© DAVID GIRALAs an undergraduate at American University in Washington, DC, Jim Pfaus played guitar in two local punk bands while also studying psychology and working in labs at the university, Planned Parenthood, and the National Institutes of Health (NIH). “I honestly wasn’t sure what I wanted to do with my life,” he says. Ultimately, Pfaus opted to go to graduate school to study sexual behavior and keep music as a hobby. “I figured there’s no way the government would give me grants to do sex research in my basement, so that helped me make up my mind,” says Pfaus with a laugh.
It was the beginning of a whirlwind romance with behavioral neurobiology. In studies on rats and humans, Pfaus has mapped out neurotransmitter systems, cell-signaling mechanisms, and behavioral responses to sexual stimuli. He has also shown that a species’ sexual behaviors are not fixed; they can be conditioned and changed.
“Everybody seems to do it, so what is it about sex that is so taboo?”
Here, Pfaus opens his little black book to divulge how the word “sex” got him suspended from primary school, why good sex is like a good drug, and how targeting excitatory brain systems could help treat sexual dysfunction.
PFAUS MAKES A PLAN
Three-letter word. “When I was in elementary school, I had a precocious interest in sex. As far [back] as I can remember, I wanted to know where babies came from. If a sperm and an egg mixed, what do they do to make a baby? I was always intrigued, to the point that in grade three I wrote the word ‘sex’ on my notebook. My teacher had an apoplectic fit and sent me to the principal’s office. The principal sees this little three-letter word and turns into a stammering idiot, asking me if I knew what that word means. I said, ‘Yes. It’s how babies are made.’ And then he stammered even more. So I said, ‘Well, it also has a second meaning—whether you’re a boy or a girl.’ Then he got on the phone and called my mom and told her to come pick me up, that I was suspended for the day. Suspended! For writing a three-letter word that seemed important for the maintenance of our species. I couldn’t understand why that little word had such power. Everybody seems to do it, so what is it about sex that is so taboo? That thought just kept driving me to figure it out.”
Sex ed. When Pfaus became sexually active in his teens, he had so many questions that he began checking out books on sex and reproduction from the library. “But none of them really addressed the question of why I felt like I did [during sex]. Why did it feel good? What was going on in my brain and body? I remember starting to put it together that this had to be the essence of why everyone wanted Helen of Troy. There was something about her or what she did that made men crazy.” Pfaus even cultivated a small book club—“me and a bunch of women,” he admits—that read and discussed books, like Simone de Beauvoir’s The Second Sex, on the role of sexuality in the lives of men and women.
Work experience. In college at American, Pfaus worked in the laboratory of Anthony Riley doing studies of conditioned taste aversions to delayed-onset toxins. He also took a part-time job as a lab tech at Planned Parenthood in downtown DC, doing pregnancy tests and STD analyses. Later he added a position as a staff research assistant for Judith Walters, a neurophysiological pharmacologist at the NIH who was exploring the role of dopamine in the basal ganglia. There, Pfaus learned electrophysiology and observed the response of dopamine neurons to antipsychotic medicines. “That got me into pharmacology. I started looking at drugs as tools and looking at what these things do to individual cells, knowing they are mind-altering substances. It was like being in Candyland.”
In real time. After opting for a research career over one in punk rock, Pfaus got his PhD at the University of British Columbia in Vancouver, Canada, working first with Boris Gorzalka on the effects of opioids on sexual behavior and then with neuroscientist Anthony Phillips on the role of dopamine in sexual behavior. “Tony had voltammetry in his lab, so we could assess dopamine release at the moment it was happening,” says Pfaus. Together, they observed that different dopamine receptor antagonists, such as haloperidol and clozapine, caused declines in different aspects of rats’ sexual behavior: copulation, ejaculation, and/or interest in sex. They also found that dopamine in the male rat brain increases during sex but then precipitously decreases afterwards. By the time he graduated in 1990, Pfaus had published 14 papers.
