Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats
Introduction
There are several lines of evidence suggesting a strong link between estrogen and emotional disturbances in humans. Mood fluctuations, depression, irritability, and anxiety have been associated with low levels of estrogen in postmenopausal women [1], [2], and estrogen replacement therapy has been shown to ameliorate these psychological symptoms [1], [2], [3]. In mice and rats models, the effects of estrogen deprivation induced by ovariectomy followed by estrogen supplementation on anxiety-like behaviors have been studied although the results are inconsistent. For instance, anxiolytic effect was demonstrated in ovariectomized (Ovx) rats that received subchronic or chronic doses of estrogen when tested with elevated plus maze (EPM) [4], [5], [6], [7]; however, single dose of estrogen given to either Ovx or diestrous female rats (with naturally low levels of estrogen) could have either anxiolytic effect [8], [9], [10] or no effect on anxiety-like behavior [11], [12]. Interestingly, Ovx mice treated with estrogen were found to be either anxiogenic [13], [14] or showed no effect [15], [16]. These divergent effects of estrogen may be influenced by the specific anxiety task, the duration of estrogen treatment and the animal species or strain.
There are a number of studies demonstrating that estrogen could modulate serotonergic neurotransmission through changes in the number of serotonergic receptors, serotonin reuptake transporters, monoamine oxidase or tryptophan hydroxylase activities [reviewed by Ref. [17]]. Furthermore, selective serotonin reuptake inhibitors (SSRIs) in combination with estrogen treatment could enhance their effectiveness [18]. In addition to the serotonergic system, noradrenergic and dopaminergic systems also respond to estrogen as well. For instance, the increased levels of tyrosine hydroxylase mRNA [19] and the potentiation of dopaminergic neuron activity were demonstrated following estrogen treatment [20], [21]. Further, during proestrus, the rise in estrogen levels in rats could increase norepinephrine and dopamine turnover rates [22], [23]. On the other hand, Ovx female rats had impaired catecholaminergic activity with an increase in norepinephrine release and a decrease in dopamine release [22], [23].
Monoaminergic neurotransmitters, serotonin, norepinephrine, dopamine, are thought to play an important role in the pathophysiology of anxiety. Clinical trials have demonstrated that SSRIs, such as paroxetine and fluoxetine are anxiolytic [24], [25]. In addition to serotonin, anxiety has also been associated with dysregulation of brain norepinephrine. Panic-like anxiety was elicited in patients after oral administration of an α2-adrenergic receptor antagonist [26], whereas the administration of an α2-adrenergic receptor agonist produced less anxiety and fear [27], [28], [29]. For the dopamine system, anxiety-related behaviors could be produced following dopaminergic agonists [30], [31] and were reduced in D3 dopamine receptor knockout mice [32]. Therefore, anxiety is not regulated by one system of neurotransmitters, but is controlled by complex combinations of these systems and may further be modulated with hormones.
While evidence of estrogen's effects on anxiety is growing, the specific processes by which the hormone regulates anxiety are currently unclear. The present study was designed to examine the effects of chronic estrogen treatment (4 weeks) on anxiety-like behavior utilizing the EPM test. Furthermore, we investigated the changes of monoamine levels, following the EPM task, in brain areas involved in anxiety in rats using high-performance liquid chromatography (HPLC)-electrochemical detection (ECD). We hypothesized that chronic estrogen treatment in Ovx rats would decrease anxiety, as evidenced by increased exploration of the EPM test, with a corresponding change in monoamine concentrations in brain areas related to anxiety.
Section snippets
Animals
Adult female Wistar rats weighing 170–190 g at the beginning of the experiments were obtained from the National Laboratory Animal Center, Mahidol University (NLAC-MU), Thailand. All animals were housed two per cage and were maintained at 25 ± 2 °C on 12-h light/dark cycles with lights on at 0600 h and were given standard rat chow and water ad libitum. Body weight and food intake were measured daily and uterine weight was determined on the day of sacrifice. All procedures were done with the
Body weight, food intake and uterine weight
Initial body weights did not differ among groups (Table 1). Four weeks after ovariectomy, the Ovx rats demonstrated a significantly higher body weight (t(12) = 5.87; P < 0.001) and daily weight gain (t = 4.93; P < 0.001) when compared to the Ovx + E2 group (Table 1). In addition, the daily food intakes were greater (t = 6.88; P < 0.001) in the Ovx rats compared to the Ovx + E2 rats (Table 1). As expected, the uterine weights of the Ovx rats were significantly lower than the Ovx + E2 rats (t = 9.51; P < 0.001).
Discussion
In the present study, we evaluated the effects of estrogen on anxiety-related behavior and monoaminergic neurotransmissions in Ovx rats with or without estrogen supplementation. Four weeks after ovariectomy, rats were tested with the EPM to assess the state of anxiety. As we expected, estrogen-treated rats spent more time exploring the aversive open arms as indicated by more time spent in these arms, as well as a higher time per entry in these arms. We suggest that such increases may indicate
Acknowledgements
This research was supported in part by the Veterinary Research Fund of the Faculty of Veterinary Science (RG21/2548), Chulalongkorn University, Bangkok, Thailand. We would like to thank Dr. Karen A. Keller, Ph.D., for her assistance in the correction of the manuscript.
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