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Raphe-Hippocampal Serotonin Neurotransmission In The Sex Related Differences of Adaptation to Stress: Focus on Serotonin-1A Receptor.
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Stress is the major predisposing and precipitating factor in the onset of depression which is the most significant mental health risk for women. Behavioral studies in animal models show that female sex though less affected by an acute stressor; exposure to repeated stressors induces coping deficits to impair adaptation in them. A decrease in the function of 5-hydroxytryptamine (5-HT; serotonin) in the hippocampus and an increased function of the 5-HT-1A receptor in the raphe nucleus coexist in depression. Pharmacological and neurochemical data are relevant that facilitation of serotonin neurotransmission via hippocampus due to desensitization of somatodendritic 5-HT1A receptors may lead to adaptation to stress. The present article reviews research on sex related differences of raphe-hippocampal serotonin neurotransmission to find a possible answer that may account for the sex differences of adaptation to stress reported in preclinical research and greater incidence of depression in women than men.
Authors:
Darakhshan Jabeen Haleem
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Type:  Journal Article    
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Title:  Current neuropharmacology     Volume:  9     ISSN:  1875-6190     ISO Abbreviation:  Curr Neuropharmacol     Publication Date:  2011 Sep 
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Created Date:  2012-03-01     Completed Date:  2012-08-23     Revised Date:  2013-05-29    
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Nlm Unique ID:  101157239     Medline TA:  Curr Neuropharmacol     Country:  United Arab Emirates    
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Languages:  eng     Pagination:  512-21     Citation Subset:  -    
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Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research Unit, University of Karachi, Karachi 75270, Pakistan.
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Journal ID (nlm-ta): Curr Neuropharmacol
Journal ID (publisher-id): CN
ISSN: 1570-159X
ISSN: 1875-6190
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Received Day: 19 Month: 1 Year: 2010
Revision Received Day: 7 Month: 5 Year: 2010
Accepted Day: 29 Month: 10 Year: 2010
Print publication date: Month: 9 Year: 2011
Volume: 9 Issue: 3
First Page: 512 Last Page: 521
ID: 3151603
PubMed Id: 22379463
Publisher Id: CN-9-512
DOI: 10.2174/157015911796558019

Raphe-Hippocampal Serotonin Neurotransmission In The Sex Related Differences of Adaptation to Stress: Focus on Serotonin-1A Receptor
Darakhshan Jabeen Haleem*
Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research Unit, University of Karachi, Karachi 75270, Pakistan
*Address correspondence to this author at the Department of Biochemistry University of Karachi, Karachi 75270, Pakistan; Tel: 03003390776; E-mails: darakhshan_haleem@yahoo.com, djhaleem@uok.edu.pk

1.  INTRODUCTION

It is well accepted that males and females can behave differently but how much of that difference is attributable to genetic, environmental and neurobiological factors has often been a matter of debate [1-3]. Evidence suggests that the effects of sex hormones on brain organization occur so early in life that from the start the environment is acting on differently wired brains in the two sexes. Human studies on sex differences of brain function are often supported by preclinical research suggesting that the differences are attributable to biological differences between males and females because there are few environmental or socio-cultural factors to consider in preclinical research.

Women are at least twice as likely as men to suffer from depression and anxiety [4-6]. These sex differences are seen in different countries and cultures, suggesting a biological basis. Evidence from animal studies also suggests that behavioral and neurobiological effects of stress are sexually dimorphic. However, despite great interest in this area [7], mechanisms that may contribute to this striking sex difference have remained elusive.

A dysfunctional 5-hydroxytryptamine (5-HT; serotonin)-ergic system is a vulnerability factor for major depressive disorder and other forms of affective illnesses [2]. At least 14 different types and subtypes of serotonin receptors have been identified [8]. A number of these receptors such as 5-HT-2 [9, 10], 5-HT-3 [11] and 5-HT-1A [12] receptors play a role in the genesis of psychiatric illnesses. Studies on animal models show that raphe hippocampal serotonin neurotransmission and its regulation via 5-HT-1A receptors can explain vulnerability or resistance to stress stimuli. The 5-HT-1A receptor which is a key mediator of serotonergic signaling in the central nervous system is also implicated in the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) [13-16], while some studies indicate that sex may moderate the response to antidepressants with women exhibiting a preferential response to SSRIs compared to tricyclic antidepressants (TCAs) [17].