Fired up. While working toward his PhD, Pfaus attended a lecture at UBC by Rockefeller University professor Donald Pfaff, who studies how steroid hormones in the brain direct behaviors, including arousal. “I went up to the mic and asked a question, and he didn’t really have a good answer to it. I didn’t think twice about it, but afterwards he came up to me, looked at my nametag, and said, ‘Oh, another Pfa- person.’ You know, because he’s Pfaff and I’m Pfaus. I said, ‘Okay . . .’ He said I had asked a very good question, one he imagined a Pfa- person would ask. We talked and talked, and even though I hadn’t even finished my master’s yet, he offered me a postdoc. All of a sudden, my future was sealed.” In 1990, Pfaus went to New York City to work in Pfaff’s lab, where he started by studying opioids in the brain, but soon became sidetracked by a new technique utilizing c-fos, an early gene product regularly expressed when neurons fire that can therefore serve as a marker of neuronal activity. “That was like, ‘Oh my God. Drop everything. Now we can actually look at neurons that are activated.’ It was like an fMRI study but at a cellular resolution.” Using the c-fos technique, Pfaus began mapping areas of the female rat brain activated by different kinds of sexual stimulation, such as clitoral stimulation or vaginal-cervical stimulation.
Love at first sight. Pfaus was all set to take a faculty position in Seattle when he visited Concordia University in Montréal. “It was like a Hollywood movie: I was engaged to one girl but then met the girl of my dreams. It really felt that way. I am walking around Montréal on a beautiful summer night thinking, ‘I love this city!’ Then I see the old logo of the Montreal Urban Community,” a regional government that has since merged with others, “and it looked like the crystalline ring structure of estrogen—like a bunch of benzene rings. And then, since it’s Québec and it’s French and everything is Saint-something, I see on the buses the label ‘STCUM’. Of course, it was the Société de Transport de la Communauté Urbaine de Montréal, but it looked like ‘St. Cum.’ I thought, ‘This is amazing. I’m home.’”
Conditional success. In 1992 Pfaus joined the Concordia faculty, where he has built a research program based on two pillars: the work he began in New York mapping the excitatory and inhibitory brain circuits involved in sexual behavior and a new foray into studying the conditioned activation of sexual responses. “In grad school, I had done this one fleeting little study looking at conditioned activation of sex behavior in male rats.” Pfaus had discovered that if he trained a male to associate a neutral almond odor with a receptive female, he could then use that same odor to encourage the male to mount an unreceptive female—an action that an unconditioned male rat would never attempt. He also found that once a male rat was conditioned, the odor alone stimulated a rise in dopamine, the “attention-to-reward” transmitter, in its brain. “If we were getting a conditional rise in dopamine from the odor, then it was looking more and more like sex follows a similar pattern to drug addiction: a cue that predicts a reward. This got me onto a whole second area of interest.”
Flexible sex. That interest led Pfaus to question a dogma he had been taught in school: that sexual strategies are fixed in species. “We study the prairie vole because it’s monogamous, and the meadow vole because it’s promiscuous. But in male or female rats, you can associate a neutral odor with sexual reward, and animals change their behavior. For instance, rats are promiscuous, but if we give [a conditioned rat] an open field to chose between two partners, one that’s scented and one that isn’t, he will pick the one that is. And if you give a female rat one and only one male for her first, really rewarding experience, she will not only [subsequently] choose that male over [any] other, but she will mate-guard that male, but not other males, from competitor females. That is astonishing. It turns out a simple Pavlovian procedure can redirect a sexual strategy. I’m beginning to think that maybe monogamy and promiscuity are inherent in the brains of every [species]. It’s just your ecological niche that determines it.” Pfaus went on to map where pheromones and sexually conditioned neutral odors are received in the brain. In 2003, he found that although they activate different pathways, those pathways converge in regions of the hypothalamus and limbic system, including the nucleus accumbens core, pointing to that location as a processing hub for sexual stimuli.
