Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain

Abstract

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival, neurite outgrowth and synapse formation. Recent observations suggest that treatment with typical and atypical antipsychotic drugs affect NGF and BDNF levels in the rat brain. The atypical antipsychotic olanzapine has a low incidence of side effects, such as extrapyramidal and anticholinergic symptoms. Since NGF and BDNF are involved in the regulation of cholinergic, dopaminergic and serotonergic neurons in the central nervous system (CNS) we hypothesized that chronic olanzapine treatment will influence the distribution of NGF and BDNF in the rat brain. To test this hypothesis we administered olanzapine for 29 days in the drinking water at the doses of 3 and 15 mg/kg body weight and measured the levels of NGF and BDNF in the brain of Wistar rats. Olanzapine increased NGF in the hippocampus, occipital cortex and hypothalamus. In contrast, olanzapine decreased BDNF in the hippocampus and frontal cortex. Although the significance of these findings is not clear, a heuristic hypothesis is that olanzapine's clinical effects and a favorable side effect profile are in part mediated by neurotrophins.

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 (5HT_2A, 5HT_2C, 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.