Antidepressive and antipsychotic treatments : effects on nerve growth factor and brain-derived neurotrophic factor in rat brain

Recently it has been reported that depression and schizophrenia, the two major psychiatric disorders, are characterized by loss of neurons in specific brain regions. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). It has been also hypothesized that these molecules play a role in the pathophysiology of CNS disorders.

To test this hypothesis, we measured by ELISA NGF and BDNF in an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Hinders Resistant Line (FRL). Increased NGF and BDNF concentrations were found in frontal cortex of female and in occipital cortex of male of "depressed" FSL compared to FRL control rats. These observations suggest that NGF and BDNF might be relevant to some of the neurochemical changes in depression. Using the same model of depression, (FSL/FRL rats), we investigated effects of electroconvulsive stimuli (ECS), a model of antidepressant treatment, on brain NGF and BDNF. In the hippocampus ECS increased NGF concentration in FSL, but not FRL. ECS decreased NGF concentration in the frontal cortex of FSL rats. In both FSL and FRL rats ECS increased NGF levels in the striatum. The data obtained support the notion that ECS may alter NGF brain concentration. In contrast, ECS did not change BDNF concentration in hippocampus, frontal cortex and striatum of FSL and FRL rats. Previous studies have reported that BDNF mRNA increases after ECS in hippocampus of Sprague Dawley rats.

To further investigate the effect of ECT, we investigated if ECS alter the regional brain protein concentrations of NGF, BDNF and glial cell line-derived neurotrophic factor (GDNF), another trophic factor for dopaminergic neurons, in Sprague Dawley rats from which the two Flinders lines were originally bred. ECS increased the concentrations of NGF in the frontal cortex and concentrations of BDNF in hippocampus, striatum and occipital cortex. In contrast, ECS decreased GDNF concentrations in hippocampus and striatum.

ECS is used as a model of electroconvulsive therapy (ECT) which was originally introduced as a treatment for schizophrenia, and sometimes still used for that purpose. Since recent findings have raised the possibility that NGF and BDNF are also altered in the CNS of animal models of schizophrenia, we also investigated whether treatment with antipsychotic drugs (haloperidol, risperidone and olanzapine) affects the constitutive levels of NGF, BDNF, choline acetyltransferase (ChAT) immunoreactivities, and the receptor TrkB in the CNS. Haloperidol and risperidone elevated NGF concentrations in hypothalamus but decreased NGF in the striatum and hippocampus. They also decreased ChAT-immunoreactivity in large-size neurons in the septum as well as the Meynert's nucleus. Both haloperidol and risperidone decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and altered TrkB receptors in selected brain structures. Olanzapine increased NGF in the hippocampus, occipital cortex and hypothalamus but decreased NGF mRNA in hippocampus and occipital cortex. Olanzapine decreased BDNF in the hippocampus and increased BDNF mRNA in the hippocampus and hypothalamus. In the frontal cortex olanzapine decreased both BDNF and BDNF mRNA.

Our findings demonstrate that both typical and atypical antipsychotic drugs can alter the regional brain levels of NGF, BDNF, their mRNAs, and expression of ChAT and TrkB. Since NGF and BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of these neurotrophins could constitute part of the biochemical alterations induced by antipsychotic drugs. The neurotrophin hypothesis of schizophrenia proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity both in young and adult subjects, thus constituting a potential line of research for understanding the etiopathogenesis of schizophrenia and development of new methods for diagnosis and treatment.

List of scientific papers

I. Angelucci F, Aloe L, Vasquez PJ, Mathe AA (2000). Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression. Neuroreport. 11(6): 1369-73.
https://pubmed.ncbi.nlm.nih.gov/10817624

II. Angelucci F, Aloe L, Jimenez-Vasquez P, Mathe AA (2002). Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of rat model of depression. [Submitted]

III. Angelucci F, Aloe L, Jimenez-Vasquez P, Mathe AA (2002). Electroconvulsive stimuli alter the regional concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in adult rat brain. J ECT.

IV. Angelucci F, Aloe L, Gruber SH, Fiore M, Mathe AA (2000). Chronic antipsychotic treatment selectively alters nerve growth factor and neuropeptide Y immunoreactivity and the distribution of choline acetyl transferase in rat brain regions. Int J Neuropsychopharmacol. 3(1): 13-25.
https://pubmed.ncbi.nlm.nih.gov/11343574

V. Angelucci F, Mathe AA, Aloe L (2000). Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res. 60(6): 783-94.
https://pubmed.ncbi.nlm.nih.gov/10861791

VI. Angelucci F, Aloe L, Gruber SHM, Mathe AA (2002). Affect f chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor and the mRNAs in the rat brain. [Manuscript]