GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice

The GPR30 is a novel estrogen receptor (ER) that is a candidate membrane ER based on its binding to 17beta estradiol and its rapid signaling properties such as activation of the extracellular-regulated kinase (ERK) pathway. Its distribution in the mouse limbic system predicts a role for this receptor in the estrogenic modulation of anxiety behaviors in the mouse. A previous study showed that chronic administration of a selective agonist to the GPR30 receptor, G-1, in the female rat can improve spatial memory, suggesting that GPR30 plays a role in hippocampal-dependent cognition. In this study, we investigated the effect of a similar chronic administration of G-1 on behaviors that denote anxiety in adult ovariectomized female mice, using the elevated plus maze (EPM) and the open field test as well as the activation of the ERK pathway in the hippocampus. Although estradiol benzoate had no effect on behaviors in the EPM or the open field, G-1 had an anxiolytic effect solely in the open field that was independent of ERK signaling in either the ventral or dorsal hippocampus. Such an anxiolytic effect may underlie the ability of G-1 to increase spatial memory, by acting on the hippocampus.

Longitudinal study of daily variation of rats' behavior in the elevated plus-maze

We conducted a longitudinal study about daily variation of Wistar male rats' behavior in the elevated plus-maze (EPM) evaluated in the 1st, 2nd, 3rd, 6th, 12th, and 18th months of life. Animals were submitted to the plus-maze in 12 sessions at 2-h intervals (n=72, 6 per time point). Spontaneous rest-activity rhythm of four animals was assessed by observation of 24-h videotape records. Time series were analyzed by Cosinor method. Behavioral rates on the six occasions and in light and dark phases were compared by means of two-way ANOVA with repeated measures. Exploratory behavior in EPM was smaller in the light phase and in older animals. Higher values of open and closed arms exploration were observed in the first and third months of the dark phase, and in the first month of the light phase. Adjustment to the 24-h period was significant at all stages for rest-activity data, number of entries in closed arms, and time on center, and for three to five stages for open-arm exploration. In general, 24 h variability was more pronounced in younger animals compared with older ones. The present study showed that: (1) a significant amount of total variability of the behavioral indexes analyzed could be attributed to 24 h variation, (2) light/dark phases differences in EPM exploration were present at all developmental stages, (3) older Wistar rats explored less the EPM and were less active in their home cage compared with younger ones, and (4) behavioral indexes (EPM) decrease was phase related and partially related to a reorganization of rest-activity rhythm. (C) 2003 Elsevier B.V. All rights reserved.

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze

Serotonin (5-HT) can either increase or decrease anxiety-like behaviour in animals, actions that depend upon neuroanatomical site of action and 5-HT receptor subtype. Although systemic studies with 5-HT(2) receptor agonists and antagonists suggest a facilitatory role for this receptor subtype in anxiety, somewhat inconsistent results have been obtained when such compounds have been directly applied to limbic targets such as the hippocampus and amygdala. The present study investigated the effects of the 5-HT(2B/2C) receptor agonist mCPP bilaterally microinjected into the dorsal hippocampus (DH: 0, 0.3 1.0 or 3.0 nmol/0.2 mu l), the ventral hippocampus (VH: 0, 0.3, 1.0 or 3.0 nmol/0.2 mu l) or the amygdaloid complex (0, 0.15, 0.5, 1.0 or 3.0 nmol/0.1 mu l) in mice exposed to the elevated plus-maze (EPM). Test sessions were videotaped and subsequently scored for conventional indices of anxiety (percentage of open arm entries and percentage of open arm time) and locomotor activity (closed arm entries). Results showed that mCPP microinfusions into the DH or VH failed to affect any behavioural measure in the EPM. However, when injected into the amygdaloid complex, the dose of 1.0 nmol of this 5HT(2B/2C) receptor agonist increased behavioural indices of anxiety without significantly altering general activity levels. This anxiogenic-like effect of mCPP was selectively and completely blocked by local injection of a behaviourally-inactive dose of SDZ SER-082 (10 nmol/0.1 mu l), a preferential 5-HT(2C) receptor antagonist. These data suggest that 5HT(2C) receptors located within the amygdaloid complex (but not the dorsal or ventral hippocampus) play a facilitatory role in plus-maze anxiety in mice. (c) 2007 Elsevier B.V. All rights reserved.

