated when
satiety that presents as a “refractory phase.” Kinsey sexual excitatory mechanisms are endogenously blunted,
et al. [128] hypothesized that sexual refractoriness as may occur in hypogonadal individuals or those taking
drugs that diminish excitatory influences directly (e.g., major
in males occurs after ejaculation to allow time to tranqiulizers). SSRI = selective serotonin reuptake inhibitor;
generate more sperm for a subsequent ejaculation. DA = dopamine; NE = noradrenaline; OT = oxytocin; MC =
Bancroft and Janssen [28] argued that a normal melanocortin; ECB = endocannabinoid.

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Pathways of Sexual Desire 1517

either because of lesions or neurochemical imbal- hungry rat are positive reinforcers because they
ance, have great difficulty focusing attention on increase responding for them. Playing with one’s
tasks, are unable to inhibit competing responses, hair or sideways glances during a bout of flirting
and experience retroactive and proactive interfer- would also be considered positive reinforcers if
ence [133–137]. With regard to sexual behavior, it they increase the degree of responding between
is assumed that cultures superimpose a moral value the flirting pair [140]. However, large rewards,
of “right” and “wrong” on the hierarchies so that such as one or more orgasms that induce satiety,
some behaviors that feel good are “right” and can force the theory to become curvilinear because
be experienced without guilt, whereas others are such mechanisms place negative feedback on
“wrong” and carry the weight of guilt and/or rule behavior by activating inhibitory neural pathways.
of law against them. This type of inhibition rep- Satiety mechanisms are absolutely critical for
resents an “approach-avoidance” conflict, where any regulatory behavior [141]. But is satiety
the expectation of reward drives the desire, but the rewarding?
inhibition imposed by the real or perceived aver- In any motivational system, rewards should be
sive consequences of engaging in sexual activity considered a dynamic function with an inverted
blunts the initiation of behavior. Finally, sexual U-shaped relationship to ongoing behavior: Low
inhibition can also be induced by sexual nonre- rewards do not sustain behavior, moderate to ideal
ward. This type of inhibition overlays itself on rewards do, and high rewards induce the inhibi-
desire components directly to suppress them. tory feedback that characterizes satiety. With
Accordingly, the “prosexual” nature of drugs such regard to sexual behavior, rewards that sustain
as alcohol or cocaine may be a function of their sexual arousal and desire might be considered low
ability to disinhibit such suppressed sexual to moderate, whereas high rewards like orgasm(s)
responding. For example, sexually active male rats might be those that induce a period of sexual
have to learn to inhibit their sexual advances refractoriness. The reward value of satiety may
toward sexually nonreceptive females [138]. Once also depend on the time frame. Although sexual
learned, this inhibition can be disinhibited by low satiety decreases sexual responding in the short
doses of alcohol. term, the reward associated with it in male and
To the extent that a blunting of attention female rats is necessary for the conditioning of
toward sexual incentives and the inhibition of sexual preferences and heightened anticipation for
sexual responses are observed naturally during the sex in the long term. A final note of caution: In the
sexual refractory state, it can be speculated that study of feeding, satiety lies on a continuum to
inhibitory systems exist in the brain that are acti- aversion where continued food ingestion after one
vated by mechanisms of sexual reward and satiety is full leads to emesis. Likewise, continued genital
(Figure 7). These systems inhibit the activation of stimulation after an orgasm can be experienced
excitatory mechanisms reviewed above and possi- as aversive in both men and women [10], al-
bly shift attention and behavior to nonsexual though the nature of the sensation is obviously
stimuli or situations. At least three neurochemical different.
systems may do this simultaneously in the brain: Opiates like heroin produce a rush of euphoria
opioids, which mediate sexual reward states; followed by a prolonged period of relaxation [142],
endocannabinoids, which induce sedation; and a state that has been referred to as a “pharmaco-
serotonin, which induces satiety. genic orgasm” [143]. This opioid reward state
induces a dramatic decline in sexual arousal and
Opioids and Reward desire in both men and women and inhibits the
Sexual desire is inextricably linked to sexual ability to achieve an orgasm in those who are able
rewards. However, it is difficult to know exactly to generate enough sexual arousal to sustain sexual
what is rewarding for any person or within a intercourse [142]. A “natural” version of this state
culture, and sexual behavior can occur for reasons is induced by an orgasm (e.g., [144]) and by certain
that have nothing to do with sexual gratification copulatory behaviors in rats. For example, ejacu-
per se. But sexual reward as a general concept has lation in male rats induces the release of endog-
a more pervasive problem: its association in psy- enous opioids [145] and is the critical component
chology with positive reinforcement. Positive of sexual reward that supports the induction of
reinforcers are traditionally considered events or conditioned place and partner preferences [13,21].
stimuli that increase the probability of ongoing This reward state is dependent on opioid trans-
behavior (e.g., [139]). Small food pellets to a mission because the administration of naloxone

