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 (10μM), 
clozapine (10 and 100μM) or alstonine (1-100μM), alone or in combination with 
apomorphine (100μM), and 5-HT(2) receptor antagonists (0.01μM altanserin and 
0.1μM 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 D(2) 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.