The Biologic Basis for Libido

James G. Pfaus, PhD*, and Lisa [Link], MA

Address arousal, desire, reward, and inhibition. In turn, these

*Center for Studies in Behavioral Neurobiology, aspects of sexual function feed back on mechanisms of
Department of Psychology, Concordia University, motivation, either to increase (as in the case of arousal,
7141 Sherbrooke West, Montréal QC H4B 1R6, Canada.
E-mail: [Link]@[Link] desire, or reward) or decrease (as in the case of reward or
inhibition) the expression of sexual interest or libido
Current Sexual Health Reports 2005, 2:95–100
Current Science Inc. ISSN 1548-3584 (Fig. 1). Delineating the neural mechanisms that underlie
Copyright © 2005 by Current Science Inc. these aspects of sexual function has been the focus of
recent research in both animals and humans.
Libido refers to a fluctuating state of sexual motivation in all
organisms. Sexual motivation is altered by internal factors,
such as circulating steroid hormone levels and feedback from
Sexual Arousal
Physiologic sexual arousal in all animals can be defined as
sexual stimulation; external factors, such as the presence of
increased autonomic activation that prepares the body for
sexually relevant incentives; and by the cognitive processing
sexual activity. This includes parasympathetic blood flow
of these factors that provides variations in sexual arousability
to genital and erectile tissues and sympathetic blood flow
and expectation of sexual reward. Libido thus reflects
from the heart to striated and smooth muscles that partici-
constant fluctuations in sexual arousal, desire, reward, and
pate in sexual responses (eg, increased breathing rate, heart
inhibition. Recent advances in neurochemical detection,
rate, pupil dilation). Sexual arousal also includes a central
pharmacologic analyses, and brain imaging, have helped
component that increases the psychologic preparedness to
identify neuroanatomic and neurochemical systems that reg-
respond to sexual incentives.
ulate these four aspects of sexual function. Another impor-
Increases in general sympathetic outflow produce
tant factor is the activation of central monoamine and
increases in libido. This can occur following the use of psy-
neuropeptide systems that link incentive motivation, reward,
chomotor stimulant drugs [1] or the ingestion of herbal
and inhibition together with autonomic pathways that detect
“aphrodisiacs” that contain psychoactive alkaloids or other
and relay sexual arousal. The activation of these systems by
substances that stimulate the autonomic nervous system
steroid hormones, and modulation by expectancy of sexual
[2]. However, these putative increases in libido are most
reward, are critical features of the neural “state” in which
likely to occur in sexually specific situations, indicating an
reactivity to sexual incentives is altered.
interaction between autonomic activation and the central
processing of sexual incentives in the immediate environ-
ment. High sympathetic activation is an important ante-
Introduction cedent of premature ejaculation [3], which is often
Libido has always been associated with sexual motivation. characterized by “high” libido in anticipation of sexual
Indeed, the Latin root refers specifically to sexual lust, a activity. In women, situations such as acute exercise or
term that conjures images of highly motivated behavior. exposure to stimuli that arouse a sympathetic response can
Libido is observed in the strength of desire and response produce increases in physiologic sexual arousal. However,
toward a sexual incentive. Therefore, it can be regarded as a although vaginal pulse amplitude in response to visual
conscious reflection of sexual motivation, which we define erotica can be increased following exercise [4] or ephedrine
here as the energizing force that generates our level of [5], this does not translate into an increase in subjective
sexual interest at any given time. It drives our sexual fanta- sexual arousal. Thus, general stimulation of sympathetic
sies; compels us to seek out and evaluate sexual incentives; outflow appears to make individuals more aroused in gen-
regulates our levels of sexual arousal and desire; and eral and may increase libido if the situation contains
enables us to masturbate, copulate, or engage in other appropriate sexual cues.
forms of sex play. Sexual motivation is often viewed as an
internal process built upon neuroendocrine mechanisms, Penile erection
such as alterations in brain neurochemical function set Erection is stimulated in hypogonadal men and castrated
forth by steroid hormone actions. It is, however, also mod- male rats by androgens [6]. Treatments that enhance penile
ulated by experiences and expectations; learned patterns of erection in nonhypogonadal men with erectile dysfunction
behavior; and underlying neural activity related to sexual also enhance penile erection in gonadally intact male rats.
96 Androgen Deficiency

Figure 1. Hypothetical relationship of

experience, hormonal activation, arousability,
attention, and stimulus processing from
genital sensations and external incentives
on libido. Note that excitatory and inhibitory
feedback can occur anywhere in this flow
chart to strengthen or reduce responding.
Such feedback provides moment-to-moment
modulation of libido.

