Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain
Introduction
Disturbed neural development has been postulated to be a factor in the pathophysiology of schizophrenia. The neurotrophin hypothesis of schizophrenia proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity, thus being an important event in the pathogenesis of schizophrenic psychoses (Thome et al., 1998). The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in a variety of neuromodulatory processes in the brain, including neuronal survival, neurite outgrowth and synapse formation (Altar and DiStefano, 1998). Recent studies have raised the possibility that NGF and BDNF are abnormally regulated in the central nervous system (CNS) of animal models of schizophrenia (Aloe et al., 2000, Angelucci et al., 2004, Fiore et al., 2000, Lipska et al., 2001). Furthermore, studies of post-mortem tissues have shown that BDNF is reduced in the prefrontal cortex (Weickert et al., 2003) and elevated in the anterior cingulate cortex and hippocampus of schizophrenic patients (Iritani et al., 2003, Takahashi et al., 2000).
Findings that antipsychotic drugs can alter the brain levels of neurotrophins may also indicate that neurotrophins play a role in pathogenesis of schizophrenia. In previous studies we have demonstrated that the typical antipsychotic, haloperidol and the atypical, risperidone decreased NGF concentrations in the hippocampus and striatum (Angelucci et al., 2000a). These drugs also decreased choline acetyl tranferase (ChAT)-immunoreactivity in large-size neurons in the septum and Meynert's basal nucleus. Similarly, haloperidol and risperidone decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and altered TrkB receptor in hippocampal regions (Angelucci et al., 2000b). These observations suggest that neurotrophins may be implicated in the mechanisms regulating the action of antipsychotic drugs.
Clinical studies have shown that olanzapine reduces both positive and negative symptoms in schizophrenia, with a low incidence of side effects (e.g. extrapyramidal and anticholinergic symptoms, tardive dyskinesia, hyperprolactinemia) when given in therapeutically relevant dosages (Bymaster et al., 1996, Li et al., 1998). Moreover, it also improves cognitive symptoms, an important and sometimes neglected aspect of schizophrenia. Olanzapine, an atypical antipsychotic [atypicals are sometimes also called serotonin-dopamine antagonists (SDAs)], acts on multiple dopamine (D1, D2, D3 and D4) and serotonin receptors (5HT2A, 5HT2C, 5HT3 and 5HT6). Other neurotransmitter systems affected by olanzapine include the noradrenergic (α1 blockade), the cholinergic (muscarinic blockade) and the histamine systems (Bymaster et al., 1999).
Since NGF and BDNF are involved in the regulation of cholinergic, dopaminergic and serotonergic neurons, we posed the question whether chronic olanzapine treatment influences the synthesis and release of brain NGF and BDNF. To test this assumption we investigated the effect of chronic olanzapine (given in the drinking water) on the concentration of NGF and BDNF in selected rat brain regions.
Section snippets
Animals
39 Wistar rats, weighing 200 g at the beginning of the experiment, were used (B and K Lab, Sollentuna, Sweden). Animals were housed four per cage in Plexiglas boxes under standard conditions of humidity, with white light on from 7.00 a.m. to 7.00 p.m. Standard pellet food and water were available ad libitum. All the experiments were conducted in accordance with the Karolinska Institute's Guidelines for the Care and Use of Laboratory Animals and approved by the Stockholm's Ethical Committee for
Olanzapine administration and plasma levels
Rats were weighted every second day. The concentration of olanzapine in the drinking water was calculated according to the weight of the animals and the amount of solution consumed by each animal. Thus, the amounts of olanzapine given to the animals were between 0.6 and 0.9 mg/ day for the dosage corresponding to 3 mg/kg and between 3 and 4.5 mg/day for the dosage corresponding to 15 mg/kg. Olanzapine plasma levels are showed in Table 1.
Effect of olanzapine on brain NGF concentrations
Both doses of olanzapine increased NGF concentration in
Discussion
The present study indicates that chronic treatment with olanzapine, an antipsychotic agent with D2/D3, 5-HT2a and muscarinic receptors antagonism (Bymaster et al., 1999), alters NGF and BDNF concentrations in the rat brain.
Specifically, olanzapine increased the concentration of NGF in the hippocampus and occipital cortex. One possibility is that NGF accumulates in these brain regions since the release in the NGF-target regions (septum and Meynert basal nucleus) localized in basal forebrain
Acknowledgements
This study has been supported by the Swedish Medical Research Council grant 10414, Medicinsk Promotion SE AB, and the Karolinska Institutet. This work was also supported by the Italian National Research Council (CNR, fellowship bando no. 203.04.21).
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