Toxoplasma gondii infects approximately 30% of the world’s population, but causes overt clinical symptoms in only a small proportion of people. In recent years, the ability of the parasite to manipulate the behaviour of infected mice and rats and alter personality attributes of humans has been reported. Furthermore, a number of studies have now suggested T. gondii infection as a risk factor for the development of schizophrenia and depression in humans. As T. gondii forms cysts that are located in various anatomical sites including the brain during a chronic infection, it is well placed anatomically to mediate these effects directly. The T. gondii genome is known to contain 2 aromatic amino acid hydroxylases that potentially could directly affect dopamine and/or serotonin biosynthesis. However, stimulation of the immune response has also recently been associated with mood and behavioural alterations in humans, and compounds designed to alter mood, such as fluoxetine, have been demonstrated to alter aspects of immune function. Herein, the evidence for T.-gondii-induced behavioural changes relevant to schizophrenia and depression is reviewed. Potential mechanisms responsible for these changes in behaviour including the role of tryptophan metabolism and the hypothalamic-pituitary-adrenal axis are discussed.

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The cannabinoid CB 1 receptor-mediated modulation of g-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A 1 receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A 1 receptors localized in GABAergic cells do not directly influence GABA release. CB 1 and A 1 receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: D 9 -tetrahydrocannabinol (THC, a CB 1 receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A 1 -CB 1 interaction influences GABA and glutamate release in the hippocampus. We found that A 1 receptor activation attenuated the CB 1 -mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, 412 h before trials) led to an A 1 -mediated enhancement of the CB 1 -dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB 1 receptor number and an attenuation of CB 1 coupling with G protein. A 1 receptor levels were increased following chronic caffeine administration. This study shows that A 1 receptors exert a negative modulatory effect on CB 1 -mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory.

Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive function, the processes contributing to the observed cognitive deficits are unclear, as are the causal relationships between these impairments and marijuana exposure. In particular, marijuana-related deficits in cognitive flexibility may affect the social functioning of the individual and may contribute to continued marijuana use. We therefore examined the ability of rats to perform affective and attentional shifts following acute administration of D 9 -tetrahydrocannabinol (THC), the primary psychoactive marijuana constituent. Administration of 1 mg/kg THC produced marked impairments in the ability to reverse previously relevant associations between stimulus features and reward presentation, while the ability to transfer attentional set between dimensional stimulus properties was unaffected. Concurrent in situ hybridization analysis of regional c-fos and ngfi-b expression highlighted areas of the prefrontal cortex and striatum that were recruited in response to both THC administration and task performance. Furthermore, the alterations in mRNA expression in the orbitofrontal cortex and striatum were associated with the ability to perform the reversal discriminations. These findings suggest that marijuana use may produce inelasticity in updating affective associations between stimuli and reinforcement value, and that this effect may arise through dysregulation of orbitofrontal and striatal circuitry.