Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats

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Abstract

Exposure to uncontrollable stressors causes behavioral changes that have been related to depressive states in humans. Poststress intrahippocampal administration of amino-7-phosphonoheptanoic acid (AP-7), a glutamate NMDA-receptor antagonist, attenuated the restraint-induced decreased exploration of an elevated plus maze 24 h later. The objective of the study was to test if this treatment would also attenuate the increased immobility seem in the forced swim test (FST) due to preexposition to this stressful situation. Male Wistar rats with cannulae aimed at the dorsal hippocampus were submitted to 15 min of forced swimming and tested 24 h later. They received bilateral intrahippocampal injections of AP-7 (10 nmol) either before or after the pretest swimming session or before the test. Poststress treatment increased latency to display the first episode of immobility and tended to reduce total immobility time. The drug was ineffective when given before stress or before test and in nonstressed animals. This suggests that glutamate NMDA receptors located in the dorsal hippocampus are involved in the behavioral changes observed in the FST.

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)

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