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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.

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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 infected, treated with sulfadiazine, did not develop symptoms, and were killed at five weeks (= chronic group). Ten control mice were also killed at five weeks. The brains were assessed neurochemically and compared to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine was 28 percent decreased in acute but not in chronic infection. Homovanillic acid (HVA) was 40 percent increased in acute but not chronic infection. Dopamine was normal in acute infection but 14 percent increased in the treated mice with chronic infection. Stibbs concluded that T. gondii causes abnormalities in catecholamine metabolism and that these “may be factors contributing to the psychological and motor changes” seen in experimentally infected rodents (Stibbs, 1985).

Joanne Webster and her colleagues at Oxford infected rats with T. gondii, then treated them with haloperidol, an antipsychotic known to block dopamine. The effect of the haloperidol was to reverse the behavioral effects of T. gondii. They speculated that possible explanatory mechanisms include the ability of haloperidol “to inhibit T. gondii replication and to reduce, directly and indirectly, dopamine levels” (Webster et al., 2006).

Jaroslav Flegr and his colleagues in Prague have studied the effects of T. gondii infection on the behavior of mice. They reported that giving the mice a dopamine reuptake inhibitor (GBR 12909) altered the behavior of the mice and concluded that “the proximal causes of alterations in mice behavior induced by Toxoplasma gondii are probably changes in the dopaminergic system” (Skallová et al., 2006). In other publications, Flegr and colleagues have speculated that dopamine is the “missing link between schizophrenia and toxoplasmosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr et al., 2003; Flegr, 2007).

The intriguing thing about this research is its possible relevance to schizophrenia. For more than 40 years, it has been clear that an excess of dopamine is somehow involved in the pathogenesis of schizophrenia. Despite hundreds of studies, however, relatively few abnormalities have been identified in the dopamine production of individuals with schizophrenia. If T. gondii is part of the disease’s etiology, the excess dopamine may be being introduced exogenously by the parasite. If true, this would introduce a whole new approach to treatment.

An important aspect of this body of work is that it provides an evolutionary basis for why an infectious agent might lead to altered behavior. In terms of Toxoplasma, this association is based on the organism’s life cycle. The primary host for Toxoplasma is the cat. Toxoplasma organisms can complete their replication cycle, including their sexual stage, within members of the feline species. If other animals become infected, the organisms can undergo some replication but cannot complete the sexual stage. The Toxoplasma organism must thus do something in order to get back into the cat if it is to complete its life cycle. Since the organism cannot get around on its own, it has to alter the behavior of its host if it is to accomplish this vital evolutionary goal. Dr. Sapolsky and others have documented the behavioral alterations associated with Toxoplasma infection. If the host is a rodent, the end result of these alterations is that the rodent gets eaten and the Toxoplasma is quite happy (even if the rodent is obviously not). This may also have been the case for prehistoric humans, who were also the frequent prey of large cats. While getting eaten by cats is not a problem for most modern humans, the Toxoplasma organism does not know this and still attempts to alter the behavior of its host. The vestigial effect of Toxoplasma infection may thus result in the altered behaviors that are the hallmark of schizophrenia, bipolar disorder, and other psychiatric disorders.

A summary of current research on T. gondii and schizophrenia can be found on the SMRI website (Laboratory of Developmental Neurovirology, Toxoplasmosis–Schizophrenia Research).

References:

Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432. Abstract

Stibbs HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157. Abstract

Webster JP, Lamberton PH, Donnelly CA, Torrey EF. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour. Proc Biol Sci. 2006 Apr 22;273(1589):1023-30. Abstract

Skallová A, Kodym P, Frynta D, Flegr J. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. Parasitology. 2006 Nov 1;133(Pt 5):525-35. Abstract

Flegr J, Preiss M, Klose J, Havlícek J, Vitáková M, Kodym P. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol. 2003 Jul 1;63(3):253-68. Abstract

Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757-760. Abstract

View all comments by Fuller Torrey
View all comments by Robert YolkenComment 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 product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance.

