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, copyright
1985, 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).
Additional studies on the
effect of T. gondii on neurotransmitters being carried out in our
laboratory have shown a differential effect of different strains on
neurotransmitter-related gene expression (Xiao J, not yet published).
Toxoplasma infection also has effects on the expression of a number of other
genes in neural cell cultures and in experimentally infected mice.
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.