One neurotransmitter to rule sexual preference?

I was planning on taking a small break from blogging after the #CAN2013 shebang, but this study is just too sweet to pass on. Serotonin! Sexual preference! Lesbian mice! From my Alma Matar! Interested? Read on.

“Which way do you swing?” It’s such a simple, but loaded question. Social-economic issues aside, even the biological basis of sexual preference is hotly debated. Homosexual behavior isn’t limited to humans; it’s evolutionarily conserved in species as diverse as the lowly fruit fly to the mighty lion. Some argue that genes are involved, but so far the hunt for “gay genes” have only led to dead ends (and a lot of controversy!). Sex hormones are the next suspect, but they seem to only change sex drive, not so much preference.

Now this study suggests that the answer may be as simple as one SINGLE neurotransmitter: serotonin.

Zhang S et al. 2013. Serotonin signaling in the brain of adult female mice is required for sexual preference. PNAS Early Edition. doi:10.1073/pnas.1220712110

First off, why serotonin? We know that serotonin is involved in sexual behaviour. SSRI antidepressants, like Celexa and Zoloft, work by increasing the amount of serotonin in the synapses. This relieves depressive symptoms, but has the unfortunate side effect of lowering libido. Many other studies converge to support the same simple conclusion: more serotonin=less sexual behaviour, less serotonin= more sexual behaviour.

But what about PREFERENCE? The same group published a highly controversial study a few years ago, in which they argued that abolishing serotonin in male mice wiped out their preference for females. These mice showed sexual interest in both males and females, and mounted both sexes equally when given the chance. It caused quite a stir back then, with many pointing out that their conclusions were premature. One major problem is that serotonin-lacking mice are much more likely to engage in sexual behavior. Hence, they might have just been so horny that they didn’t care to pick-and-choose, mounting everything within sight regardless of gender.

Now the authors are back with more data, tackling the question whether serotonin also controls sexual preference in female mice. They first worked with animals lacking a gene called Lmx1b, which is required to make serotonergic neurons in the brain (leaving peripheral serotonin intact). Like humans, mice have a stereotypical "mating dance", where they display sexual interest by sniffing the head and genital areas of the other party.

When given the choice between a strange male and female, wild-type (+/+) females steadily approached male mice, spending MUCH more time sniffing his “erotic zones” than those of female mice (blue bar). Amazingly, females lacking both copies of Lmx1b REVERSED this behavior, showing much more interest in the female than male (red). On average, they sniffed female genitals for longer and often went back for more. Meanwhile, females with one functioning copy of Lmx1b (+/-) showed an intermediate behaviour (green). This is remarkably different from the previous study with serotonin-deficient male mice; they showed a lack of preference towards either sex, not a reversal of preference.

Of course, it takes two to tango, so researchers wondered if sexual choice might have been influenced by behaviours of the object of affection – the target mice. To rule this out, instead of using live animals, researchers presented Lmx1b lacking females with slides smeared with male and female genital secretions on each side. As before, Lmx1b females showed a clear preference for female odors. When given the choice between smells from an intact and a castrated male, unlike wild-type females, serotonin-lacking females didn’t seem to care one way or the other.

This interest in females translated into behavior. When given a receptive female, 68.4% of Lmx1b females sniffed and tried to mount the target (complete with NSFW grasping and pelvic thrusts), while only ~30% of wild-type mice showed the same behavior.

However, when given a male mouse, Lmx1b females behaved just like their wild-type littermates: very few tried to mount the male, instead showing typical female mating behaviour. That is, they ran away and fought the male at first, but subsequently became more receptive (playing hard to get?). These results show that wiping out serotonin didn’t indiscriminately increase female sex drive; it just enhanced sexual behaviour towards other females.

To further support their idea, researchers repeated these experiments on another serotonin-lacking mutant (Tph2 mice), as well as on wild-type mice chemically depleted of serotonin. Just like Lmx1b females, these mice also preferred female to male odors and mounted females more when one was available. When given the choice between bedding smeared with either female of male excretions, Tph2 lacking mice lingered on female bedding and avoided male bedding (red), while wild-type mice (blue) didn't display any preference (the equivalent to smelling underwear...? Just putting it out there).

Finally, researchers chemically boosted serotonin levels in Tph2 females by giving them an injection of the precursor 5-HTP. Remarkably, after this simple treatment, Tph2 females lost their love for female bedding, spending similar amounts of time on both (yellow).

Bedding preference. Or lack-thereof.

Additional experiments showed that serotonin-depleted mice had no problems detecting odors and phermones, and that their sex hormone levels were no different than that of wild-type mice. Researchers hence concluded that serotonin, by acting in the brain, controls female sexual preference.

Overall, this paper builds on the group’s previous study, making a much stronger case for serotonin in controlling sexual preference. Hypersexuality can’t explain serotonin-depleted females’ reversal of partner choice. Neither can lack of smell, since these females can clearly discriminate between males and females. Unfortunately, the paper didn’t comment on the elephant in the room: serotonin affects MUCH more than just sexual behaviour; it also regulates everything from aggression to social interaction to mood and memory. I find it quite interesting that serotonin-lacking females didn’t approach males more, as they should be friendlier (and hornier) than wild-type females (although this is predicted based on studies with male mice, it's possible serotonin doesn't affect females the same way).

So how well does this translate into humans? We really don’t know. Although serotonin is evolutionarily conserved, it has different effects on different species, depending on the type, amount and distribution of its 14 (!!!) different receptors. Human sexual behavior is obviously much more complex than that of mice, often tinged with past experience and social pressure. We absolutely cannot make the claim that serotonin is THE agent inhibiting same-sex attraction in humans. Results presented in this paper are very intriguing, but making the leap from mice to men is premature.

Finally, just to make it crystal clear, this paper DOES NOT provide proof that human homosexuality “can be cured”. In fact, increasing evidence points to sexual preference as a continuum - something that is fluid, modulated by past relationships and current concepts, and maybe (just maybe) influenced by the level of serotonin in the brain.

Zhang, S., Liu, Y., & Rao, Y. (2013). Serotonin signaling in the brain of adult female mice is required for sexual preference Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1220712110