24 November 2008. Like some other parasites, Toxoplasma gondii, a protozoan implicated in schizophrenia, manipulates the behavior of its host to advance its own ends. It goads rats that have been infected with it to seek out cat smells, essentially turning them into cat chow so that it can enter the feline gut in order to reproduce. According to Robert Sapolsky of Stanford University in Palo Alto, California, T. gondii accomplishes this by tampering with the dopamine reward system in the rats’ brains. On October 27, Sapolsky gave an overview of his laboratory’s research on T. gondii at the 46th annual New Horizons in Science, a meeting organized by the Council for the Advancement of Science Writing and held at Stanford University.
Typically, humans become exposed to T. gondii by handling the feces of infected cats, eating meat from infected animals, or drinking contaminated water. In addition, pregnant women can pass it to the fetus, and severe eye or brain damage may result. The acute infection brings on mild symptoms, if any, in healthy people; however, the parasite forms cysts in the brain. The belief that T. gondii lies dormant in the chronic phase of infection is being questioned, and a recent meta-analysis found a higher prevalence of antibodies to T. gondii in individuals with schizophrenia than in control populations (see SRF related news story; also see Torrey et al., 2007), fueling suspicions that the parasite contributes to the risk of developing schizophrenia (see SRF forum discussion).
A wily parasite
Parasites know how to manipulate other organisms to get what they need, Sapolsky said. For instance, a type of barnacle that piggybacks on a male sand crab injects it with excess estrogen, prompting the crab to dig a hole that the barnacle can use for its own nest. It destroys the gonads of the female crab, preventing her from laying eggs, so that when she builds a nest, the barnacle can claim it as a cozy nook for its own eggs.
Since T. gondii can reproduce sexually only in the cat, it has learned how to get there. It enlists the help of rodents, which become infected by eating cat droppings. As previously reported by Ajai Vyas, Sapolsky, and others at Stanford University, the parasite turns rats’ innate, self-preserving dislike of the smell of cat urine into a fatal feline attraction (Vyas et al., 2007). When T. gondii-infected male rats smell "eau de cat," their testosterone levels rise and their testes swell, which Sapolsky said shows that the odor “is smelling sexually attractive to these males.” Drawn to the cat, the rat becomes cat food, and T. gondii adds another generation to its family tree.
Disputing the notion that the infected rats may have felt too sick to avoid predators, the study found that they gained as much weight as uninfected animals. Furthermore, infected rats did not show decreases in other kinds of fear-driven behaviors; like uninfected rats, they still avoided open spaces and novel food. They remained able to learn fear-motivated tasks. Judging from their reaction to other odors, their sense of smell worked fine, too. Rather, it seemed that T. gondii caused limited, specific effects on their brains.
Using bioluminescence imaging, the study found T. gondii cysts throughout the brains of infected animals, especially in the amygdala, which seems to serve as a switchboard for fear and other emotions (for more on the amygdala, see LeDoux, 2007). Further evidence suggested that the infection had shut down parts of the amygdala.
The amygdala may also be involved in reward-motivated behavior, and Sapolsky thinks that T. gondii has evolved to commandeer the dopamine reward pathway in rodents’ brains (see SRF related news story). He has found that the Toxoplasma genome contains mammalian versions of two genes for substances involved in dopamine production—namely, phenylalanine hydroxylase and tyrosine hydroxylase. In other words, “T. gondii knows how to make dopamine,” Sapolsky said. The relationship between dopamine and schizophrenia remains unclear at the etiologic level (see SRF current hypothesis by Anissa Abi-Dargham), but all currently approved antipsychotic drugs appear to work by blocking D2-type dopamine receptors.
Sapolsky noted that a few studies suggest that T. gondii changes behavior in humans as well as rats (for a review, see Flegr, 2007). For example, he cited a study in Turkey that found greater T. gondii exposure among drivers involved in traffic accidents than in control subjects (Yereli et al., 2006).
Via e-mail, Sapolsky told SRF that he sees “Toxo as having tremendous potential implications for psychiatry.” He cautioned that his work has not focused on schizophrenia, but rather on T. gondii’s possible ties to fear, anxiety, and phobias. On the other hand, recent hints of a link between the parasite and schizophrenia come from a 2006 study led by Joanne Webster of the University of Oxford (Webster et al., 2006). It found that the antipsychotic drug haloperidol worked as well as an anti-T. gondii drug combo at preventing the parasite from manipulating rats’ behavior. In other words, the dopamine blocker may help preserve rats’ healthy fear of cats.—Victoria L. Wilcox.