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1518 Pfaus

state also requires a critical level of arousal prior to

ejaculation to support the conditioned preferences
[147], suggesting an interaction between the
intensity of sexual activity prior to an ejaculation
or an orgasm and the degree of reward experi-
enced from it.
Opioid peptides are derived not only from
POMC (b-endorphin) but also from pro-
enkephalin (Met5- and Leu5-enkephalin) and pro-
dynorphin (DYN-A, DYN-B), which bind
differentially to the three classes of opioid recep-
tors: m, d, and k [148]. Opioid neurons exist as
projection neurons from POMC-rich periarcuate
fields (the same neurons that give rise to a-MSH)
and as interneurons in forebrain and midbrain
regions of the VTA, NAcc, striatum, ACC, and
cortex (Figure 8) [109]. Infusions of m opioid
receptor agonists to the mPOA inhibit sexual
Figure 8 Brain opioid systems overlaid on opioid binding behavior in male rats [149–151], and infusions to
regions (high density of receptors indicated by red to yellow, the mPOA or VMH inhibit sexual behavior in
lower density in green to blue). Three systems exist: the female rats [152]. Conversely, m opioid receptors
pro-opiomelanocortin (POMC)-derived opioids such as
are activated in the mPOA following copulation in
b-endorphin, which arise from the same population of pro-
jection neurons that produce the melanocortins; the inter- male rats [153], and infusions of a m antagonist to
neurons in the cortex, limbic system, hypothalamus, and the mPOA, but not NAcc, block sexually condi-
brain stem, which produce enkephalins and dynorphins; tioned place preference [154]. Enkephalin levels
and the intrinsic hypothalamic fibers, which contain endo-
morphins. These systems are activated at orgasm in
humans, at ejaculation in male rats, and during paced copu-
lation in female rats. They shut down hypothalamic regions
associated with sexual arousal and desire, thereby inducing
refractoriness. However, opioids are also released in the
VTA during phases of sexual arousal and desire and help to
disinhibit DA neurons and, thereby increasing DA release in
mesolimbic terminals. This is an important mechanism by
which experience with sexual rewards sensitizes sexual
excitement once the inhibitory effects of refractoriness
and satiety wear off. VTA = ventral tegmental area;
DA = dopamine; mPOA = medial preoptic area; mPFC =
medial prefrontal cortex; NAcc = nucleus accumbens;
PIR = piriform cortex; MeA = medial amygdala.

during training blocks the development of the

preferences [21]. Injections of the nonselective
opioid receptor antagonists naloxone or naltrex-
one also reverse the sexual inhibition displayed by
male rats after reaching sexual exhaustion [146].
Similarly, in female rats, the ability to control
or “pace” the initiation and rate of copulation
Figure 9 Brain endocannabinoid systems. Cortical, limbic,
supports the conditioning of place and partner hypothalamic, and motor regions contain medium to high
preferences that are blocked if naloxone is admin- density of CB1 receptors (in blue), and cells that make
istered during training [12,22–25]. In female rats, endocannabinoids (e.g., anandamide) are intrinsic to those
the expectation of sexual nonreward (induced by regions. This system induces a natural anxiolytic and seda-
naloxone during their first few sexual experiences tive effect that counteracts stress activation through the
modulation of DA and NE release. It is itself modulated by
with males) creates a state in which solicitations brain opioid and serotonin release. CB1 = cannabinoid;
are inhibited, despite full priming with steroid DA = dopamine; NE = noradrenaline; NAcc = nucleus
hormones [12]. Interestingly, in males, the reward accumbens; mPOA = medial preoptic area.

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Pathways of Sexual Desire 1519

