Distinct ventral and dorsal hippocampus AP5 anxiolytic effects revealed in the elevated plus-maze task in rats

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Abstract

The hippocampal formation (HPC) mediates processes associated with learning, memory, anxiety and fear. The glutamate N-methyl-d-aspartate (NMDA)-receptor subtype is involved in many HPC functional processes related to learning and memory. Although not tested for the HPC, NMDA-receptor antagonists reduced fear and anxiety related responses when applied to other brain regions mediating defensive behaviour. Consequently, this study evaluated the effects of ventral or dorsal HPC application of the NMDA-receptor antagonist, AP5, in rats submitted to the Trial 1/Trial 2 elevated plus-maze (EPM) task. Ventral, but not dorsal, infusions of AP5 (6 and 24 nmol) before EPM Trial 1 increased open arms exploration and reduced risk assessment behavior, suggesting an anxiolytic-like effect. Furthermore, no interference in the avoidance responses was detected during EPM Trial 2 after AP5 infusion into the ventral or dorsal HPC before Trial 1, post-trial 1, or before Trial 2. These data support the notion of differential involvement of ventral HPC, but not dorsal, in mechanisms associated with anxiety and suggest the participation of the glutamatergic transmission, through NMDA receptor, into the ventral HPC in the mediation of defensive behavior.

Introduction

The hippocampal formation (HPC) is a cortical area localized in the temporal lobe, distributed along its septotemporal or dorsoventral axis, and comprising the dentate gyrus, the hippocampus (areas CA1, CA2, and CA3), the subicular complex and the entorhinal cortex (Amaral & Witter, 1989). Recently, a specific functional role for the HPC, suggesting segregation along its dorsoventral axis, has been revealed by studies on intrinsic and extrinsic anatomical connections (Risold and Swanson, 1996, Witter et al., 2000), emotional behavioral responses (Alves et al., 2004, Bannerman et al., 2004, Bertoglio et al., 2006, Gray and McNaughton, 2000, Kjelstrup et al., 2002, Moser and Moser, 1998, Nunes-de-Souza et al., 2002, Pentkowski et al., 2006), genes expression differences (Leonardo, Richardson-Jones, Sibille, Kottman, & Hen, 2006), and neurochemical organization (Pandis et al., 2006, Sotiriou et al., 2005).

It is well established that the glutamate N-methyl-d-aspartate (NMDA)-receptor subtype is involved in many functional processes including learning and memory (Bannerman et al., 2006, Morris and Davis, 1994, for review). Behavioral studies have also drawn attention to the participation of NMDA receptors in the mediation of defensive behavior, fear and anxiety (Carobrez, Teixeira, & Graeff, 2001, for review). Therefore, the injection, either systemically or directly into the midbrain periaqueductal gray matter, of NMDA receptor antagonists, acting either as NMDA competitive antagonists, or as uncompetitive channel blockers, produces an anti-aversive profile of action (Bertoglio and Carobrez, 2003, Carobrez et al., 2001, Dunn et al., 1989, Guimaraes et al., 1991). NMDA receptors have also been shown to be a key element in processes related to emotional learning and memory (Bliss and Collingridge, 1993, Fanselow et al., 1994, Stewart and McKay, 2000). The involvement of the HPC in contextual learning has received support from studies of Pavlovian fear conditioning in rats, indicating that the ventral, but not the dorsal HPC, participates in contextual fear conditioning (Maren and Holt, 2004, Richmond et al., 1999). In addition, several studies indicate that the ventral but not the dorsal HPC is also involved in the modulation of anxiety-like behaviors (Alves et al., 2004, Kjelstrup et al., 2002, McHugh et al., 2004, Nunes-de-Souza et al., 2002, Pentkowski et al., 2006, Trivedi and Coover, 2004).

Altogether, the findings clearly show an HPC GLU-transmission involvement in the mediation of emotion-related tasks and of learning and memory processes. It is not clear, however, whether differences in NMDA receptor density found within dorsal and ventral HPC (Pandis et al., 2006) might represent also a functional dichotomy, with learning and memory being mediated by the dorsal area, and defensive behavior being mediated by more ventral regions of the HPC. Based on this information, the present study sought to investigate the role of NMDA receptors in the ventral and dorsal HPC in the modulation of behaviors related to anxiety and the emotional learning and memory related to the task. In order to address this issue, the behavioral performance of HPC-treated rats was appraised in the EPM Trial 1-Trial 2 protocol (Bertoglio and Carobrez, 2004, Carobrez and Bertoglio, 2005) to evaluate emotional and mnemonic aspects of the task.

Section snippets

Subjects

The subjects were 184 male Wistar rats weighing 300–350 g, housed in groups of three per cage (50 cm × 30 cm × 15 cm), under a 12 h light:12 h dark cycle, in a temperature-controlled environment (23 ± 1 °C) and with free access to food and water. All procedures were conducted in accordance with the Brazilian Society of Neuroscience and Behavior Guidelines for care and use of laboratory animals.

Stereotaxic surgery

Animals were anaesthetized using 1.5 ml/kg of a solution containing xylazine (10 mg/ml; Dopaser®, Laboratorios Calier

Microinjection site (Fig. 1)

Histology confirmed that a total of 103 rats had accurate bilateral cannula placements in the ventral HPC, while 81 rats had accurate bilateral cannula placements in the dorsal HPC. The center of the infusion sites was concentrated within or in the surroundings of the CA1 region in either the dorsal or the ventral HPC (Fig. 1).

Effects on the EPM performance of AP5 infusion into the ventral or the dorsal HPC

A general two factor ANOVA comparing the effects of the 6 and 24 nmol dose of AP5 showed a significant treatment versus cannula placement effect, for the % open arms time

Discussion

The main findings of the present study are: (1) Ventral, but not dorsal, HPC infusions of AP5, prior to EPM Trial 1 increased the %OAT and the %OAE and reduced risk assessment behavior; and (2) No behavioral changes were detected during EPM Trial 2 after AP5 infusion into the ventral or the dorsal HPC prior to Trial 1, post-Trial 1, or prior to Trial 2.

A number of reports have highlighted the neurotransmitter glutamate as an important element in the modulation of defensive behaviors (Bergink et

Acknowledgments

This work was supported by FAPESP, CAPES, PRONEX, FAPESC, and CNPq from which Luciane P.N. Hackl received a doctoral fellowship and Antonio P. Carobrez a research fellowship. The authors are grateful to Gareth Cuttle for English corrections on the manuscript.

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