Examples of these treatments include phosphodiesterase claustrum, hypothalamus, and amygdala [13–17,18•].
type 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and However, the last two structures are activated more in
vardenafil; dopamine receptor agonists, such as apomor- men than in women viewing the same sexual stimuli
phine; melanocortin agonists, such as PT-141, prostaglandin [17,18•]. Activation of the inferior extrastriate cortex,
E1, oxytocin; α2 receptor agonists, such as yohimbine, ida- inferolateral prefrontal cortex, hypothalamus, and mid-
zoxan, and imiloxan; and vasodilators that act through brain was correlated with subjective sexual arousal in
nitric oxide substrates, such as nitroglycerine, sodium nitro- men after viewing an erotic film [15,17,18•], whereas
prusside, and linsidomine [6,7]. It is presumed that these activation of the parietal cortex alone in men viewing
compounds exert their erectogenic actions in the autonomic erotic pictures was correlated with subjective
nervous system, although some of the drugs, such as apo- sexual arousal [16]. However, men with hypoactive sexual
morphine, oxytocin, and the α2 receptor agonists, could desire disorder (HSDD) display an abnormal activation
exert actions centrally. In fact, apomorphine can induce of the medial orbitofrontal cortex, a region previously
erectile responses in male rats after infusions to the medial implicated in the inhibitory control of motivated behav-
preoptic area (mPOA) of the anterior hypothalamus [8]. ior, relative to control subjects [19•]. In male and female
Psychogenic erections can be stimulated in men by rats, nearly identical regions of the brain are activated by
exposure to visual sexual stimuli. The ease with which men copulatory stimulation, including ejaculation and vagi-
achieve or maintain erection in response to erotic cues can nocervical stimulation. A subset of those regions (nucleus
be taken as an index of libido, and latency to, and duration accumbens, hypothalamus, amygdala) is activated by
of, full erection can be measured. A recent study of both exposure of male rats to sexually arousing estrous odors
healthy men and those with erectile dysfunction found or neutral odors paired with sexual reward [20].
that the melanocortin agonist PT-141 induced erections in
healthy men and enhanced erection in response to visual Vaginal/clitoral arousal
sexual stimuli in men with erectile dysfunction [9]. “Non- Relative to our understanding of the mechanisms under-
contact” erections in rats can be provoked by exposure to lying penile erection, far less is known about the activation
sexually receptive females or vaginal estrous secretions of physiologic or psychogenic sexual arousal in females.
[10]. Such erections are potentiated by androgens, by drugs The nitric oxide-cyclic guanosine monophosphate pathway
that stimulate nitric oxide release in the paraventricular appears to be critical for vaginal blood flow, as it is for
hypothalamus, or by dopamine release in the mPOA [11]. penile blood flow. Treatment with androgens facilitates
Conversely, dopamine receptor antagonists, such as halo- vaginal nitric oxide synthase activity, along with vaginal
peridol, reduce both physiologic and subjective sexual smooth muscle relaxation [21]. However, studies testing
arousal in men [1] and inhibit erections in male rats [12]. the efficacy of PDE5 inhibitors to increase vaginal blood
Brain activation during the presentation of visual flow or pulse amplitude on their own, or to augment
sexual stimuli has been studied using positron emission genital responses during the presentation of visual sexual
tomography (PET) and functional MRI. These studies stimuli, have generated conflicting results. These results
have found common regions of activation in men and range from no appreciable effects, to increases in subjective
women, including the anterior cingulate cortex, medial arousal, to increases in genital arousal without correspond-
prefrontal cortex, ventral striatum/nucleus accumbens, ing increases in subjective arousal [22]. Recently, a signifi-
 The Biologic Basis for Libido • Pfaus and Scepkowski 97