are also elevated in the frontal cortex, hypothala- provoking or stressful stimuli [169]. The sedative
mus, and midbrain of sexually exhausted or inac- effects of cannabinoids have been known for cen-
tive male rats [155]. These data suggest that opioid turies [170]. The discovery of the cannabinoid
release in the hypothalamus, and in particular the type 1 (CB1) receptor in motor, limbic, and hy-
mPOA, produces a reward state and is a major pothalamic regions of the mammalian brain
factor in sexual refractoriness. (Figure 9), and endogenous ligands for those
In contrast to the induction of sexual refracto- receptors in diffuse populations of neurons and
riness in the mPOA, opioids in the VTA stimulate glial cells, has generated a flurry of research into
sexual activity in sexually sluggish male rats. For their endogenous function [171]. It has become
example, infusions of morphine or dynorphin 1-13 clear that a variety of emotional and regulatory
to the VTA stimulated female-directed behavior functions, such as pain, anxiety, feeding, and sexual
and mounting in male rats, and repeated adminis- desire, are mediated by endocannabinoids. In
tration of morphine to this region sensitized DA addition, endocannabinoids appear to “cross-
release in the NAcc [156]. Interestingly, repeated talk” with hormone receptor-induced changes in
exposure of male rats to sexually receptive females second-messenger actions in the hypothalamus to
also sensitized DA release in the NAcc, an effect generate changes in behavior [172]. Several can-
that was attenuated by pretreatment with naloxone nabinoid agonists and antagonists have been sug-
[157]. Naloxone infusions to the VTA also block gested for clinical use in the treatment of pain,
the development of anticipatory level changing in inflammation, feeding, and sexual disorders [173].
bilevel chambers [158]. Opioids in the VTA stimu- Sexually, cannabinoid agonists such as D9-
late DA release in the NAcc [159,160]. This occurs tetrahydrocannabinol (D9-THC) have not only
by opioid-induced inhibition of g-aminobutyric effects similar to alcohol, with disinhibited sexual
acid (GABA) interneurons, which normally place a desire in putatively inhibited individuals but also a
tonic block on the stimulation of DA cell bodies in blunting of somatosensory awareness that leads to
the VTA [161]. Thus, opioid release in the VTA an increase in erection and ejaculation latencies
appears to sensitize responses to sexual incentive [174]. Similar effects have been reported in male
stimuli. However, opioid release also occurs in the rats with both THC and the endogenous cannab-
VTA in response to sexual incentive stimuli prior inoid agonist anadamide [175,176]. Antagonists of
to copulation. the CB1 receptor, such as SR141716A or AM251,
Finally, infusion of d receptor agonists to the facilitate erection and ejaculation [177–179].
lateral ventricles or VMH facilitates sexual However, sexual motivation in presumably nonin-
behavior in female rats [162,163], whereas infu- hibited male rats is impaired by THC treatment
sion to the mPOA inhibits female sexual behavior [176]. In that study, approach of a male toward a
[164]. A similar effect has been reported for sexually receptive female was impaired by THC
GABA A agonists in the VMH and mPOA of treatment. Although THC facilitates lordosis in
female rats [165]. Local effects of opioids in female rats [172,180], CB1 agonists can inhibit
different hypothalamic regions may modulate both lordosis and proximal solicitations (procep-
the overall electrophysiological responsiveness of tive hops and darts) [181]. Conversely, treatment
neurons to change the way that sexual stimuli are of estrogen-primed female rats with the CB1
processed or responded to [166], and estrogens antagonist AM251 increases both lordosis and
may set this up by stimulating the synthesis of solicitation behaviors [182]. As in male rats,
enkephalin in the VMH [167]. Interestingly, in appetitive sexual motivation (speed in a runway
the mPOA, estrogen causes the internalization of where a male is in the goal box) can be enhanced
m opioid receptors (a signature of activation), but by CB1 antagonists, suggesting that a state of
progesterone decreases this internalization, sug- endocannabinoid activation may carry with it a
gesting a mechanism by which the pattern of concomitant inhibition of sexual desire [182].
estrogen and progesterone actions could “time” Interestingly, extracellular concentrations of
sexual behavior to coincide with ovulation in the endocannabinoids in the hypothalamus are highest
rat [168]. in female rats during diestrus, a period of sexual
inhibition, and decrease toward proestrus and
Endocannabinoids and Sedation estrus, when females are at their peak of sexual
Engaging in sexual activity to ejaculation or responsiveness [183,184]. Although the study of
orgasm(s) induces a state of sedation in which indi- endocannabinoids is relatively new, the powerful
viduals and animals are less responsive to anxiety- effect of drugs acting as CB1 agonists or antago-

