Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

https://doi.org/10.1016/j.pnpbp.2007.07.027Get rights and content

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.

Introduction

Depression is one of the most prevalent and costly psychopathologies 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 treatment, emphasizing the need to discover novel antidepressants (Pacher et al., 2001). The challenges for the design of new agents to 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 modulated in the brain by different receptor types, including ionotropic and metabotropic receptors. Studies have 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 injected into distinct brain areas and subjected to various animal models of anxiety and depression (Kos et al., 2006a, Molchanov and Guimarães, 2002, Menard and Treit, 2000, Adamec et al., 1999, Matheus and Guimarães, 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 of N-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 ketamine and 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.

Section snippets

Animals

Male Adult Wistar rats (60 days old) were obtained from UNESC (Universidade do Extremo Sul Catarinense, Criciúma, 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

Results

As depicted in Fig. 1, the acute administration of the standard antidepressant imipramine reduced, in a significant manner, the immobility time of rats at 20 and 30 mg/kg compared to saline (F(6–97) = 5.45; p < 0.05; 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(6–97) = 5.45; p < 0.05; Fig. 1). In the open-field test, the treatment with ketamine and imiprimine at all doses tested did

Discussion

The present study demonstrated that: (1) the acute treatment 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, but not imipramine, increased BDNF protein levels in the rat hippocampus.

The behavioral effects induced by ketamine in rats reported in the

Conclusion

The antidepressant-like effects of ketamine are in agreement with literature data, 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, monoaminergic, 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

Acknowledgements

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

References (40)

  • T. Kos et al.

    Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice

    Eur Neuropsychopharmacol

    (2006)
  • N. Lindefors et al.

    Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex

    Brain Res

    (1997)
  • R. McArthur et al.

    Animal models of depression in drug discovery: a historical perspective

    Pharmacol Biochem Behav

    (2006)
  • E. Przegalinski et al.

    Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist

    Neuropharmacology

    (1997)
  • T. Rantamaki et al.

    The effects of acute and long-term lithium treatment on TrkB neurotrophin receptor activation in the mouse hippocampus and anterior cirgulate cortex

    Neuropharmacology

    (2006)
  • J.A. Siuciak et al.

    Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)

    Pharmacol Biochem Behav

    (1997)
  • R. Trullas et al.

    Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

    Eur J Pharmacol

    (1990)
  • C.-S. Wong et al.

    Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: Binding at μ-opioid receptors

    Eur J Pharmacol

    (1996)
  • R.E. Adamec et al.

    Unilateral block of lasting increases in anxiety-like behavior and unconditioned startle effective hemisphere depends on the behavior

    Physiol Behav

    (1999)
  • H.K. Chaturvedi et al.

    Effect of fluvoxamine and N-methyl-d-aspartate receptor antagonists on shock-induced depression in mice

    Indian J Physiol Pharmacol

    (2001)
  • Cited by (0)

    View full text