cant positive effect of sildenafil was shown on both occur in control animals that receive either no association
subjective arousal and perception of genital arousal in of the odor with reward or that receive random association
women with arousal disorder and lower vaginal pulse of the odor with reward and non-reward [31]. Indeed, we
amplitude [23]. Part of the problem with conducting have found selective activation of both oxytocin- and
studies of female arousal is the high degree of variability in GnRH-containing neurons by the odors in males and
physiologic and subjective responses. This may reflect females, respectively, indicating that systems for sex and
several variables, including differences in placement of a reproduction are being activated selectively. Finally, the
vaginal plethysmograph, exposure to different types of melanocortin receptor agonist PT-141 increases rates of
sexual stimuli, and the phase of the ovulatory cycle in solicitation in female rats primed with estrogen and
which women are tested. progesterone, or estrogen alone [32•]. In preliminary stud-
ies, we found that the dopamine receptor agonist apomor-
phine also increases rates of solicitation in females primed
Sexual Desire with estrogen alone. To the extent that solicitation in
Sexual desire has been extremely difficult to define. No female rats and anticipatory psychomotor stimulation in
agreed-upon definition exists except that inferred from the male rats are analogies of “sexual desire,” the activation of
definition of HSDD in the Diagnostic and Statistical Manual these two neurochemical systems in the brain may form an
of Mental Disorders (DSM-IV-TR) [24]. HSDD is defined as a important part of the pathway that mediates libido. Inter-
condition in which “desire for and fantasy about sexual estingly, estradiol increases both dopamine and melano-
activity are chronically or recurrently deficient or absent.” By cortin synthesis in hypothalamic and limbic structures,
converse logic, sexual desire would be the presence of desire and androgens activate nitric oxide pathways that facilitate
for, and fantasy about, sexual activity. Desire can be viewed dopamine release. The increase in female-initiated sexual
as distinct from arousal in animals and humans, with desire activity around the time of ovulation [33], and the increase
constituting a psychologic interest in sex and behaviors that in anticipatory sexual activity in males, may be primed by
reflect such interest. Despite the fact that desire and arousal the activation of these two systems by steroid hormones.
are separate processes, desire may be informed or confirmed
by the presence of autonomic or central arousal. In fact,
many women and men regard sexual desire and arousal as Sexual Reward
parts of one another, despite their distinct definitions An emerging idea from animal studies is that desire is
[25,26]. Thus, desire as it is expressed physically in linked to an expectation of reward and that such expecta-
conscious goal-directed behavior, most closely resembles tion fluctuates over time given the actual level of reward
the “lust” of libido. experienced. Sexual reward is inferred in animals by the
Desire can be inferred in animals by their willingness strength of operant or instrumental responding toward a
to work for sexual reinforcers or in behavior that reflects particular sexual reinforcer and by the strength of copula-
the anticipation of sexual activity [27]. Several lines of tory responding (ie, behaviors that typically denote desire).
evidence link the desire for sex to the activation of brain Contextual factors, such as settings, are also important
dopamine systems. Microdialysis studies have shown that components of positive sexual experiences for both men
dopamine release in the mPOA and nucleus accumbens and women. Recent work using the conditioned place pref-
increases in male rats in response to both conditioned and erence (CPP) paradigm has been particularly useful in
unconditioned incentive cues that predict sexual reward delineating the behaviors and neurochemical systems
[28]. Dopamine receptor antagonists injected peripherally necessary for sexual reward in rats [34,35]. For male rats,
or centrally to these regions disrupt anticipatory ejaculation is critical in the formation of CPP, whereas for
conditioned excitement [29]. Lesions of the basolateral female rats, the ability to control the initiation and rate of
amygdala (a region that sends glutamate afferents to the copulation (pacing) is critical. If one distinctive side of a
nucleus accumbens) decrease operant responding for sec- CPP apparatus is paired with a rewarding sexual experience
ondary sexual reinforcers. This decrease can be reversed by and the other side is paired with a less rewarding sexual
infusions of amphetamine to the nucleus accumbens [30]. experience (eg, copulation but not ejaculation in males;
Conditioned partner preferences in rats occur when a nonpaced copulation in females), both male and female
neutral stimulus (eg, almond odor) is paired with a sexual rats will spend significantly more time in the side associ-
reward. In male and female rats, we have shown that pre- ated with reward. This indicates a preference for contextual
sentation of the conditioned stimulus alone induces anti- cues associated with reward. Systemic administration of
cipatory psychomotor stimulation and activates brain the opioid receptor antagonist naloxone during rewarded
regions associated with incentive motivation and attention training trials blocks the induction of sexual CPP in both
(eg, nucleus accumbens, ventral tegmentum), sexual males and females. This suggests that the release of endo-
behavior (mPOA, basolateral and medial amygdala), and genous opioids is a critical factor in the sexual reward
reproductive processes (supraoptic and paraventricular induced by ejaculation in males and pacing in females.
nuclei of the hypothalamus). Such activation does not Interestingly, treatment with dopamine receptor antago-
98 Androgen Deficiency