Blocked. “We’ve not only studied reward, but non-reward,” says Pfaus. His team found that female rats that are treated with opioid-blocking drugs—and thus receive no opioid reward—during their first several sexual experiences later reject any males that try to mount them. That finding held true even for females primed with estrogen and progesterone, even though such animals typically solicit copulation with anything that moves. “The steroids activate sexual behavior, but that collides with the expectation of bad sex. And expectation wins. This is interesting because we have not had a good model of inhibited sexual desire, and we don’t really understand why it is that some premenopausal women have inhibited sexual desire. It seems that reward itself signals gene expression, and without that gene expression, your brain is not looking for a sexual reward.”
Libido test. Pfaus also uses his rats to test drug compounds for sexual effects. A company sends him a drug they want tested, and pays him to run a full double-blind trial, testing whether a drug increases the number of solicitations a female rat performs when she wants to copulate. “I’ve done this now with about 22 different companies, and there have only been four compounds that have produced increases in solicitations.” One of those was being developed by New Jersey–based Palatin Technologies. “Palatin came to me with a drug they wanted tested. When they broke the code [of the double-blind test], well, holy toot, it whoppingly increased solicitations. Of course, the drug was bremelanotide.” Bremelanotide, which activates dopamine release in a region of the hypothalamus called the medial preoptic area, is one of several drugs currently in clinical trials to treat low female libido. (See “That Loving Feeling.”) “I think many companies were targeting the wrong thing. They were going after estrogen or something that will keep estrogen bound. They should be targeting excitatory systems directly: dopamine, oxytocin, noradrenaline. Dopamine controls sexual solicitation, and there are probably many ways into that system.”
All in the eyes. Recently, Pfaus teamed up with Aaron Johnson, a cognitive psychologist at Concordia, to extend his research to humans. “We’re using eye-tracking technology to come up with an objective measure of desire in people. People often think of autonomic arousal—things like vaginal, clitoral, and penile blood flow—as an indication of desire. Of course in men, penile blood flow and desire are generally concordant. But for women, this has been a real bone of contention. Many show discordance between vaginal blood flow and desire.” So pharmaceutical companies seeking to make drugs that affect desire have struggled for ways to measure it in clinical trials. (See “Quantifying Libido.”) Pfaus and Johnson are developing tasks that utilize an old technique called the Stroop test, in which men and women are presented briefly (50 milliseconds) with sexual words or pictures that are tinted in a particular color. Subjects are then asked to state the color. “It turns out that the more a person is horny, the longer they take to state the color.” In other tasks, subjects are presented with erotic pictures, one at a time for 10 seconds each. The picture is marked with either a green dot or a red dot, and subjects are instructed to look at the pictures with a green dot and look away from those presented with a red dot. “The hornier you are,” says Pfaus, “the more you make these involuntary eye movements to the picture [with a red dot]. These effects are really beautiful, and both it and the Stroop tasks are positively and highly correlated with people’s subjective sexual desire, and not so much with their [autonomic] arousal.”
Sex Prof. “I love teaching, and sex makes up a large part of what I teach in the upper-level courses. Obviously some people are going to laugh and go back to grade five with some of the course material, but most are truly interested in it. And I get many, many requests to work in my lab. This year I had eight [undergraduate] honors students, and six are going on to grad school. I’m so proud of them.”
Birds and the bees. “I’ve got a 10-year-old son named Josh. When he was very young he was interested in where babies came from. So of course I told him. I remember when he was three I got called into his daycare because of a problem. His teacher was going on maternity leave, and she’d told him and the rest of the class that a baby was growing in her tummy. He started saying, ‘No, no, no,’ and the teacher thought he was having some kind of separation anxiety. But he told them, ‘No, food goes in your tummy. Babies grow in a uterus!’ Today, he knows what I do, but he’s at an age now where he gets shy talking about it. But if he’s got a serious question, like how to ‘really’ kiss a girl, he asks.”