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1520 Pfaus

nists is stimulating a rapid assessment of their use tonin synthesis, release, or receptor binding facili-
in clinical medicine. Antagonists may well be tated sexual behavior. Evidence for an inhibitory
developed for use in the stimulation of desire effect of serotonin on sexual behavior came ini-
that has been inhibited by hyperstimulation of tially from studies using treatments that inhibited
endocannabinoid release. serotonin neurotransmission. For example, sys-
temic treatment with the serotonin synthesis
Serotonin and Satiety inhibitor parachlorophenylalanine (PCPA) facili-
Serotonin neurons arise in the Raphé nuclei of the tates sexual behavior in sexually sluggish, gonad-
midbrain and send extensive axonal projections to ally intact or castrated male rats [45,187].
brainstem, midbrain, and forebrain sites, including Electrolytic or neurotoxic lesions of serotonin
the hypothalamus, limbic system, hippocampus, neurons or systemic PCPA treatment of sexually
and cortex, and down the spinal cord to lower vigorous male rats produces a dramatic reduction
lumbar and sacral regions that control genital in the length of the postejaculatory refractory
reflexes (Figure 10). The idea that brain serotonin period [188], suggesting that serotonergic trans-
induces satiety comes from the feeding literature, mission inhibits the resumption of sexual behavior
in which serotonin transmission in certain hypo- after ejaculation. Neurotoxic lesions of descending
thalamic regions decreases appetite [185]. This serotonin pathways to the spinal cord facilitate
notion linked nicely to those put forth in the 1960s penile reflexes in rats [189], suggesting that they
by Meyerson [186] that brain serotonin was are under tonic inhibition by descending serotonin
responsible for sexual inhibition and that seroto- action. Conversely, delayed or inhibited ejacula-
nin and DA systems were interconnected and tion and anorgasmia are common side effects of
mutually inhibitory with regard to sexual behavior. SSRIs used for the treatment of depression [174].
In his view, treatments that stimulated serotonin Similar effects occur in male rats treated chroni-
release and postsynaptic binding decreased sexual cally with fluoxetine or other SSRIs [15,122], and
behavior, whereas treatments that inhibited sero- these effects lead to a decrease in sexual motivation
and desire [118,190]. These effects have led to the
idea that serotonin mediates sexual inhibition
during periods of “sexual satiety” (e.g., after ejacu-
lation, when sexual exhaustion has been reached,
or in females with subthreshold hormone priming)
[66,191]. Steroid hormones do not produce con-
sistent effects on this system, suggesting that it
operates relatively independently of hormonal
modulation [191,192].
The development of selective serotonin recep-
tor agonists and antagonists, and the molecular
cloning of serotonin receptors generated a baffling
number of morphologically and physiologically
distinct receptor subtypes. These were reclassified
a decade ago into four main receptor classes
(5-HT1, 5-HT2, 5-HT3, and 5-HT4) that
contain seven functional receptor subtypes and
four recombinant receptors (5-HT1Da, 5-
HT1Db, 5-ht1E and 5-ht1F), along with four
additional recombinant receptors (5-ht5A, 5-ht5B,
5-ht6 and 5-ht7) [193]. Drugs selective for those
Figure 10 Brain serotonin system. Cells arise from the
Raphé nuclei in the brainstem and project caudally to the receptors have aided researchers in elucidating the
brainstem and spinal cord and rostrally to the midbrain, role played by serotonin in sexual behavior. For
hypothalamus, limbic, motor, and cortical regions. In con- example, systemic treatment of male rats with
trast to the euphoria of opioid reward, the activation of this the 5-HT1A autoreceptor agonist 8-OH-DPAT
system produces a general sense of satiety, relaxation, and (which decreases serotonin release presynaptically)
fulfillment. This system appears to inhibit mesolimbic and
incertohypothalamic DA release mechanisms in limbic and dramatically facilitates ejaculation [194–196].
preoptic terminals by the modulation of descending inhibi- However, far from facilitating sexual behavior, the
tion from the prefrontal cortex. DA = dopamine. drug delays the initiation of copulation, and, when

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Pathways of Sexual Desire 1521

