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Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

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.

Human implications
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.

 
Comments on News and Primary Papers
Comment by:  Fuller TorreyRobert Yolken
Submitted 2 December 2008 Posted 2 December 2008

The research being carried out by Dr. Sapolsky and colleagues at Stanford is potentially very important for understanding schizophrenia. (In regard to full disclosure, it should be noted that the Stanley Medical Research Institute (SMRI) is funding Dr. Sapolsky’s research as well as other research on dopamine and Toxoplasma gondii.)

The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine levels by 34 percent in infected rats (Stibbs, 1984). He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were...  Read more


View all comments by Fuller Torrey
View all comments by Robert Yolken

Comment by:  Tamas Treuer
Submitted 9 December 2008 Posted 9 December 2008

Congratulations to Profs. Sapolsky, Torrey, and Yolken for their important contribution to this field. The question for me is rather an evolutionary one: is there any trace in the neuron-immuno-endocrine system of patients with schizophrenia that can reflect the adaptation to this hijacking attempt of this protozoon? Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia (Torrey and Yolken, 2007). Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the...  Read more


View all comments by Tamas Treuer

Comment by:  Jaroslav Flegr
Submitted 9 December 2008 Posted 9 December 2008

The results of the research performed by Dr. Sapolsky and colleagues at Stanford, elaborating the results obtained by Drs. Berdoy and Webster at Oxford (Berdoy et al., 2000), are really fascinating. It should not be forgotten, however, that dopamine is not the only suspected molecule. There are several indirect and recently even direct indications for changed levels of testosterone in subjects with latent toxoplasmosis (Flegr et al., 2008). Moreover, the increased levels of dopamine in Toxoplasma infected mice and men seem to be byproducts of local brain inflammations, rather than a product of biologically important manipulation of the host behavior by the parasite. The results from human cytomegalovirus, i.e., the parasite transmitted by direct contact, not by predation, suggest that an infection of brain tissue by various parasites could increase the level of brain dopamine (Skallová et al., 2005). From the point of view of...  Read more


View all comments by Jaroslav Flegr

Comment by:  Huan Ngo
Submitted 16 December 2008 Posted 16 December 2008

Drs. Sapolsky's and Vyas's recent body of data have provided significant mechanistic insights into the parasite manipulation hypothesis, the dopamine hypothesis of schizophrenia and the gene-environment etiological paradigm.

Since most of the human epidemiological data currently emphasizes Toxoplasma exposure from the prenatal period, do we know whether maternal infection results in dopamine alteration in the prenatal, neonatal or postnatal amydala? Is the effect caused directly by transplacental migration of the parasite to the prenatal amydala, or indirectly by maternal cytokine effects, such as IL6 or IL8, on the embryonic brain?

View all comments by Huan Ngo


Comment by:  Artyom Tikhomirov
Submitted 18 December 2008 Posted 22 December 2008

It seems like both bacteria and protozoa have been shown to either increase or decrease certain defensin levels in humans (Sperandio et al., 2008; Wiesenfeld et al., 2002). Then there's a single report from Sabine Bahn's group of increased α-defensins in schizophrenia (Craddock et al., 2008). It is interesting to speculate whether Toxoplasma gondii might contribute to the change in defensin levels.

References:

Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med. 2008 May 12;205(5):1121-32. Abstract

Craddock RM, Huang JT, Jackson E, Harris N, Torrey EF, Herberth M, Bahn S. Increased alpha-defensins as a blood marker for schizophrenia susceptibility. Mol Cell Proteomics. 2008 Jul 1;7(7):1204-13. Abstract

Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL, Amortegui AA, Nicolazzo M, Sweet RL. Association between elevated neutrophil defensin levels and endometritis. J Infect Dis. 2002 Sep 15;186(6):792-7. Abstract

View all comments by Artyom Tikhomirov

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