nists does not block the induction of sexual CPP, indicat- neuronal markers typically used in rat brain sections (eg,
ing that dopamine activation is not a necessary component induction of nuclear Fos protein). It is possible that small
of sexual reward [36]. However, dopamine is required for hypothalamic regions may still have been activated but
animals to display conditioned appetitive responses and undetected. In women with complete spinal cord injury who
may be necessary for smaller, more appetitive types of still experienced orgasm from masturbation, fMRI revealed
reward when animals attempt to gain access to sex partners an activation of hypothalamic structures including the
and solicit sex. Systemic administration of opioid agonists paraventricular nucleus; the medial amygdala; the anterior
disrupts the initiation of sexual behavior in both male and cingulate; the frontal, parietal, and insular cortices; and the
female rats [37], and opioid agonists infused directly into cerebellum. Because of the spinal damage, it was concluded
the mPOA have similar inhibitory effects in male rats. that the stimulation of orgasm traveled through the Vagus
Dopamine release decreases abruptly in the nucleus nerve to activate the brain.
accumbens and in the mPOA when male rats ejaculate,
and the incentive salience of females is diminished during
the absolute refractory period. The decrease in dopamine Sexual Inhibition
release in the nucleus accumbens may be due to an activa- Sexual inhibition can be induced by stressful life events or
tion of serotonin release in the lateral hypothalamus by after high sexual rewards (ie, during a refractory period in
ejaculation [38]. Lesion studies suggest that the nucleus which reproductive capacity needs to be regenerated before
accumbens plays an excitatory role in sexual arousal, resumption of copulation) [47]. In either case, the activa-
whereas the lateral hypothalamus plays an inhibitory role tion of inhibitory pathways for sexual arousal and desire
in sexual arousal but an excitatory role in the regulation of generates a state of reduced libido.
ejaculation [39]. Activation of opioid and serotonin release during sexual
Activation of oxytocin and vasopressin pathways by reward is associated with inhibition of ongoing sexual
sexual reward may be a critical component of future social behavior. This has been studied in male rats following sex-
bonding. Monogamous prairie voles bond with their first ual exhaustion. Male rats allowed to copulate to sexual
sex partner for life and share parental duties [40]. Polyga- exhaustion with multiple ejaculations do not respond to
mous montane voles do not and neither do rats. Monoga- female solicitations for a period of 24 to 72 hours. This inhi-
mous bonding in female prairie voles can be disrupted by bition can be reversed by the 5-HT1A agonist 8-OH-DPAT
injections of an oxytocin antagonist, whereas bonding in (an autoreceptor agonist that inhibits serotonin release), the
male prairie voles is disrupted by injections of a vaso- α2 receptor agonist yohimbine, and the opioid receptor
pressin antagonist [41]. Male prairie voles have a greater antagonist naloxone [48]. Thus, blockade of opioid or sero-
density of the vasopressin type 1a (V1a) receptor in the tonin transmission, or activation of parasympathetic path-
ventral pallidum compared with male montane voles, and ways involved in erection, can overcome the state of
viral gene transfection of the V1a receptor to the ventral inhibition induced by sexual exhaustion. Activation of
pallidum of male montane voles renders them behavior- opioid transmission by stress may also play a role in sexual
ally monogamous [42••]. Polygamous male and female inhibition. Male rats find novel environments stressful. In
rats can be conditioned to display a partner preference fact, males that are not desensitized to the environment in
based on odors or other cues associated with sexual reward which they have their first sexual experiences often will
[43,44], and we have recently found that such cues activate never copulate. Pre-exposure to the environment, or treat-
oxytocin and vasopressin neurons, in addition to dopam- ment with naloxone, increases the proportion of males that
ine release. Thus, a consequence of early sexual reward is copulate on their first trial [49]. Interestingly, sexually naïve
bonding to cues that predict the reward, cues that become males sensitized to amphetamine do not show inhibition
highly arousing and desired. In humans, this process may during their first exposure to females in a novel environ-
play an important role in the formation of preferences for ment, despite the drug exposure happening weeks before
cues that we find attractive at a distance. [50]. Although sexually experienced males show signs of
Brain imaging studies have also been conducted in men fear (eg, freezing) in novel environments, they do not show
and women during manual genital stimulation to orgasm subsequent sexual inhibition if a receptive female is placed
[45•,46•]. In men stimulated to ejaculation, PET revealed an into the environment. Together, these data suggest that sen-
increased activation of the cerebellum and midbrain regions, sitized dopamine systems, produced either by sexual experi-
including the ventral tegmental area, zona incerta, sub- ence, amphetamine preexposure, or blockade of opioid
parafascicular nucleus, intralaminar thalamus, lateral puta- transmission, can overcome the stress-induced inhibition of
men, and claustrum. No increased activation was observed in sexual responding in males.
hypothalamic regions, and decreased activation was
observed in the amygdala and surrounding entorhinal
cortex. Most of these regions are activated by ejaculation in Conclusions
male rats, although the general activation patterns offered by Libido reflects our level of sexual interest at any given time.
PET do not have the fine-grained spatial resolution of the It is determined by the interaction of neural systems that
 The Biologic Basis for Libido • Pfaus and Scepkowski 99