male rats finally mount, most ejaculate during the appears to inhibit or facilitate lordosis, depending
first or second intromission. Indeed, the experi- on the type of serotonin receptor activated [191].
ence of ejaculation under the influence of 8-OH- For example, systemic treatment with 8-OH-
DPAT does not induce a conditioned place DPAT inhibits lordosis [212], whereas treatment
preference [197], further reinforcing the idea that with 5-HT2 antagonists facilitates this behavior
ejaculation needs to ride on a sufficient level of [213]. The neural mechanisms that generate the
arousal to induce a sufficient intensity of sexual stationary spinal dorsiflexion that characterizes
rewards that supports conditioned preferences. lordosis are likely not those that underlie the active
However, in male rats made sexually exhausted, headwise orientation and runaway that character-
8-OH-DPAT can facilitate mounting behavior izes full solicitations or the hops and darts that
[198,199]. Systemic administration of the 5-HT2/ characterize partial solicitations in the female rat
5-HT1C agonist DOI suppressed sexual activity in [6]. In fact, like mPOA lesions, major tranquilizers
male rats [200,201], an effect that was antagonized that act as both DA and 5-HT2 receptor antago-
by co-treatment with different selective 5-HT2 nists (e.g., haloperidol) typically enhance lordosis
receptor antagonists, all at doses that did not by while concomitantly abolishing solicitations [85],
themselves affect sexual activity. Similarly, admin- suggesting that lordosis and solicitations are mutu-
istration of the 5-HT1B/2C agonist TFMPP ally exclusive behavioral patterns. However, it is
abolished copulation in male rabbits [202]. As also the case that high-intensity lordosis postures
mentioned above, the delay in ejaculatory thresh- are almost always observed in females that engage
old induced by SSRIs can be reversed by systemic in a high degree of solicitation of preferred part-
administration of OT [14,123] or 8-OH-DPAT ners [12,21], indicating a positive relationship
[15] or by lesions of the nucleus paragigantocellu- between those separate neural systems. Systemic
laris [203], a region of the rostral medulla that treatment with the monoamine oxidase inhibitor
contains a large density of serotonin neurons that pargyline inhibits lordosis and induces a concomi-
project to other brain stem and midbrain regions tant increase in serotonin levels in the mPOA
[204]. [214]. Infusions of 8-OH-DPAT to the mPOA
Infusions of serotonin or TFMPP into the inhibit lordosis, especially in a mid-rostrocaudal
mPOA or NAcc of male rats increased the number section of the region [215]. Interestingly, in that
of mounts and delayed ejaculation in male rats study, a majority of females displayed a “frenzied”
[205], whereas infusions of 8-OH-DPAT into pattern of hops and darts following 8-OH-DPAT
these brain areas facilitated ejaculation. Indeed, infusions to the same region that suppressed lor-
reverse-dialysis of 8-OH-DPAT to the mPOA dosis, suggesting that 5-HT1A receptors in the
increased extracellular concentrations of both DA mPOA play a role in several components of female
and serotonin there [206]. Levels of the serotonin sexual behavior and perhaps as a mechanism that
metabolite 5-hydroxyindoleacetic acid increase in allows the switching between solicitations and
the NAcc during multiejaculatory copulations lordosis.
[207]. Serotonin is released in the anterior lateral Finally, serotonin appears to exert control over
hypothalamus (LHAA) at the time of ejaculation, executive function in the prefrontal cortex.
and infusions of SSRIs there delay the onset of Ascending serotonin fibers innervate the prefron-
copulation and delay ejaculation after copulation tal cortex [216] and modulate descending outputs
begins [208]. Interestingly, serotonin release in the to a variety of limbic, thalamic, hypothalamic, and
LHAA is associated with a decrease in DA release midbrain regions, including the mPOA, NAcc,
in the NAcc [209], suggesting that ejaculation- and DA neurons in the VTA [217,218]. The pre-
induced serotonin release there contributes to frontal cortex contains a high density of 5-HT1
the abrupt decrease in NAcc DA following and 2 receptors, which play a role in inhibiting or
ejaculation. facilitating the activity of glutamatergic pyramidal
Although much of the literature on the role neurons, respectively [219,220]. 5-HT3 receptors
played by serotonin in female sexual behavior in prefrontal cortex also appear to modulate the
comes from studies of lordosis, there are occa- ability of fluoxetine to increase DA release there
sional hints at effects on female desire. Chronic (which in turn produces inhibitory feedback onto
treatment of female rats with SSRIs reduces lor- mesolimbic DA neurons) [221]. Outputs from pre-
dosis and the amount of time females spend near frontal cortex are excitatory but can stimulate or
males [210,211], although tolerance appears to inhibit DA transmission, depending on whether
accrue to those effects. However, serotonin they innervate DA neurons directly or stimulate

