Ketamine Induced Release of Bdnf

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Acute administration of ketamine induces antidepressant-like effects in the

forced swimming test and increases BDNF levels in the rat hippocampus

Lda S.B. Garcia a, Clarissa M. Comim a, Samira S. Valvassori a, Gislaine Z. Rus a,Luciana M. Barbosa a, Ana Cristina Andreazza b, Laura Stertz b, Gabriel R. Fries b,

Elaine Cristina Gavioli a, Flavio Kapczinski b, Joo Quevedo a,

aLaboratrio de Neurocincias, Programa de Ps-Graduao em Cincias da Sade, Unidade Acadmica de Cincias da Sade,

Universidade do Extremo Sul Catarinense, 88806-000 Cricima, SC, Brazilb Departamento de Bioqumica, Instituto de Cincias Bsicas da Sade, Universidade Federal do Rio Grande do Sul, Bipolar Disorders Program,

Centro de Pesquisas, Hospital de Clnicas. Rua Ramiro Barcelos, 2350, 90035-003 Porto Alegre, RS, Brazil

Received 24 May 2007; received in revised form 31 July 2007; accepted 31 July 2007

Available online 8 August 2007

Abstract

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-D-aspartate (NMDA) receptor. Clinical findings point to a

rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to

exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of

acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine

(10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein

hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of

10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity.Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat

hippocampus. In conclusion, our findings suggest that the increase of hippocampal BDNF protein levels induced by ketamine might be necessary

to produce a rapid onset of antidepressant action.

2007 Elsevier Inc. All rights reserved.

Keywords: Antidepressants; BDNF; Forced swimming test; Imipramine; Ketamine; NMDA receptor

1. Introduction

Depression is one of the most prevalent and costly psy-chopathologies and a leading cause of morbidity and mortality in

the world. It is worthy of note that the pharmacotherapy of

depression is costly and widely prescribed by physicians, although

less than half of treated patients attain complete remission after

therapy with a single antidepressant. Others exhibit partial,

refractory or intolerant responses to the pharmacological treat-

ment, emphasizing the need to discover novel antidepressants

(Pacher et al., 2001). The challenges for the design of new agentsto treat depression are threefold: rapid onset of antidepressant

response, broader efficacy, and fewer adverse effects. While

progress has been made to reduce side-effects, currently available

antidepressants do not show convincing evidence for a shorter

delay of onset of therapeutic actions neither for improved efficacy

on the treatment of major depression (Nutt, 2002). Thus, there is

clearly a need to develop rapidly acting and potent treatments for

major depression.

Glutamate is the primary excitatory neurotransmitter in the

mammalian brain. Glutamatergic neurotransmission may be mo-

dulated in the brain by different receptor types, including

Available online at www.sciencedirect.com

Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 140144www.elsevier.com/locate/pnpbp

Abbreviations: BDNF, brain-derived-neurotrophic factor; IP, intraperitoneal;

EGTA, ethylene glycol tetraacetic acid; IMI, imipramine; KET, ketamine;

NMDA, N-methyl-D-aspartate; OD, optical density; PMSF, phenylmethylsulfo-

nyl fluoride; PBS, phosphate buffer solution. Corresponding author. Fax: +55 48 3443 4817.

E-mail address: [email protected] (J. Quevedo).

0278-5846/$ - see front matter 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.pnpbp.2007.07.027
mailto:[email protected]://dx.doi.org/10.1016/j.pnpbp.2007.07.027http://dx.doi.org/10.1016/j.pnpbp.2007.07.027mailto:[email protected]


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ionotropic and metabotropic receptors. Studieshave pointed to the

ionotropic glutamate N-methyl-D-aspartate receptor (NMDA) as

an important player in the etiology of psychopathologies, such as

anxiety and major depression (Javitt, 2004; Krystal et al., 1999).

Several preclinical studies have demonstrated that NMDA

antagonists, such as MK-801, AP7, CPP, neramexane and others,

display anxiolytic- and antidepressant-like effects in rats injectedinto distinct brain areas and subjected to various animal models of

anxiety and depression (Kos et al., 2006a; Molchanov and

Guimares, 2002; Menard and Treit, 2000; Adamec et al., 1999;

Matheus and Guimares, 1997; Przegalinski et al.,1997; Skolnick

et al., 1996; Maj et al., 1992; Trullas and Skolnick, 1990).

