Alcohol induced depressive-like behavior is associated with a reduction in hippocampal BDNF☆
Highlights
► WKY rats have a lower hippocampal BDNF compared to Wistar rats. ► Alcohol-induced depressive like behavior causes a decrease in hippocampal BDNF. ► Treatments with antidepressants normalize hippocampal BDNF.
Introduction
Epidemiological studies have consistently shown that alcoholism and depression commonly occur together (Regier et al., 1990, Grant and Harford, 1995, Sullivan et al., 2005). Depressed patients have higher rates of current and lifetime alcohol problems than the general population (Regier et al., 1990, Grant and Harford, 1995, Kessler et al., 1996, Sullivan et al., 2005) and similarly alcohol dependent individuals have a high prevalence for depression (Kessler et al., 1996).
Alcoholism and depression seem to share similar behavioral, neurochemical and pathophysiological changes. Prolonged exposure and withdrawal from alcohol has been shown to induce depression-like symptoms that disappear after period of abstinence (Davidson, 1995, Schuckit et al., 1997). A dysregulation in serotonergic system has been implicated in the development of depression (Hariri and Holmes, 2006, Davis, 2008) and subpopulations of alcoholic patients (Nevo and Hamon, 1995, Ressler and Nemeroff, 2000, Davis, 2008). Selective serotonin reuptake inhibitor (SSRI) treatments can help reduce depression and it has been suggested that understanding the modulation of the 5-HT system may lead to viable pharmacological therapies for alcoholism in a sub-set of patients (Nevo and Hamon, 1995, Johnson, 2004, Wrase et al., 2006, Davis, 2008). Disruptions in the hypothalamic–pituitary–adrenal (HPA) axis have also been implicated in both depression and alcoholism, dampening the ability to cope with stress in both populations (Nemeroff et al., 1984, Lovallo et al., 2000, O'Malley et al., 2002, Kiefer and Wiedemann, 2004, Adinoff et al., 2005, Nemeroff and Vale, 2005, Pariante and Lightman, 2008). Imaging studies reveal reductions in hippocampal volume and in the frontal lobes of both alcoholics and depressed patients (Coffey et al., 1993, Sullivan et al., 1995, Sheline et al., 1996, Agartz et al., 1999, Kril and Halliday, 1999, Bremner et al., 2000, Miguel-Hidalgo and Rajkowska, 2003, Gerritsen et al., 2011). However, the causal link between these two disorders is still unclear.
Brain derived neurotrophic factor (BDNF) is a molecule of interest thought to be involved in a number of psychiatric disorders such as depression, stress, anxiety, and drug addictions (Horger et al., 1999, Hall et al., 2003, Murakami et al., 2005, Pandey et al., 2006, Davis, 2008). BDNF, like most neurotrophins is responsible for neuronal survival, development and plasticity. It also acts as a modulator of some neurotransmitters and plays an important role in use-dependent plasticity such as long-term potentiation and learning and memory (Hyman et al., 1991, Thoenen, 1995, Li et al., 1998, Lyons et al., 1999, Hall et al., 2000, Huang and Reichardt, 2001, Guillin et al., 2001, Chao, 2003). BDNF supports survival of cholinergic (Alderson et al., 1990), nigral dopaminergic (Hyman et al., 1991) and serotonergic neurons (Altar, 1999, Madhav et al., 2001, Davis, 2008).
Human studies have shown significant reduction in peripheral levels of BDNF in several psychiatric disorders including major depression (Karege et al., 2002, Shimizu et al., 2003, Gonul et al., 2005, Karege et al., 2005, Aydemir et al., 2005, Aydemir et al., 2006, Cunha et al., 2006, Lee et al., 2007), suicidal depression (Kim et al., 2007) and alcohol dependent patients (Joe et al., 2007). Similar findings in central nervous system (CNS) of postmortem suicide patients have also been observed. Thus, significant decreases of BDNF protein (Dwivedi et al., 2003, Karege et al., 2005) and BDNF mRNA (Dwivedi et al., 2003) in the hippocampus and frontal cortex have been reported in this population. Finally, antidepressant treatments can increase peripheral and central BDNF levels (Chen et al., 2001, Shimizu et al., 2003, Aydemir et al., 2005, Gervasoni et al., 2005, Gonul et al., 2005, Bocchio-Chiavetto et al., 2006).