J Sex Med 2009;6:1506–1533

1522 Pfaus

inhibitory GABA interneurons. In this way, drug therapies can be envisioned to target one or
ascending serotonin fibers exert finely tuned both of those systems. However, that is easier said
control over the inhibitory mechanisms of execu- than done. Amplification of brain DA transmission
tive function reviewed above. Activation of 5- carries a risk of drug dependence, addiction,
HT1A and/or blockade of 5-HT2A receptors obsessive–compulsive or hypomanic episodes,
in the prefrontal cortex enhances the activity of anxiety, and a sensitization of psychosis, as has
VTA DA neurons that project to the cortex and been reported for drugs like cocaine [2,230,231].
increases mesocortical DA release [222,223], sug- Inhibition of brain opioid, endocannabinoid, or
gesting an indirect inhibition of mesolimbic DA serotonin systems carries a risk of anxiety, dyspho-
transmission by serotonin. Interestingly, 5-HT2C ria, or depression [232,233]. Much of “drug dis-
receptors are found in GABA interneurons of the covery” is serendipitous, and sexual effects are
prefrontal cortex and appear to modulate their often not recognized until enough subjects in
ability to inhibit descending pyramidal neurons clinical trials or treatment offer the information
[224]. In general, however, activation of 5-HT1A, (e.g., as occurred with fluoxetine [234] and the
1B, 2A, 3, and 4 receptors facilitates DA phosphodiesterase type 5 (PDE-5) inhibitor
release, whereas activation of 5-HT2C receptors sildenafil [235]).
inhibits release [225] Moreover, binding of Several compounds have been tested in the
serotonin to 5-HT2 receptors increases the release treatment of HSDD. Although the DA agonist
of endocannabinoids [226], suggesting that or- apomorphine induces reliable penile erection in
gasm(s) may result in sexual satiety and a blunting rats and men [79,80,236], its induction of emesis
of sexual motivation through multiple neuro- [237] and lack of effect on desire [238] limit its
chemical events that ultimately change the focus of utility. Other drugs have proven more successful.
motivational attention and action to nonsexual The first to receive peer-reviewed, published clini-
incentives. The picture that emerges is of seroto- cal findings were the MC analogs MT-II and its
nin inputs focusing the behavioral inhibition that metabolite bremelanotide. As mentioned above,
characterizes executive function by a complex both drugs stimulated erections in men and male
action on multiple 5-HT receptors in prefrontal rats and solicitations in female rats, which
cortex. The inhibition occurs in part because of prompted successful clinical trials in men as an
inhibitory actions on mesolimbic and hypotha- erection enhancer [112,113] and in women as a
lamic systems involved in general and specific promoter of sexual arousal and desire [115]. In the
attention toward external incentives. Therefore, in latter case, intranasal bremelanotide was success-
cases where serotonergic transmission in this ful in the stimulation of desire in women with
system is overactive, as would occur in individuals decreased libido, and its side effects (nausea,
on SSRIs, the level of behavioral inhibition should increased systolic blood pressure) were transient
be greater. Add to this the refractory-like state that and well tolerated in most individuals. The
serotonin can induce on sexual behavior directly increase in systolic blood pressure in some men,
through actions in the mPOA and NAcc, and however, was severe enough for the U.S. Food and
a pattern reminiscent of the one proposed by Drug Administration to demand further safety
Bancroft and Janssen [28] emerges of overactive trials, which effectively ended clinical development
inhibitory systems inducing a propensity for sexual of the drug for the treatment of sexual arousal
dysfunction, in this case, a propensity for sexual or desire disorders. Systemic administration of
excitement to be suppressed by hyperfunctional bremelanotide activates the mPOA and PVN in
serotonin activity in the brain. Interestingly, SSRIs both male and female rats and stimulates incerto-
are used to help manage paraphilias [227] and to hypothalamic DA release selectively in female rats
treat premature ejaculation [228,229], both of [20]. Bremelanotide stimulated solicitations in
which may result from a hyperactive excitatory or female rats following bilateral infusions to the
arousal systems. mPOA, but not VMH, and its systemic ability to do
this was blocked by infusions of a selective MC-4
antagonist [20]. Interestingly, the ability of sys-
Rational Drug Targets
temic administration of bremelanotide to stimulate
To the extent that both physiological and psycho- solicitations in female rats was blocked by infusions
logical “causes” of HSDD involve a hypofunc- of a DA D1 receptor antagonist to the mPOA,
tional excitatory system, a hyperfunctional suggesting strongly that the stimulation of DA
inhibitory system, or some mix of the two, rational release in the mPOA and the subsequent activation

J Sex Med 2009;6:1506–1533

Pathways of Sexual Desire 1523

Figure 11 Putative neurochemical

“targets” in the mPOA that modulate
sexual arousal and desire through the
activation of incertohypothalamic DA
transmission (melanocortins that sti-
mulate DA release or DA agonists that
stimulate DA receptors) or the inhibi-
tion of g-aminobutyric acid (GABA),
opioid, or serotonin transmission. Endo-
cannabinoids may act here as well.
Modified from Hull et al. [67]. MSH =
melanocyte-stimulating hormone;
DA = dopamine; mPOA = medial pre-
optic area.

of D1 receptors there are a critical mechanism of the second target for drug development may be the
action in the stimulation of solicitations. Systemic inactivation of inhibitory serotonin inputs to the
administration of bremelanotide also activates the excitatory system.
PVN, NAcc, and VTA, an effect that may result A critical feature of both bremelanotide and
secondarily from the activation of the mPOA and flibanserin is that they do not stimulate brain DA
its efferents to those regions. Thus, the first targets systems through direct receptor activation, nor do
for the stimulation of desire may well be DA they block the reuptake mechanisms for DA that
release in the mPOA, its binding to D1 receptors, characterizes psychomotor stimulants like cocaine
and intracellular events downstream of D1 binding and amphetamine. Rather, bremelanotide stimu-
in postsynaptic neurons that lead to the stimulation lates DA release presynaptically in the mPOA,
of its outputs to the VTA. These in turn may whereas flibanserin may contribute to its stimula-
facilitate the stimulation of mesolimbic DA trans- tion by blocking inhibitory serotonergic outflow in
mission to bring the specific activation of sexual the prefrontal cortex, lateral hypothalamus, and/or
desire in synchrony with general incentive atten- mPOA (Figure 11). This may yield important
tion. This pathway may form an important “core” safety benefits, in that it would be highly unlikely
of the excitatory system. that either drug would contribute to the develop-
The second drug to enter clinical trials for the ment of addiction or dependence. Indeed, neither
treatment of HSDD has been flibanserin. This drug alone induces conditioned place preference
drug works as a mixed 5-HT1A agonist and [116,242]. It is also important that neither drug
5-HT2A antagonist [239,240] and is capable of alters the opioid release that underlies sexual
lowering serotonin levels and increasing DA and reward, which may reduce the likelihood of
NE levels in rat prefrontal cortex [241]. Fli- “hypersexualization” of patients using these com-
banserin is able to counter the inhibitory effects of pounds. Should flibanserin and related compounds
stress on behavior but does not induce a condi- prove successful in the treatment of low sexual
tioned place preference in rats [242]. The unique desire in a number of different populations (e.g.,
pharmacological profile of this drug appears to premenopausal women with low desire or
place two “brakes” on the inhibitory serotonergic contraceptive-induced loss of desire, postmeno-
system: the first to diminish serotonin release by pausal women with low desire, individuals treated
5-HT1A agonism and the second to inhibit with SSRIs), then the theoretical question of
binding to the 5-HT2A receptor involved in whether the sexual excitatory and inhibitory
inhibitory cortical outflow. To the extent that such systems operate independently can be answered.
outflow inhibits the activation of incertohypotha- This will allow researchers to focus on how the
lamic and mesolimbic DA release, this drug should two systems are connected neurologically and
be able to counteract a hyperactive inhibitory how they inhibit one another during the normal
system by restoring a more “normal” level of DA expression of sexual behavior. From the studies
and noradrenergic function, in addition to toning of Rodríguez-Manzo and Fernández-Guasti on
down inhibitory serotonergic function. Thus, sexual exhaustion in male rats, it would appear that