Ketamine is a non-competitive antagonist to the phencyclidine

site ofN-methyl-D-aspartate (NMDA) receptor for glutamate, but

it also interacts with voltage sensitive Ca+2 channels, and opioid,

monoaminergic, and muscarinic receptors (for a review see: Hirota

and Lambert, 1996). Recently, clinical studies suggested that acute

administration of ketamine ameliorate depressive symptoms in

patients suffering from major depression (Zarate et al., 2006;Berman et al., 2000). In agreement with these clinical findings,

some evidence from the literature suggests that ketamine induces

anxiolytic- and antidepressant-like effects in rodents subjected to

animal models of anxiety and depression (Kos et al., 2006b;

Yilmaz et al., 2002; Chaturvedi et al., 2001; Silvestre et al., 1997).

Brain-derived-neurotrophic factor (BDNF) is one of several

endogenous proteins that play critical roles in the survival,

maintenance, and growth of the brain and peripheral neurons

(Lewin and Barde, 1997). A growing body of evidence suggests

that BDNF could be mediating the pathophysiology of mood

disorders. In fact, reduced brain BDNF levels have been found in

postmortem samples from depressed patients (Karege et al.,

2002), whereas brain infusion of BDNF produces antidepressant-like action in rats (Siuciak et al., 1997). In addition, exposure to

stress decreases levels of BDNF in brain regions associated with

depression, while antidepressant treatment produces opposite

actions and blocks the effects of stress on BDNF (for a review see:

Duman and Monteggia, 2006). Interestingly, chronic, but not

acute, antidepressant treatment induces increasing of BDNF

expression and BDNF immunoreactive fibers in the hippocampus

of rodents (Nibuya et al., 1996; De Foubert et al., 2004). Thus,

agents capable of rapidly enhancing BDNF levels may lead aid

the development of innovative antidepressant drugs.

The main aim of the present study was to compare behavioral

and molecular effects induced by acute administration of ketamineand imipramine in rats. The behavioral effects of both drugs were

evaluated in the forced swimming test, which is a behavioral

despair assay widely used for screening antidepressant drugs

(McArthur and Borsini, 2006). The BDNF protein levels were

measured using an ELISA kit in the hippocampus of rats acutely

treated with ketamine and imipramine.

2. Materials and methods

2.1. Animals

Male Adult Wistar rats (60 days old) were obtained from

UNESC (Universidade do Extremo Sul Catarinense, Cricima,

Brazil) breeding colony. They were housed five per cage with

food and water available ad libitum and were maintained on a

12-h light/dark cycle (lights on at 7:00 AM). All experimental

procedures involving animals were performed in accordance

with the NIH Guide for the Care and Use of Laboratory Animals

and the Brazilian Society for Neuroscience and Behavior

(SBNeC) recommendations for animal care.

2.2. Drugs and treatments

Ketamine was obtained from Fort Dodge (Brazil) and imip-

ramine, the standard antidepressant, from Novartis Pharmaceuti-

cal Industry (Brazil). Different groups of rats (n =15 each) were

administered intraperitoneally (IP) with saline or different doses

of ketamine (5, 10 and 15 mg/kg) or imipramine (10, 20 and

30 mg/kg) 60 minutes before the test sessions, i.e. forced swim-

ming or open-field tests. All treatments were administered in a

volume of 1 ml/kg. The range of doses of ketamine employed in

this work was chosen basedon a previous study, which reported anincrease of spontaneous locomotion at 25 mg/kg, while no

changes were observed at 10 mg/kg (Hunt et al., 2006).

2.3. Apparatus

The forced swimming test was conducted according to pre-

vious reports (Porsolt et al., 1977; Detke et al., 1995). The test

involves two individual exposures to a cylindrical tank with water

in which rats cannot touch the bottom of the tank or escape. The

tank is made of transparent Plexiglas, 80 cm tall, 30 cm in

diameter, and filled with water (2223 C) to a depth of 40 cm.

Water in the tank was changed after each rat. For the first

exposure, rats without drug treatment were placed in the water for15 min (pre-test session). Twenty-four hours later, rats were

placed in the water again for a 5 min session (test session), and the

immobility time of rats were recorded in seconds. Rats were

treated with ketamine, imipramine or saline only 60 min before

the second exposure to the cylindrical tank of water (test session).

In a separate series of experiments,nave rats were treated with

ketamine (515 mg/kg), imipramine (1030 mg/kg) and saline

60 min before the exposure to the open-field apparatus, in order to

assess possible effects of drug treatment on spontaneous loco-

motor activity. Analysis of rat spontaneous activity was carried

out in an open field apparatus, which is an arena 4560 cm

surrounded by 50 cm high walls made of brown plywood with afrontal glass wall. The floor of the open field was divided into 9

rectangles (1520 cm each) by black lines. Animals were gently

placed on the left rear quadrant, and left to explore the arena for

5 min. The number of horizontal (crossings) and vertical

(rearings) activity performed by each rat during the 5-min

observation period was counted by an expert observer.