Although it would be important to established treatment trials, specifically by demonstrating that medications suppressing T. gondii infections improve the clinical symptoms of schizophrenia, it is not clear whether this would be a direct link. This experiment would be similar to the observations made in children affected by the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) syndrome. The term is used to describe children who are believed to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as the Tourette syndrome following a group-Aβ-hemolytic streptococcal infection. However, studies with PANDAS children have shown that antibiotic treatment is not consistently effective in reducing the infection rate or the severity of obsessive-compulsive and/or tic symptoms in these children. Once the damage has occurred, corrective treatment against the infective agent is not always beneficial.

Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. Neuroendocrine changes in the brain and body of people with schizophrenia are probably ancient traces of survival strategy on these individuals. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. I believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia and related disorders (Treuer and Karagianis, 2006; Treuer et al., 2007; Treuer et al., 2008).

References:

Torrey Ef, Yolken RH. Schizophrenia and Toxoplasmosis. Schizophrenia Bulletin. 2007;33:727-728. Abstract

Treuer T, Martenyi F, Karagianis J: Parasitosis, Dopaminergic Modulation and Metabolic Disturbances in Schizophrenia: Evolution of a Hypothesis. NeuroEndocrinology Letters. 2007 Oct;28(5):535-40. Abstract

Treuer T, Karagianis J: Is Hunger a Driver of Cognitive Development? Neuropsychopharmacology. Oct 2006;(31)10:2326-2327. Abstract

Treuer T, Karagianis J, Hoffmann VP: Can Increased Food Intake Improve Psychosis? A Brief Review and Hypothesis. Current Molecular Pharmacology. 2008 November;1(3):270-272.

Treuer T: The Potential Role of Ghrelin in the Mechanism of Sleep Deprivation Therapy for Depression. Sleep Medicine Reviews. 2007 Dec;11(6):523-4.

View all comments by Tamas TreuerComment 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 schizophrenia research or even clinical practice, the question of whether the increased level of dopamine is a product of manipulation or a byproduct of brain infection, is, of course, not so important.

Recently, results of several large independent studies suggest that RHD positive subjects, especially heterozygotes, are protected against latent toxoplasmosis-induced impairment of reaction times (Novotná et al., 2008; Flegr et al., 2008). The RhD protein, which is the RHD gene product and a major component of the Rh blood group system, carries the strongest blood group immunogen, the D-antigen. The structure homology data suggest that the RhD protein acts as an ion pump of uncertain specificity and unknown physiological role. The protein is present mainly on the surface of erythrocytes; however, expression library data suggest that the RHD gene is expressed also in brain tissue. It seems to me that possible association between RhD phenotype and schizophrenia should be studied in the future.

References:

Berdoy M, Webster JP, Macdonald DW. Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci. 2000 Aug 7;267(1452):1591-4. Abstract

Flegr J, Lindová J, Kodym P. Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology. 2008 Apr 1;135(4):427-31. Abstract

Skallová A, Novotná M, Kolbeková P, Gasová Z, Veselý V, Sechovská M, Flegr J. Decreased level of novelty seeking in blood donors infected with Toxoplasma. Neuro Endocrinol Lett. 2005 Oct 1;26(5):480-6. Abstract

Novotná M, Havlícek J, Smith AP, Kolbeková P, Skallová A, Klose J, Gasová Z, Písacka M, Sechovská M, Flegr J. Toxoplasma and reaction time: role of toxoplasmosis in the origin, preservation and geographical distribution of Rh blood group polymorphism. Parasitology. 2008 Sep 1;135(11):1253-61. Abstract

Flegr J, Novotná M, Lindová J, Havlícek J. Neurophysiological effect of the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced impairment of reaction times in women. Neuro Endocrinol Lett. 2008 Aug 1;29(4):475-81. Abstract

View all comments by Jaroslav FlegrComment 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 NgoComment 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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