Alcohol induced depressive-like behavior is associated with a reduction in hippocampal BDNF

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Abstract

Strong positive correlation between depression and alcoholism is evident in epidemiological reports. However, a causal relationship for this co-morbidity has not been established. We have observed that chronic daily exposure to a relatively high dose of alcohol can induce depressive-like behavior in rats and that pretreatment with nomifensine or imipramine can block the “depressogenic” effects of alcohol. Since brain derived neurotrophic factor (BDNF) is considered to play an important role in depressive-like behaviors and its elevation, particularly in the hippocampus, appears to be critical for the action of many antidepressants, we hypothesized that: 1. WKY rats, a putative animal model of depression, will show a lower hippocampal BDNF compared to their control Wistar rats, 2. Alcohol-induced depressive like behavior will be associated with a significant decrease in hippocampal BDNF and 3. Treatments with antidepressants will normalize hippocampal BDNF. These postulates were verified by measuring hippocampal BDNF in Wistar and WKY rats at baseline, following chronic (10 day) treatment with alcohol and combination of alcohol with nomifensine or imipramine. Alcohol was administered via inhalation chamber (3 h/day) such that a blood alcohol level of approximately 150 mg% was achieved. Nomifensine (10 mg/kg) or imipramine (10 mg/kg) was administered i.p. daily immediately after alcohol exposure. BDNF was measured by standard ELISA kit. The results support a role for central BDNF in depressogenic effects of alcohol and antidepressant effects of nomifensine and imipramine. Moreover, depression per se as manifested in WKY rats may be 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.

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    Supported by NIH/NIGMS (2SO6 GM08016-39) and NIAAA (P20 AA014643) and NIH-RCMI 2G12 RR003048.

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