2.4. Experimental procedure

Immediately after the forced swimming test, acutely saline,

imipramine and ketamine-treated rats were sacrificed and the

skulls were removedand hippocampus was dissected and stored at

80 C for biochemical analyses. BDNF levels in hippocampus

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were measured by anti-BDNF sandwich-ELISA, according to the

manufacturer instructions (Chemicon, USA). Briefly, rat hippo-

campus was homogenized in phosphate buffer solution (PBS)

with 1 mM phenylmethylsulfonyl fluoride (PMSF) and 1 mM(EGTA). Microtiter plates (96-well flat-bottom) were coated for

24 h with the samples diluted 1:2 in sample diluent and standard

curve ranged from 7.8 to 500 pg/ml of BNDF. The plates were

then washed four times with sample diluent and a monoclonal

anti-BNDF rabbit antibody diluted 1:1000 in sample diluent was

added to each well and incubated for 3 h at room temperature.

After washing, a peroxidase conjugated anti-rabbit antibody

(diluted 1:1000) was added to each well and incubated at room

temperature for 1 h. After addition of streptavidin-enzyme,

substrate and stop solution, the amount of BDNF was determined

by absorbance in 450 nm. The standard curve demonstrates a

direct relationship between Optical Density (OD) and BDNF

concentration. Total protein was measured by Lowry's method

using bovine serum albumin as a standard, as previously described

by Frey et al. (2006).

2.5. Statistical analysis

All data are presented as meanS.E.M. Differences among

experimental groups in the forced swimming, open field test and

in the assessment of BDNF levels were determined by one-way

ANOVA, followed by Tukey post-hoc test when ANOVA was

significant;p values less than 0.05 were considered to be statistical

significant.

3. Results

As depicted in Fig. 1, the acute administration of the standardantidepressant imipramine reduced, in a significant manner, the

immobility time of rats at 20 and 30 mg/kg compared to saline

(F(697)=5.45; pb0.05; Fig. 1). The intraperitoneal treatment

with ketamine at the doses of 10 and 15 mg/kg decreased

significantly the immobility time of rats compared to saline group

(F(697)=5.45; pb0.05; Fig. 1). In the open-field test, the

treatment with ketamine and imiprimine at all doses tested did

not modify the number of crossing and rearing compared to saline

treated-rats (Fig. 2A and B).

Fig. 3 illustrated the effects of the acute treatment with imip-

ramine (10, 20 and 30 mg/kg), ketamine (5, 10 and 15 mg/kg) and

saline in BDNF protein hippocampus levels of rats. A statisticalsignificant increase in BDNF protein levels in the hippocampus

was observed in rats treated with ketamine only at the higher dose

(15 mg/kg; F(336)=5.73; pb0.05), but not with imipramine,

compared to saline group.

4. Discussion

The present study demonstrated that: (1) the acute treat-

ment with ketamine (10 and 15 mg/kg) and imipramine (20

and 30 mg/kg) decreased the immobility time of rats in the

forced swimming test; (2) ketamine and imipramine did not

affect spontaneous locomotor activity in the open-field test;

and (3) the acute treatment with ketamine at the higher dose,

Fig. 1. Effects of the acute administration of ketamine (5, 10 and 15 mg/kg, i.p.)

and imipramine (10, 20 and 30 mg/kg, i.p.) on the immobility time of rats

subjected to the forced swimming test. Bars represent meansS.E.M. of 15 rats.pb0.05 vs. saline according to ANOVA followed by Tukey post-hoc test.


and imipramine (10, 20 and 30 mg/kg, i.p.) on the number of crossings (A) and

rearings (B)of rats subjectedto theopenfieldtest. Bars representmeans S.E.M.of15 rats. pb0.05 vs. saline according to ANOVA followed by Tukeypost-hoc test.


and imipramine (10, 20 and 30 mg/kg, i.p.) on the BDNF levels in the rat

hippocampus. Bars represent means S.E.M. of 15 rats. pb0.05 vs. saline

according to ANOVA followed by Tukey post-hoc test.

142 L.S.B. Garcia et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 140144


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but not imipramine, increased BDNF protein levels in the rat

hippocampus.

The behavioral effects induced by ketamine in rats reported in

the present study are in agreement with literature data, which

support an antidepressant action for ketamine in basic and clinical

studies. In fact, the treatment with ketamine reversed the shock-

induced increase of immobility time in the mouse forcedswimming test (Chaturvedi et al., 2001). Another study

demonstrated that a single injection of an anesthetic dose of

ketamine (160 mg/kg) induced antidepressant-like effects in rats

tested in 3, 7, or 10 days after the forced swimming test ( Yilmaz

et al., 2002). Additionally, in the mouse tail suspension test

ketamine produced anti-immobility effects, suggesting an

antidepressant-like action in mice (Kos et al., 2006b). Taken

together, our findings are in agreement with these previous

observations, and are strengthening the view that ketamine

induces antidepressant-like effects in rodents.

