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.