Toxoplasma gondii in rodents as a model for human schizophrenia
With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring, and the 21st century has seen a proliferation of studies and meta-analyses examining the potential associations between T. gondii infection and a wide variety of cognitive and neuropsychiatric disorders in humans. These include, for example, Alzheimer’s disease, bipolar disorder, epilepsy and obsessive-compulsive disorder (Torrey 2024). However, whilst the strength of evidence for some of these disorders is variable and/or questionable (Milne et al. 2020b), such studies and meta-analyses have repeatedly demonstrated consistent and continued support for a link between T. gondii and schizophrenia (see also Torrey 2024, Flegr 2025) this issue).
Indeed, the first studies describing potential associa- tions between latent T. gondii infection and human neuropsychiatric disorders, specifically that of schizophrenia, were published in the 1950s, even before the parasite life cycle was completely understood. Two beautiful publications that particularly sparked our interest here in terms of our own research avenues were: firstly the observation that T. gondii antibodies of schizophrenia patients treated with antipsychotic drugs were intermediate between those of patients never treated and those of control groups, with a significant further reduction in those patients undergo- ing current drug treatment, suggesting that antipsychotic treatment may affect T. gondii levels (Leweke et al. 2004); and secondly, that this theory was supported by the observation that many antipsychotic drugs commonly used in the treatment of schizophrenia were demonstrated to inhibit the replication of T. gondii tachyzoites in cell culture (Jones-Brando et al. 2003). One could therefore suspect that the antipsychotic and mood stabilising activity of some medications may be achieved, or at least augmented, through their inhibition of T. gondii replication and invasion in infected individuals.
Accordingly, this hypothesis was tested in vivo (Webster et al. 2006). In particular we predicted, again using our epidemiologically and clinically applicable ‘Fatal Feline Attraction’ protocol, that haloperidol, an antipsychotic used in the treatment of mental illnesses including schizophrenia and/or valproic acid, a mood stabiliser used in the treatment of mental illnesses including schizophrenia, both of which showed the strongest in vitro anti-tachyzoite properties (Jones-Brando et al. 2003), would be, at least, as effective in preventing the development of T. gondii -associated behavioural and cognitive alterations as the standard anti- T. gondii chemotherapeutics pyrimethamine with dapsone.
To again keep our studies as minimally stressful to our rats as possible, all drugs or placebo controls were given contained within fruit-flavoured jelly cubes (our rats liked blackcurrant flavour best of all), to which the rats had been previously habituated to eat daily. Accordingly we observed that, whilst T. gondii again appeared to alter the rats’ perception of predation risk turning their innate aversion into a ‘suicidal’ feline attraction, the anti-psychotic drugs indeed proved at least as efficient, actually more so, than anti- T. gondii drugs in preventing such behavioural alterations (Webster et al. 2006).
Publication Date: 2025-05-30