In 2000, a pilot study showed that a single dose of ketamine

produced antidepressant effects in patients suffering from majordepression (Berman et al., 2000). Recently, Zarate et al. (2006)

extended this study to a higher number of patients, and they

found that the acute administration of ketamine rapidly

improved depressive symptoms in patients with major depres-

sion. In this study, ketamine ameliorates the symptoms of

depression within 110 minutes after injection, and these effects

remained significant until 7 days after ketamine injection

(Zarate et al., 2006). Therefore, these data strongly suggest that

ketamine can induce robust and rapid antidepressant effects in

depressed patients after a single intravenous injection.

Our findings also showed that acute administration of keta-

mine, but not imipramine, significantly increased BDNF

protein levels in the rat hippocampus compared with salinegroup. Several studies have suggested that normal BDNF-TrkB

receptor signaling is both necessary and sufficient for anti-

depressant drug action (for a review see: Castrn et al., 2007).

Some authors have found that antidepressants acting through

different mechanisms rapidly increase TrkB receptor activation

and signaling within an hour after drug administration

(Saarelainen et al., 2003; Rantamaki et al., 2006). Despite

that, studies have shown that rats treated with fluoxetine for 4,

7, 14 and 21 days displayed unaltered hippocampal BDNF

protein levels when assessed by ELISA assay (De Foubert et

al., 2004), and the same holds true to 3 weeks of treatment with

desipramine (Jacobsen and Mork, 2004). Thus, taken togetherour data are showing that acute administration of ketamine

increase hippocampal BDNF protein levels, whist acute

(present data) and chronic treatment with classic antidepressant

did not affect it.

A growing body of evidence support an important role of

neurotrophic factors in mood disorders. In fact, reduced brain

BDNF levels predispose to depression, whereas increases in

brain BDNF levels produce an antidepressant action (for a

review see: Castrn et al., 2007). Our present findings revealed

that acute administration of ketamine causes an increase of

BDNF hippocampal levels detected immediately after the

forced swimming test. Importantly, our data did not evaluate

the duration of ketamine effects on BNDF levels in rats. Further

studies aiming to establish a timeresponse curve to ketamine in

behavioral and molecular assays are worthy of doing.

Altogether, our findings support a quite unique effect induced

by ketamine in the hippocampal BDNF protein levels, which

suggests that the rapid onset of action of ketamine in the clinic

might be due to the increase of hippocampal BDNF protein

levels. Additionally, our findings contribute in explaining theslow onset of antidepressant activity observed with classic

antidepressants.

Finally, it should be noted that although ketamine is a high-

affinity NMDA receptor antagonist, it has less, but potentially

relevant, affinity for opiate, monoaminergic, and muscarinic

receptors and also interacts with voltage sensitive Ca+2 channels

(Lindefors et al., 1997; Elliott et al., 1995; Wong et al., 1996;

Kapur and Seeman, 2001; Eide et al., 1997). Thus, the

antidepressant-like effects of ketamine observed in the present

study could be due to interactions of ketamine with several

receptor systems, not only with NMDA receptors, which could

produce synergic effects on the brain pathways involved in themodulation of behavioral and molecular actions of antidepres-

sants. Lastly, basic and clinical findings suggest that brain

pathways modulated by ketamine could play an important role in

reducing the onset of action of antidepressants.

5. Conclusion

The antidepressant-like effects of ketamine are in agreement

with literaturedata, which support an important role played by the

NMDA receptor signaling in major depression. However, it

should be kept in mind that, besides NMDA receptors, ketamine

interacts with distinct receptor systems, such opioid, monoamin-

ergic, muscarinic receptors and voltage sensitive Ca+2 channels,which could produce synergic effects on the brain pathways

involved in the modulation of behavioral and molecular actions of

antidepressants.

Interestingly enough, our study demonstrated that ketamine,

but not imipramine, increased BDNF levels in rat hippocampus

after one single injection. Altogether, basic and clinical findings

might suggest that acute increase of BDNF protein levels in

hippocampus might be critical to antidepressant drugs with rapid

onset of action. Future studies need to be carried out in an

attempt to further investigate pharmacological and molecular

mechanism by which ketamine, and other NMDA antagonists,

induce antidepressant-like effects.

Acknowledgements

This study was supported in part by CNPq (Brazil), UNESC

(Brazil), FAPESC (Brazil).

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Ketamine Induced Release of Bdnf

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