Experimental studies have shown that different stress paradigms (i.e. forced swim test, learned helplessness, restraint stress) that induce depressive-like symptoms in rodents can reduce BDNF protein and mRNA levels in the hippocampus and/or frontal cortex (Itoh et al., 2004, Russo-Neustadt et al., 2001, Murakami et al., 2005, Song et al., 2006, Takeda et al., 2006). In addition, hippocampal BDNF mRNA expression is suppressed after chronic ethanol (EtOH) exposure (MacLennan et al., 1995). In vitro, studies provide further evidence that chronic EtOH can reduce BDNF secretion, which suggests that BDNF might be linked to EtOH-induced cell damage (McGough et al., 2004, Sakai et al., 2005).
Wistar–Kyoto (WKY) rats are considered a putative animal model of depression. These animals exhibit a number of depressive-like symptoms such as psychomotor retardation, behavioral despair, abnormalities in monoamines and hyperactivity in the HPA axis reflected in high circulating corticosterone levels (Paré, 1992a, Paré, 1992b, Paré and Redei, 1993a, Paré and Redei, 1993b, Redei et al., 1994, Tejani-Butt et al., 1994, Paré and Kluczynski, 1997, De La Garza and Mahoney, 2004, Getachew et al., 2010). Moreover, WKY rats may also be considered a model for treatment resistant depression as they do not respond to selective serotonin reuptake inhibitors (SSRIs) (Tejani-Butt et al., 2003, Lopez-Rubalcava and Lucki, 2000, Griebel et al., 1999). However, these rats do respond to tricyclic antidepressants such as imipramine and nomifensine (Tejani-Butt et al., 2003, Paré et al., 2001, Paré et al., 1999, Getachew et al., 2008, Getachew et al., 2010). Interestingly, similar to what is seen in human population (Kessler et al., 1993, Kessler et al., 1996), higher prevalence of these behaviors is manifested in the female compared to male WKY rats (Paré and Redei, 1993a). However, the relationship between BDNF and the depressive-like characteristics observed in this animal model has not been explored.
Previous findings from our laboratory indicated that exposure to a relatively high ethanol level (150 mg%) via inhalation induced depressive like behavior in female Wistar rats and exacerbated that of WKY rats (Getachew et al., 2008, Getachew et al., 2010). In addition, treatment with the clinically effective antidepressants nomifensine a NE/DA uptake inhibitor and imipramine, a NE/5HT uptake inhibitor, reduced EtOH-induced changes in both strains (Getachew et al., 2010). In the current study we sought to test the hypotheses that: 1) there are baseline differences in BDNF levels in discrete brain regions (hippocampus, and frontal cortex) between female WKY and WIS rats, 2) chronic EtOH will reduce BDNF and 3) treatments with nomifensine or imipramine will normalize the BDNF levels.
Section snippets
Animals and drugs
Age matched adult female WKY and Wistar rats (Harlan, Indianapolis, IN) were used throughout the study. The animals were housed four per cage and kept on a 12:12 hour reversed light/dark cycle (lights on at 7:00 A.M.) in a temperature-controlled room (24–26 °C). The animals had ad libitum access to food and water. USP 200 proof ethyl alcohol (VWR Scientific Products, USA) was diluted down (95% ethanol v/v) with distilled water to be used in the vapor inhalation chamber. Nomifensine and imipramine
Results
Fig. 1 depicts the basal BDNF level and the effect of chronic alcohol in the hippocampus of WKY and Wistar (WIS) rats. A two-way ANOVA showed significant main effects for strain where WKY rats had significantly lower baseline BDNF levels (approx 19%) in the hippocampus [F (1, 28) = 12.65, p = 0.001] compared to WIS rats. There was significant main effect of treatment where EtOH resulted in significant reduction in BDNF levels in both WKY (approx 12%) and WIS (approx 29%) rats [F (1, 28) = 70.70, p =
Discussion
Understanding the neural mechanisms that may be involved in mediating the co-morbidity of depression and alcoholism is a crucial step in developing novel pharmacological treatments for this condition. Previously we had observed that chronic alcohol exposure via inhalation chambers induced depressive-like behavior in Wistar rats and exacerbated the existing depressive characteristic in WKY rats (Getachew et al., 2008, Getachew et al., 2010). In addition, treatments with nomifensine and
Acknowledgment
This study was supported by NIH/NIGMS (2SO6 GM08016-39) and NIAAA (P20 AA014643) and NIH-RCMI 2G12 RR003048.
