Research ReportDifferential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments
Introduction
Neurotrophic factors play roles in both the developing and adult central nervous system. Brain-derived neurotrophic factor (BDNF) belongs to the family of related proteins called neurotrophins. BDNF is well known for its involvement in the survival and guidance of neurons during development (Segal, 2003). It is essential to the function and survival of neurons in the adult brain (McAllister et al., 1999, Thoenen, 1995). BDNF is involved in synapse formation and has profound effects on the growth, remodeling, and stability of dendrites and axons in hippocampal and cortical neurons (Elmariah et al., 2005). BDNF also regulates adult hippocampal neurogenesis (Lee et al., 2002, Sairanen et al., 2005, Scharfman et al., 2005). The key role BDNF plays in long-term potentiation (LTP) (Figurov et al., 1996, Korte et al., 1995) and its ability to affect sprouting of serotonergic neurons after injury (Mamounas et al., 1995) further demonstrates its influence on neuronal plasticity.
The neurotrophic hypothesis of depression postulates the etiology of this disease and the action of antidepressants is due, in part, to the regulation of central neurotrophin signaling, notably BDNF (Duman and Monteggia, 2006). Stress is known to precipitate or exacerbate depression in susceptible individuals (Gold and Chrousos, 2002). Moreover, depressed patients show atrophy in several brain regions, including the hippocampus, frontal cortex, and amygdala (McEwen, 2001). These anatomical changes caused by stress are paralleled by reductions in BDNF expression (Duman and Monteggia, 2006). On the other hand, chronic administration of antidepressant treatments from different classes have been reported to commonly increase the expression of BDNF mRNA in the hippocampus (Coppell et al., 2003, Dias et al., 2003, Fujimaki et al., 2000, Molteni et al., 2005, Nibuya et al., 1995, Nibuya et al., 1996). Changes in BDNF expression emerging from chronic antidepressant treatment parallel the time course of clinical response to these drugs. This could indicate that antidepressants regulate BDNF to oppose the effects of chronic stress and may be critical for therapeutic recovery.
The neurotrophic hypothesis, however, has not been supported by other studies that failed to show increases in hippocampal BDNF mRNA expression after chronic treatment with a TCA (Coppell et al., 2003) or SSRI (Altieri et al., 2004, Dias et al., 2003, Jacobsen and Mork, 2004). Moreover, few studies have measured BDNF protein levels following chronic antidepressant treatments. Chronic ECS increased BDNF protein in the hippocampus and frontal cortex (Altar et al., 2003, Jacobsen and Mork, 2004) and chronic treatment with the MAOI tranylcypramine increased protein in the frontal cortex but not the hippocampus (Altar et al., 2003).
The purpose of the following studies was to systematically measure the effects of acute and chronic treatment with pharmacologically distinct antidepressant drugs on BDNF protein levels in various brain regions associated with depression. The SSRI fluoxetine, the TCA desipramine, and the MAOI phenelzine were examined. In addition, these studies examined effects of acute and repeated administration of electroconvulsive shock, a somatic treatment for depression. Moreover, the abilities of drugs used in the treatment of other psychiatric disorders, antipsychotics and the anxiolytic chlordiazepoxide, to alter levels of BDNF protein were also examined. Doses and treatment durations were selected based on studies that had examined the effects of these classes of drugs on BDNF mRNA or on behavioral measures.
Section snippets
Baseline levels of BDNF
Levels of BDNF measured in different brain regions are given in Table 1. BDNF levels varied significantly across regions. The highest levels of BDNF were obtained in the hippocampus, when compared with the brainstem, frontal cortex, amygdala and olfactory bulb. The brainstem contained significantly more BDNF protein than the olfactory bulb, amygdala, and frontal cortex. There was no significant difference in BDNF levels between the other brain regions.
Effects of electroconvulsive shock (ECS) on BDNF protein levels
The effects of ECS on BDNF levels were
Discussion
Although a number of studies have been published concerning the effects of psychotropic drugs on BDNF, most of them have been limited in scope, examining a single drug class or brain region. This study compared the effects of acute and chronic administration of antidepressants with treatment by antipsychotic and anxiolytic drugs. BDNF protein levels were compared between five different brain regions. The results of this study demonstrated that chronic treatment with pharmacologically diverse
Animals
Male Sprague–Dawley rats (Charles River, Wilmington, MA, USA) weighing 250–275 g at the beginning of antidepressant treatments were used in these studies. The animals were housed in pairs in polycarbonate cages and maintained on a 12-h light/dark cycle (lights on at 07:00 A.M.) in a temperature (22 °C)- and humidity-controlled colony at the University of Pennsylvania. The animals were given free access to food and water. Animal procedures were conducted in accordance with the guidelines
Acknowledgments
The study was funded by NIH grant MH72832 for a National Center for Drug Discovery Group in Mood Disorders established between the University of Pennsylvania and Wyeth Research. We thank other principal members of the Group, Dr. Robert Ring at Wyeth Research and Dr. Julie Blendy at the University of Pennsylvania, for their generous advice.
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