The search of targets for developing novel drugs that can control seizures resistant to available treatments in children and adults represents a great challenge for basic science. In the past decade, emerging evidence pointed out to the crucial role played by glia, the innate immunity brain-resident cells, in the generation of hyperexcitable neuronal networks underlying seizures. Molecular and pharmacological studies targeting glia, and the inflammatory mediators released by these cells in experimental models of epilepsy, highlighted novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative disease-modifying treatments. This article will focus on the role of immunity activation in the brain and the concomitant release by glia of inflammatory molecules with neuromodulatory properties, in the pathogenesis of epileptic seizures, cell loss, and comorbidities.
Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2 À/À mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2 À/À mice while the release of dopamine (DA)was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2 À/À mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2 À/À mice. These findings indicate that amphetamineinduced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2 À/À mice may be a useful preclinical model to assess the role of 5-HTdependent mechanisms in the action of psychostimulants.
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