VI.   Neurotransmitters and T. gondii

For more than 40 years, it has been known that neurotransmitters are involved in the pathogenesis of schizophrenia. An excess of dopamine has been widely suspected, and along with genetics, dopamine-excess has been one of the most thoroughly researched theories. Despite hundreds of research projects, however, relatively few abnormalities in the dopamine system have ever been identified in individuals with schizophrenia. In recent years, more research attention has been focused on other neurotransmitters, especially glutamate and GABA.

§    Origin of interest in dopamine and T. gondii

The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, Ph.D., 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 level by 34 percent in infected rats (Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432). 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 5 weeks (= chronic group). Ten control mice were also killed at 5 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 HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157, copyright1985, Maney Publishing, www.maney.co.uk/journals/atmp; linked to PDF file with permission).

§     Toxoplasma gondii has the ability to make dopamine

In 2009, Dr. Glenn McConkey and his colleagues at the University of Leeds in the UK demonstrated that T. gondii has the genes encoding two critical enzymes needed to make dopamine. It has the gene for phenylalananine hydroxylase, which changes phenylalanine to tyrosine, and also the gene for tyrosine hydroxylase, which changes tyrosine to dopa, the precursor of dopamine. These genes were not found in any other closely related parasites except Neospora. This finding suggests the possibility that the excess dopamine thought to occur in individuals with schizophrenia might be being introduced by T. gondii rather than made by the affected individuals (Gaskell EA, Smith JE, Pinney JW et al., A unique dual activity amino acid hydroxylase in Toxoplasma gondii, PLoS ONE 2009;4:e4801).

§     Effects of changing levels of dopamine on behavior induced by T. gondii infection

Joanne Webster (SMRI grantee) 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 JP, Lamberton PHL, Donnelly CA et al., 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 R Soc B 2006;273:1023–1030, copyright 2006, the Royal Society; linked to PDF file with permission).

Jaroslav Flegr (SMRI grantee) 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 A, Kodym P, Frynta D et al., The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an etiological and ethnopharmacological study, Parasitology 2006;133:525–535).

In other publications, Flegr et al. have speculated that dopamine is the “missing link between schizophrenia and toxoplamosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr J, Preiss M, Klose J et al., 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;63:253–268; Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757–760).

Current SMRI-funded research in this area

§    Robert Sapolsky et al., Stanford University. The effects of Toxoplasma gondii on dopaminergic brain systems.

§    Glenn McConkey and Joanne Webster, University of Leeds and Imperial College London. Role of L-DOPA synthesis by Toxoplasma gondii on host behavior.