Although the question of to whom a male directs his mating attempts1, 2 is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.
At a glance
- Parent–offspring conflict. Am. Zool. 14, 249–264 (1974)
- 2006) & Homosexual Behaviour in Animals: An Evolutionary Perspective (Cambridge Univ. Press,
- Development of sexual and aggressive behaviors in Hereford bulls. J. Anim. Sci. 69, 1019–1027 (1991) &
- Ambisexual behavior with male–male anal penetration in male rhesus monkeys. Arch. Sex. Behav. 5, 9–14 (1976) &
- Loss of sex discrimination and male–male aggression in mice deficient for TRP2. Science 295, 1493–1500 (2002) , , , &
- Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl Acad. Sci. USA 99, 6376–6381 (2002) et al.
- Dopamine and serotonin: influences on male sexual behavior. Physiol. Behav. 83, 291–307 (2004) , &
- Sexual behavior in male rodents. Horm. Behav. 52, 45–55 (2007) &
- “Hypersexuality” and behavioral changes in cats caused by administration of p-chlorophenylalanine. Science 168, 499–501 (1970) et al.
- p-Chlorophenylalanine and copulatory behaviour in the male rat. Nature 232, 398–400 (1971) &
- p-Chlorophenylalanine facilitates copulatory behaviour in male rats. Nature 232, 400–401 (1971) &
- Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins. J. Neurosci. Methods 150, 111–115 (2006) , , &
- Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity. J. Neurosci. 26, 12781–12788 (2006) et al.
- Sex selectivity of mouse ultrasonic songs. Chem. Senses 32, 463–473 (2007) &
- A battery of olfactory-based screens for phenotyping the social and sexual behaviors of mice. Physiol. Behav. 85, 489–499 (2005) &
- Attractive properties of sexual pheromones in mice: innate or learned? Physiol. Behav. 77, 167–176 (2002) , , , &
- Laboratory evaluation of predator odors for eliciting an avoidance response in roof rats (Rattus rattus). J. Chem. Ecol. 24, 49–66 (1998) , , &
- Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli. Behav. Neurosci. 117, 360–368 (2003) et al.
- Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004) et al.
- Social amnesia in mice lacking the oxytocin gene. Nature Genet. 25, 284–288 (2000) et al.
- Precise circuitry links bilaterally symmetric olfactory maps. Neuron 58, 613–624 (2008) et al.
- Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J. Neural Transm. 115, 1127–1132 (2008) et al.
- Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE 3, e3301 (2008) et al.
- Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl Acad. Sci. USA 106, 10332–10337 (2009) et al.
- p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmacol. Exp. Ther. 154, 499–516 (1966) &
- Homosexual activity in male rats after p-chlorophenylalanine: effects of hypophysectomy and testosterone. Physiol. Behav. 7, 551–555 (1971) &
- Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007) et al.
- Differential brain activation in exclusively homosexual and heterosexual men produced by the selective serotonin reuptake inhibitor, fluoxetine. Brain Res. 1024, 251–254 (2004) , , &
- A double-blind study of citalopram versus placebo in the treatment of compulsive sexual behaviors in gay and bisexual men. J. Clin. Psychiatry 67, 1968–1973 (2006) et al.
- A genomewide scan of male sexual orientation. Hum. Genet. 116, 272–278 (2005) et al.
- Supplementary Information (973K)
This file contains Supplementary Figures 1-11 with legends and Supplementary Dataset 1.
- Supplementary Movie 1 (7.9M)
Mating of a wt target male by a Lmxb1-/- male. A Lmxb1-/- male mounted a wt male.
- Supplementary Movie 2 (4.4M)
Mating choice of a Lmxb1+/+ littermate. A Lmxb1+/+ male was presented with two targets, one male and one estrous female. The Lmxb1+/+ male mounted the female target.
- Supplementary Movie 3 (10.2M)
Mating choice of a Lmxb1-/- male. A Lmxb1-/- male was presented with two wt targets, one male and one estrous female. The Lmxb1-/- male mounted both the male and the female targets.
- Supplementary Movie 4 (4.2M)
Mating of a wt target male by a Tph2-/- male. A Tph2-/- male mounted a wt male.
- Supplementary Movie 5 (7.4M)
Mating choice of a Tph2 +/+ littermate. A Tph2 +/+ male was presented with two targets, one male and one estrous female. The Tph2 +/+ male mounted the female target.
- Supplementary Movie 6 (11.6M)
Mating choice of a Tph2-/- male. A Tph2-/- male was presented with two wt targets, one male and one estrous female. The Tph2-/- male mounted both the male and the female targets.