References (111)
- et al.
Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy
Biol Psychiatry
(2008) - et al.
Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture
Neuron
(1990) - et al.
Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior
Biol Psychiatry
(2009) - et al.
The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study
Prog Neuropsychopharmacol Biol Psychiatry
(2005) - et al.
Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women
Prog Neuropsychopharmacol Biol Psychiatry
(2006) - et al.
Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments
Brain Res
(2008) - et al.
Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients
Eur Neuropsychopharmacol
(2006) - et al.
Fetal alcohol spectrum disorder-associated depression: evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model
Pharmacol Biochem Behav
(2008) - et al.
Nitric oxide signaling participates in norepinephrine-induced activity of neuronal intracellular survival pathways
Life Sci
(2007) - et al.
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication
Biol Psychiatry
(2001)
Norepinephrine induces BDNF and activates the PI-3K and MAPK cascades in embryonic hippocampal neurons
Cell Signal
Venlafaxine treatment stimulates expression of brain-derived neurotrophic factor protein in frontal cortex and inhibits long-term potentiation in hippocampus
Neuroscience
Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes
Neurosci Lett
Ethanol–BDNF interactions: still more questions than answers
Pharmacol Ther
A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression
Brain Res
The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity
Neuroscience
Depression, Hypothalamic Pituitary Adrenal Axis, and Hippocampal and Entorhinal Cortex Volumes—The SMART Medea Study
Biol Psychiatry
Desipramine blocks alcohol-induced anxiety- and depressive-like behaviors in two rat strains
Pharmacol Biochem Behav
Alcohol-induced depressive-like behavior is associated with cortical norepinephrine reduction
Pharmacol Biochem Behav
Comorbidity between DSM-IV alcohol use disorders and major depression: results of a national survey
Drug Alcohol Depend
Behavioral effects of acute and chronic fluoxetine in Wistar–Kyoto rats
Physiol Behav
Genetics of emotional regulation: the role of the serotonin transporter in neural function
Trends Cogn Sci
Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice
Brain Res
Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats
Eur J Pharmacol
Decreased serum brain-derived neurotrophic factor levels in major depressed patients
Psychiatry Res
Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity
Biol Psychiatry
Antidepressants suppress bulbectomy-induced augmentation of voluntary alcohol consumption in C57B1/6j but not in DBA/2j mice
Physiol Behav
Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence
J Affect Disord
Low plasma BDNF is associated with suicidal behavior in major depression
Prog Neuropsychopharmacol Biol Psychiatry
Brain shrinkage in alcoholics: a decade on and what have we learned?
Prog Neurobiol
Are Wistar–Kyoto rats a genetic animal model of depression resistant to antidepressants?
Eur J Pharmacol
Decreased plasma BDNF level in depressive patients
J Affect Disord
Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test
Neuropsychopharmacology
Serotonergic cells of the rat raphe nuclei express mRNA of tyrosine kinase B (trkB), the high-affinity receptor for brain derived neurotrophic factor (BDNF)
Brain Res Mol Brain Res
Comparison of prefrontal cell pathology between depression and alcohol dependence
J Psychiatr Res
Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly
Neurosci Res
Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism
Neurochem Int
The performance of WKY rats on three tests of emotional behavior
Physiol Behav
Differences in the stress response of Wistar–Kyoto (WKY) rats from different vendors
Physiol Behav
Sex differences and stress response of WKY rats
Physiol Behav
Depressive behavior and stress ulcer in Wistar Kyoto rats
J Physiol Paris
Negative affect and voluntary alcohol consumption in Wistar–Kyoto (WKY) and Sprague–Dawley rats
Physiol Behav
The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats
Prog Neuropsychopharmacol Biol Psychiatry
The HPA axis in major depression: classical theories and new developments
Trends Neurosci
Physical activity–antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model
Behav Brain Res
Depression and the hippocampus: cause or effect?
Biol Psychiatry
Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants
Biol Psychiatry
Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress
Pharmacol Biochem Behav
Dissection of hypothalamic–pituitary–adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: response to ovine corticotropin-releasing factor and naloxone
Alcohol Clin Exp Res
Hippocampal volume in patients with alcohol dependence
Arch Gen Psychiatry
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Supported by NIH/NIGMS (2SO6 GM08016-39) and NIAAA (P20 AA014643) and NIH-RCMI 2G12 RR003048.