Activation of 5-HT2C receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Fos-like immunoreactivity in central nervous system of mice simultaneously exposed to the elevated plus-maze and nociception

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

ETHOPHARMACOLOGICAL ANALYSIS OF RAT BEHAVIOR ON THE ELEVATED PLUS-MAZE

Behavioral categories were measured in rats left on an elevated plus-maze for 5 min, in addition to the traditional measures. Four independent factors emerged from a factor analysis. The variables that loaded highly and positively on Factor 1, seemingly related with anxiety, were: number of entries onto open arms, time spent on open arms, percentage of open/total arm entries, percentage of time on open arms, scanning over the edge of an open arm, and open arm end-exploring. The time spent on enclosed arms loaded highly, but negatively on the same factor. Risk-assessment from an enclosed arm also loaded negatively on Factor 1. Number of enclosed arm entries, total number of arm entries and rearing loaded highly on Factor 2, probably related to motor activity. However, the total number of entries also loaded on Factor 1, being thus a mixed index. Similarly, the number of open arm entries loaded on both Factors 1 and 2. As expected, the variables having high loads on Factor 1 were changed to one direction by administration of two anxiolytics (nitrazepam and midazolam) and to the opposite direction by two anxiogenic drugs (pentylenetetrazol and FG 7142). Such pattern of drug effects was not observed with the remaining variables.

Anxiety levels and wild running susceptibility in rats: assessment with elevated plus maze test and predator odor exposure

It is reported in the literature that nearly 20% of rats are susceptible to displays of wild running (WR) behavior when submitted to high intensity acoustic stimulation. Some characteristics of WR suggest that it can be viewed as a panic-like reaction. This work aimed to test whether WR-sensitive rats show higher levels of anxiety in elevated-plus-maze (EPM) and predator-odor exposure paradigms in comparison with WR-resistant ones. Male adult Wistar rats were submitted to two trials of acoustic stimulation (104 dB, 60 s) in order to assess WR susceptibility. Seven WR-sensitive and 15 WR-resistant rats were evaluated by the EPM test. Other 13 WR-sensitive and 18 WR-resistant animals were submitted to the predator-odor exposure test which consisted of a 10 min-session of free exploration in a specific apparatus containing two odoriferous stimuli: cotton swab imbedded with snake cloacal gland secretion or with iguana feces (control). WR-sensitive rats presented a significantly higher closed-to open-ann-entry ratio in the EPM test. All rats responded with anxiety-like behaviors to the predator odor exposure, although the WR-sensitive ones showed a marked behavioral inhibition regardless of the odor condition. We conclude that WR-sensitive rats present elevated levels of anxiety manifested by means of passive behavioral strategies. (C) 2004 Elsevier B.V. All rights reserved.

Open elevated plus maze-induced antinociception in rats: A non-opioid type of pain inhibition?

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Implication of the 5-HT(2A) and 5-HT(2C) (but not 5HT(1A)) receptors located within the periaqueductal gray in the elevated plus-maze test-retest paradigm in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Similar anxiolytic-like effects following intra-amygdala infusions of benzodiazepine receptor agonist and antagonist: Evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus-maze test

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Corticosterone does not change open elevated plus maze-induced antinociception in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ethopharmacological analysis of the open elevated plus-maze in mice

Exposure of rodents to an open elevated plus-maze (oEPM) elicits antinociception and increases plasma corticosterone levels. However, no studies have yet assessed the defensive behaviour repertoire of animals in this modified test. In Experiment 1, factor analysis was employed to characterise the behavioural profile of mice exposed to the oEPM. Experiments 2 and 3 assessed the effects of acute alprazolam (0.5-1.5. mg/kg; diazepam 0.5-1.5. mg/kg), pentylenetetrazole (10.0-30.0. mg/kg), yohimbine (2.0-6.0. mg/kg), mCPP (0.3-3.0. mg/kg), and acute and chronic fluoxetine (10.0-30.0. mg/kg) and imipramine (1.0-15.0. mg/kg) on behaviours identified in Experiment 1. The factor analyses revealed that behaviour in the oEPM can largely (77% total variance) be accounted for in terms of 3 factors: factor 1 ('. depth exploration'; e.g. head-dipping on the arms), factor 2 ('. cautious exploration of arms'; e.g. flatback approach), and factor 3 ('. risk assessment'; stretched attend postures - SAP). Experiments 2 and 3 showed that, over the dose range used, alprazolam selectively attenuated all measures of defensiveness. Similar, though more modest, effects were seen with diazepam. Confirming the intensity of the emotional response to the oEPM (nociceptive, endocrine and behavioural), relatively few significant behavioural changes were seen in response to the anxiogenic compounds tested. Although acute fluoxetine or imipramine treatment failed to modify behaviour in the oEPM, chronic fluoxetine (but not chronic imipramine) attenuated total flat back approach and increased head dipping outside the central square. Together, the results indicate that the oEPM induces behavioural defensive responses that are sensitive to alprazolam and chronic fluoxetine. © 2013 Elsevier B.V.