Effects of the putative antipsychotic alstonine on glutamate uptake in acute hippocampal slices

A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake. Additionally, the effects on glutathione content and extracellular S100B levels were assessed. Acute hippocampal slices were incubated with haloperidol (10 μM), clozapine (10 and 100 μM) or alstonine (1–100 μM), alone or in combination with apomorphine (100 μM), and 5-HT₂ receptor antagonists (0.01 μM altanserin and 0.1 μM SB 242084). A reduction in glutamate uptake was observed with alstonine and clozapine, but not haloperidol. Apomorphine abolished the effect of clozapine, whereas 5-HT_2A and 5-HT_2C antagonists abolished the effects of alstonine. Increased levels of glutathione were observed only with alstonine, also the only compound that failed to decrease the release of S100B. This study shows that alstonine decreases glutamate uptake, which may be beneficial to the glutamatergic deficit observed in schizophrenia. Noteworthily, the decrease in glutamate uptake is compatible with the reversal of MK-801-induced social interaction and working memory deficits. An additional potential benefit of alstonine as an antipsychotic is its ability to increase glutathione, a key cellular antioxidant reported to be decreased in the brain of patients with schizophrenia. Adding to the characterization of the novel mechanism of action of alstonine, the lack of effect of apomorphine in alstonine-induced changes in glutamate uptake reinforces that D₂ receptors are not primarily implicated. Though clearly mediated by 5-HT_2A and 5-HT_2C serotonin receptors, the precise mechanisms that result in the effects of alstonine on glutamate uptake warrant elucidation.