underlie sexual arousal, desire, reward, and inhibition, pro- 11. Sachs BD: Contextual approaches to the physiology and
cesses that are highly influenced by steroid hormone classification of erectile function, erectile dysfunction, and
sexual arousal. Neurosci Biobehav Rev 2000, 24:541–560.
actions. This is especially true for brain dopamine systems 12. Pehek EA, Thompson JT, Eaton RC, et al.: Apomorphine and
that modulate attention toward external sexual incentives haloperidol, but not domperidone, affect penile reflexes
and help generate appropriate motor responses. The neuro- in rats. Pharmacol Biochem Behav 1988, 31:201–208.
anatomical and neurochemical mechanisms that influence 13. Stoleru S, Gregoire MC, Gerard D, et al.: Neuroanatomical
correlates of visually evoked sexual arousal in human males.
this process, and are influenced by it, are only beginning to Arch Sex Behav 1999, 28:1–21.
be understood. Likewise, studies concerning the nature of 14. Redoute J, Stoleru S, Gregoire MC, et al.: Brain processing of
sexual reward; its translation into pleasure, bonding, and visual sexual stimuli in human males. Hum Brain Mapp 2000,
11:162–177.
sexual inhibition; and the mechanisms that underlie them, 15. Bocher M, Chisin R, Parag Y, et al.: Cerebral activation associ-
have only begun. We have understood libido for centuries at ated with sexual arousal in response to a pornographic clip:
a behavioral level. Studying its biologic basis will help us a 15O-H2O PET study in heterosexual men. Neuroimage 2001,
14:105–117.
identify mechanisms of sexual function and dysfunction,
16. Karama S, Lecours AR, Leroux JM, et al.: Areas of brain
and it will perhaps allow us to better understand how func- activation in males and females during viewing of erotic
tion and dysfunction, and also desire and inhibition, are film clips. Hum Brain Mapp 2002, 16:1–13.
integrated into the experience of all individuals. 17. Mouras H, Stoleru S, Bittoun J, et al.: Brain processing of
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18.• Hamann S, Herman RA, Nolan CL, Wallen K: Men and
Acknowledgments women differ in amygdala response to visual sexual stimuli.
Nat Neurosci 2004, 7:411–416.
Research from JGP's laboratory reported here was sup- This study used fMRI to examine whether patterns of brain activation
ported by grants from the Canadian Institutes of Health differ between men and women viewing the same visual sexual
Research, Natural Sciences and Engineering Research stimuli. Although men and women showed similar activation of a
majority of brain regions, men had greater activation of the hypothal-
Council of Canada, and FCAR du Québec. amus and amygdala relative to women overall and equal activation as
LAS is currently at the Center for Anxiety and Related women who reported increased sexual arousal after the presentation.
Disorders, Department of Psychology, Boston University, Because men are reported to have a greater sensitivity to visual sexual
stimuli compared to women, the activation of these structures may
648 Beacon Street, 6th Floor, Boston, MA 02215, USA. mediate the sex difference.
E-mail: lisasc@[Link]. 19.• Stoleru S, Redoute J, Costes N, et al.: Brain processing of visual
sexual stimuli in men with hypoactive sexual desire disorder.
Psychiatry Res 2003, 124:67–86.
This study used PET to examine differences in brain activation patterns
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are typically externalized. This study shows just how malleable the sys-
tem is. One important difference between the brains of monogamous
versus polygamous voles concerns a population of V1a receptors in the
ventral pallidum, a region that receives dopamine-modulated input
from the nucleus accumbens and controls goal-directed movements.
These receptors are greater in density in monogamous voles than in
polygamous voles. To examine whether these receptors are important
in the display of selective partner preference, the authors constructed
an adeno-associated viral vector that contained the V1a receptor gene
and infused it to the ventral pallidum of sexually naïve polygamous
montane voles. This viral gene transfection was successful—the mon-
tane males subsequently displayed both sexual and parental monog-
amy, and the V1a receptor populations had grown in density. Thus,
relative differences in brain vasopressin transmission can alter patterns
of preference and entire mating strategies.