Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats
Introduction
Exposure to environmental stress has been implicated in the etiology of several human disorders, such as depression, anxiety or cardiovascular diseases (Post, 1992). Long-lasting behavioral changes are also observed in laboratory animals submitted to uncontrollable stressors. For example, rats submitted to 2 h of restrain show, 24 h later, exploratory deficits in new environments such as an open arena or an elevated plus maze Guimarães et al., 1993, Kennett et al., 1987, Padovan and Guimarães, 1993, Padovan and Guimarães, 2000, Mendonça Netto and Guimarães, 1996. This suggests that previous stressful experiences are able to modify the animal response to new aversive stimuli (Guimarães et al., 1993).
Several animal tests employed to detect antidepressant-like effects are based on behavioral consequences of uncontrollable stress exposure (Willner, 1990). For example, the forced swim test (FST) evaluates the increased immobility time caused by preexposure to a forced swimming situation Porsolt et al., 1977, Willner, 1990.
Behavioral Trullas and Skolnick, 1990, Skolnick et al., 1992, Nowak et al., 1995b, Popik et al., 2000 and neurochemical data Skolnick et al., 1996, Nowak et al., 1993, Nowak et al., 1995a, Nowak et al., 1996, Nowak et al., 1998, Paul et al., 1992, Paul et al., 1993, Paul et al., 1994 have related NMDA-mediated neurotransmission with depression. NMDA receptor antagonists, for example, show antidepressant-like effects in the FST. The brain sites involved in these effects are not completely understood, but several pieces of evidence point to the hippocampus (Przegalinski et al., 1997). This structure has been implicated in the behavioral and neurochemical responses to aversive stimuli Gray and McNaughton, 2000, Guimarães et al., 1993. Studies using c-fos mRNA detection suggest that the hippocampus is activated during restraint stress. This activation can be blocked by previous treatment with intracerebroventricular injections of 2-amino-7-phosphonoheptanoic acid (AP-7), an NMDA receptor antagonist, indicating the involvement of glutamatergic neurotransmission (Titze-de-Almeida et al., 1994). Restraint or forced swim stress produces marked increase in glutamate extra cellular levels in this region (Moghaddam, 1993). In the FST pretest, administration of CGP 37489, an NMDA receptor antagonist, had antidepressant-like effects (Przegalinski et al., 1997).
We have previously showed that interference with NMDA-mediated neurotransmission in the hippocampus modifies the behavioral consequences of restraint stress (Padovan et al., 2000). AP-7, given immediately after restraint or before the test, attenuated the stress-induced decrease of open arm exploration in an elevated plus maze.
The aim of the present work is to test the hypothesis that intrahippocampal administration of an NMDA-receptor antagonist would prevent the behavioral changes observed in the FST after preexposure to forced swimming.
Section snippets
Animals and housing
Male Wistar rats (200–220 g) were housed in pairs in a temperature-controlled room (23±1 °C) under standard laboratory conditions with free access to food and water and a 12-h light cycle (lights on at 6:30 a.m.). Procedures were conducted in conformity with the Brazilian Society of Neuroscience and Behavior guidelines for the care and use of laboratory animals, which are in compliance with international laws and politics. All efforts were made to minimize animal suffering.
Drug
AP-7 (Ciba-Geigy) was
Results
A representative brain injection site into the dorsal hippocampus can be seen in Fig. 1.
Discussion
The FST is a widely used screening test to assess potential antidepressant-like effects Porsolt et al., 1977, Willner, 1990. In this test, rodents usually display an immobile behavior after being preexposed to same context 24 h before (Porsolt et al., 1977). Other behavioral changes have also been reported. For example, 15 min of forced swimming decrease open-arm exploration of an elevated plus maze (Martijena et al., 1997).
In our first experiment, the effects of preexposure to forced swim were
Acknowledgments
The authors acknowledge the helpful technical support provided by J.C. de Aguiar. Research supported by grants from FAPESP (99/06913-9, 02/13187-2) and CNPq.
References (36)
- et al.
Stress-induced changes in messenger RNA levels of N-methyl-d-aspartate and AMPA receptor subunits in selected regions of rat hippocampus and hypothalamus
Neuroscience
(1995) - et al.
Hippocampal 5-HT receptors and consolidation of stressful memories
Behav. Brain Res.
(1993) - et al.
Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working memory task: the effect does not resemble those of AP5 and of lesions of the hippocampus or fornix
Neuropsychologia
(1996) - et al.
Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures
Neurobiol. Learn. Mem.
(1997) - et al.
Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression
Eur. J. Pharmacol.
(1987) - et al.
Prior exposure to a brief restraint session facilitates the occurrence of fear in response to a conflict situation: behavioral and neurochemical correlates
Brain Res.
(1997) Effects of adverse experiences for brains structure and function
Biol. Psychiatry
(2000)- et al.
Role of hippocampal 5-HT1A receptors on elevated plus maze exploration after a single restraint experience
Behav. Brain Res.
(1996) - et al.
Alterations in the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims
Brain Res.
(1995) - et al.
Adaptation of cortical but not hippocampal NMDA receptors after chronic citalopram treatment
Eur. J. Pharmacol.
(1996)
Adaptation of cortical NMDA receptors by chronic treatment with specific serotonin reuptake inhibitors
Eur. J. Pharmacol.
Behavioral effects in the elevated plus-maze of an NMDA antagonist injected into the dorsal hippocampus: influence of restraint stress
Pharmacol. Biochem. Behav.
Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine
Eur. J. Pharmacol.
Chronic treatment with antidepressants affects glycine/NMDA receptor function: behavioral evidence
Neuropharmacology
Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and competitive NMDA receptor antagonist
Neuropharmacology
Functional antagonists at the NMDA receptor complex exhibit antidepressant action
Eur. J. Pharmacol.
Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists
T.I.P.S.
Animal models of depression: an overview
Pharmacol. Ther.
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