J Sex Med 2009;6:1506–1533

1524 Pfaus

inhibition is more potent than excitation. In those As a general rule, inhibition appears to be more
studies, male rats are allowed copulate to sexual “powerful” than direct excitation in the nervous
exhaustion, which typically prevents males from system (e.g., phenomena such as lateral inhibition
responding to females the following day. As noted in the visual system [243]), and “disinhibition” is a
above, copulatory behaviors (mostly mounts and common mechanism by which focused activation
intromissions) in exhausted males can be stimu- of neural pathways and behavior is accomplished.
lated by treatment with the opioid receptor Sexual inhibition produces a normal end to sexual
antagonist naloxone or naltrexone, the a2 adren- behavior; however, its hyperstimulation either
ergic antagonist yohimbine, or the 5-HT1A from endogenous causes or in response to environ-
agonist 8-OH-DPAT, but not following electrical mental challenges, such as sexual nonreward and
stimulation of the mPOA [192]. Thus, as with psychiatric treatments that amplify opioid, can-
the absolute vs. relative refractory phases, sexual nabinoid, or serotonin transmission, leads to a
exhaustion as a model of sexual inhibition may propensity for sexual dysfunction, including disor-
possess absolute and relative mechanisms that can ders of arousal, desire, and/or orgasm [28]. It is not
be overcome efficiently with treatments that target yet known if stressors or experience with sexual
inhibitory serotonin systems selectively. nonreward comes to activate inhibitory mecha-
nisms globally or situationally or whether height-
ened serotonin activity in the frontal cortex, NAcc,
lateral hypothalamus, mPOA, or VTA is associated
Conclusions
with sexual inhibition. Several behavioral para-
Brain pathways for sexual excitation involve the digms exist in rats that render them sexually inhib-
activation of incertohypothalamic and mesolimbic ited, and there is a growing body of evidence that
DA transmission in the mPOA and NAcc that this can be overcome by treatments that inhibit the
focuses attention on incentive sexual stimuli and inhibition, thus bringing those systems back to a
engages motor patterns of approach and consum- normal level of functioning [14,15,123]. Bancroft
mation. Collectively, the behavioral patterns and Janssen [28] developed a Sexual Excitation
stimulated by those systems and the subjective Scale (SES) and two Sexual Inhibition Scales
feelings that accompany them constitute the (SIS1 and SIS2) for men and women, and it will be
epiphenomenon referred to as sexual desire or, interesting to see how responses on those scales
when mixed with genital and sympathetic arousal, match predictions made about sexual activity and
“libido.” The core of this pathway includes the whether they can track the ability of drugs to
mPOA and its outputs to the VTA, which contain improve sexual functioning in inhibited individu-
DA cell bodies that project to various limbic and als. The pathways reviewed here are by no means
cortical regions, such as the prefrontal cortex, exhaustive. Our understanding of the brain is still
olfactory tubercle, NAcc, ACC, lateral septum, unfolding, and new mechanisms of extracellular,
and corticomedial amygdala. Brain pathways for intracellular, and molecular processings are being
sexual inhibition involve the activation of inhibi- discovered in different brain or spinal regions. It is
tory opioid, endocannabinoid, and serotonergic hoped that the ideas put forth here will help guide
feedback to various levels of the excitatory the development of pharmacotherapy for HSDD
pathway. Collectively, the behavioral patterns and, in turn, help basic researchers and clinicians
stimulated by those actions, including sexual alike understand that sexual desire and its inhibi-
reward, satiety, refractoriness, and exhaustion, and tion are indeed, “all in the head.”
the subjective feelings that accompany them con-
stitute the epiphenomenon referred to as inhibited Acknowledgments
sexual desire. The excitatory pathway is stimulated
hormonally and conditionally by the expectancy of Research from the author’s laboratory was funded by
sexual rewards. The inhibitory pathway is acti- grants from the Canadian Institutes for Health
Research, Natural Sciences and Engineering Research
vated by sexual stimulation that reaches critical
Council of Canada, Fonds de la recherche en santé du
thresholds for sexual reward, sedation, and satiety. Québec, contract/consulting grants from Boehringer
Both steroid hormones and external incentive Ingelheim, Palatin Technologies, and Pfizer Global
stimuli can act as occasion setters for the excitatory Research and Development. The author would like to
system, especially if sufficient time has elapsed thank Drs. John Bancroft, Lori Brotto, Genaro Coria-
since sexual reward or other inhibitory actions Avila, Annamaria Giraldi, Irwin Goldstein, Elaine Hull,
were engaged. Erick Janssen, Ellen Laan, Scott Mendelson, Michael

