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The Biologic Basis for Libido James G. Pfaus, PhD*, and Lisa A.Scepkowski, MA 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.
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, 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 ofrecent 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 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 centralprocessing of sexual incentives in the immediate environ-ment. High sympathetic activation is an important ante- 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 aninternal process built upon neuroendocrine mechanisms, 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.

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 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 inhealthy men and enhanced erection in response to visual 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 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 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 confirmedby the presence of autonomic or central arousal. In fact,many women and men regard sexual desire and arousal as 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- 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 duringthe 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 wasobserved in the amygdala and surrounding entorhinalcortex. Most of these regions are activated by ejaculation in male rats, although the general activation patterns offered by Libido reflects our level of sexual interest at any given time.
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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.
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Libido is almost always directed toward sexual incentives in the exter- male rats following d-amphetamine-induced behavioral
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