The effects of diazepam on the elevated T-maze are dependent on the estrous cycle of rats.

Amauri Gouveia,Caio Maximino,Silvio Morato,Gabriela Antunes

doi:10.3922/j.psns.2009.2.016

Abstract

to determine the modulation of anxiolytic and panicolytic-like effects of diazepam by the hormonal cycle of female rats, male and female rats - the latter divided per estrous cycle phase (estrus, diestrus, metaestrus and proestrus) - were tested in the elevated T-maze, a behavioral model of panic and anxiety. Diazepam (0.5, 1.0 and 2.0 mg/kg) or saline solution was injected in individual animals that were submitted to one session in the elevated T-maze 25 min after drug/saline administration. The test consisted of three avoidance trials and one escape trial, separated by a 30 s interval, during which the animals were isolated in individual cages. The avoidance trials began with the animal being placed at the end of the maze's enclosed arm. The time necessary for the animal to leave the central square was considered as the response's latency. The trials that exceeded 300 s were considered as failures. Results demonstrate a decrease in the effects of diazepam in inhibitory avoidance (anxiety) trials in females in diestrus and proestrus, but no relation of gender or estrous cycle on diazepam effects on escape trials (fear). The results support the hypothesis that down-regulation of GABA A receptors by activation of nuclear estrogen receptors and induction of PKC-mediated GABA A receptor phosphorylation by activation of surface estrogen receptors in raphe neurons underlie the modulation of diazepam sensitivity by estrogen. Keywords: diazepam, estrous cycle, estrogen, anxiety, elevated T-maze. Received 17 July 2009; received in revised form 21 September 2009; accepted 10 November 2009. Available on line 29 December 2009.

Highlights

Anxiety is an emotional state that emerges under situations in which risk is probable, but not certain
In a previous work (Gouveia, dos Santos, Felisbino, Afonseca, Antunes, & Morato, 2004), we demonstrated that the estrous cycle modulates different parameters of conditioned and unconditioned fear in this model, with females in proestrus and estrus showing impairment in the acquisition of inhibitory avoidance but no alterations in escape, while females in diestrus showed increased baseline anxiety
The present article tested the influence of estrous cycle phase on the anxiolytic and panicolytic-like effects of diazepam, using the elevated T-maze, a rodent anxiety model

Summary

Introduction

Anxiety is an emotional state that emerges under situations in which risk is probable, but not certain. Most ligands which modulate GABAA-associated chloride currents seem to act through allosteric modulation of the opening of a chloride channel, altering the probability that this ligand-gated channel is in an “open” state (Berezhnoy et al, 2007; Costa, 1998; Olsen, 2002). Progesterone derivatives positively modulate GABA action on GABAA receptors (Puia et al, 1993); pregnelone sulfate (a progesterone derivative) negatively modulates chloride currents gated by GABA only in high concentrations (Puia et al, 1993). This neurosteroid is most efficient in its GABA-potentiating action in recombinant receptors including the γ1 subunit – a subunit whose mRNA is expressed predominantly in native GABAA receptors located in glial cells (McKernan & Whiting, 1996)

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