J Sex Med 2009;6:1506–1533

Pathways of Sexual Desire 1525

Perelman, Michael Sand, Annette Shadiack, Stephen 5 Pfaff DW. Drive: Neurobiological and molecular
Stahl, Frederick Toates, and Marcel Waldinger for mechanisms of sexual motivation. Cambridge, MA:
useful discussions. MIT Press; 1999.
6 Pfaus JG, Kippin TE, Coria-Avila GA. What can
Corresponding Author: James G. Pfaus, PhD, Center animal models tell us about human sexual
for Studies in Behavioral Neurobiology, Department of response? Annu Rev Sex Res 2003;14:1–63.
Psychology, Concordia University, 7141 Sherbrooke 7 McCall K, Meston C. Cues resulting in desire for
W., Montréal, QC H4B 1R6, Canada. Tel: +1-514-848- sexual activity in women. J Sex Med 2006;5:838–
2424 x 2189; Fax: +1-514-848-2817; E-mail: jim. 52.
[email protected] 8 Whalen RE. Sexual motivation. Psychol Rev 1964;
Conflict of Interest: The author receives federal and pro- 73:151–63.
vincial grants from the Canadian Institutes for Health 9 Kaplan HS. The new sex therapy, Vol 1. New York:
Research, Natural Sciences and Engineering Research Brunel/Mazel; 1974.
Council of Canada, Fonds de la recherche en santé du 10 Masters WH, Johnson VE. Human sexual
Québec. The author is also receives contract/consulting response. New York: Bantam Books; 1966.
grants from Boehringer Ingelheim, Palatin Technolo- 11 McClintock MK. Group mating in the domestic
gies, and Pfizer Global Research, TransTech Pharma, rat as a context for sexual selection: Consequences
and Inracellular Therapies, and is on the advisory for the analysis of sexual behavior and neuroendo-
board for several corporations, Boehringer Ingelheim, crine responses. Adv Stud Behav 1984;14:1–50.
TransTech Pharma, and Palatin Technologies. 12 Coria-Avila GA, Solomon CE, Vargas EB, Lemme
I, Ryan R, Ménard S, Gavrila AM, Pfaus JG. Neu-
rochemical basis of conditioned partner preference
Statement of Authorship in the female rat: I. Disruption by naloxone. Behav
Category 1 Neurosci 2008;122:385–95.
13 Kippin TE, Pfaus JG. The development of olfac-
(a) Conception and Design
tory conditioned ejaculatory preferences in the
James G. Pfaus
male rat. I. Nature of the unconditioned stimulus.
(b) Acquisition of Data
Physiol Behav 2001;73:457–69.
James G. Pfaus
14 de Jong TR, Veening JG, Olivier B, Waldinger
(c) Analysis and Interpretation of Data
MD. Oxytocin involvement in SSRI-induced
James G. Pfaus
delayed ejaculation: A review of animal studies.
Category 2 J Sex Med 2007;4:14–28.
15 de Jong TR, Pattij T, Veening JG, Waldinger MD,
(a) Drafting the Article
Cools AR, Olivier B. Effects of chronic selective
James G. Pfaus
serotonin reuptake inhibitors on 8-OH-DPAT-
(b) Revising It for Intellectual Content
induced facilitation of ejaculation in rats:
James G. Pfaus
Comparison of fluvoxamine and paroxetine. Psy-
Category 3 chopharmacology (Berl) 2005;179:509–15.
(a) Final Approval of the Completed Article 16 Pattij T, Olivier B, Waldinger MD. Animal models
James G. Pfaus of ejaculatory behavior. Curr Pharm Des 2005;
11:4069–77.
17 Pfaus JG. Revisiting the concept of sexual motiva-
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