Cell bodies of serotonin containing neurons are located in the raphe nuclei in the brain stem. The 5-HT-1A receptor is a G-protein-coupled receptor widely distributed in regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdale, hippocampus and hypothalamus [18, 19]. It also serves as somatodendritic autoreceptor of raphe nuclei reducing the firing rate of serotonergic neurons [8, 20-22]. The hippocampus has been extensively studied with regard to stress, depression and antidepressant action [23-25]. Sex related differences of raphe-hippocampal serotonin neurotransmission with a particular focus on 5-HT-1A receptors are accumulated in the present review as this may account for the gender differences of adaptation to stress and greater incidence of depression in women than men.


STRESS, DEPRESSION AND THE GENDER DIFFERENCE

The hypothesis that stress is the major precipitating factor in the onset of depression is consistently supported by clinical and preclinical studies [26-28] showing the relationship between previous traumatic stressful event (predisposing factor) and subsequent other stressor (precipitating factor). Both physical and psychological stressors have been shown to lead to the onset of a depressive episode. Sex in genetically predisoposed subjects may result in depression [29]. Studies in female twins show a clear interaction between genetic loading and exposure to a recent stressful life event in the precipitation of depressive episode [30].

In a study of 4,856 individuals (53% female) experiencing depression, it has been seen that different types of adverse life events are associated with different depressive symptoms profile [31]. In a follow-up study of over 7 years in 266 middle aged women, without a history of major depression at base line, 15.8% women met criteria for major depression [32]. These researchers reported that lifetime history of anxiety disorder and very stressful life events are important contributing factors in the onset of first episode of major depression.

Major depressive disorder is two times more prevalent in women than in men [4, 6, 33, 34]. The mean age of onset, the overall course of depression and the risk for chronic or recurrent depression does not differ between sexes [35], although some studies suggest that women have a higher rate of recurrent depression and slower recovery from a depressive episode [36].

Women are approximately three times more likely to develop depression in response to stress because they experience more stressful events [30, 37-39]. Women report more depressive symptoms than men, with an emphasis on worthlessness, decreased sexual interest, guilt feelings, insomnia, anxiety, and gastrointestinal symptoms [36, 40]. This prominent gender difference in depression begins in adolescence, prior to which the incidence of major depression is equal in girls and boys, suggesting the potential role of female sex hormones in female depression vulnerability [41]. Many depressed women also exhibit anxiety symptoms, and it has been suggested that women may be more likely to suffer from mixed anxiety-depressive disorder [42, 43]. Polymorphic variations in 5-HT transporter, MAO-A or 5-HT receptor may be involved in the sex related differences of adaptation to stress [29].


STRESS CONTROLLABILITY AND LEARNED HELPLESSNESS IN ANIMAL MODELS

Based upon the clinical evidence that links stressful life events with depressive episodes several animal models exhibiting stressor controllability and learned helplessness have been developed [44-47]. The most common animal model of 'stress and coping' is that of 'learned helplessness' [48, 49] in which animals are exposed to either controllable or uncontrollable stressful events and later, they are tested on a new task in which all animals are given the opportunity to control the stressor, usually by escape. In most reports, animals that are exposed to uncontrollable stressful events do not learn to escape during testing on the new task [50, 51]. This behavior has been equated with a sense of 'giving up', experienced by humans with major depression [52].

Animal models of depression should fulfill three major criteria [47]. The first criterion “face validity” assesses how well the symptoms observed in animals resemble those in human patients. The second criterion “predictive validity” addresses the question how well animals in the model respond favorably to the same drugs as human do under the same treatment conditions. The third criterion “construct validity” assesses to what extent the model is consistent with the theoretical rationale.

The learned helplessness paradigm was not developed to provide an animal model of depression or anxiety but it was shown in later studies that the model is sensitive to both antidepressants [53, 54] and anxiolytics [55-58]. Implications for the learned helplessness paradigm as an animal model of either depression or anxiety have been discussed [45,59]. The paradigm is widely used to understand neural mechanism and degree of behavioral adaptation to an uncontrollable stressor [60-63].

Animals exposed to other unpredictable and uncontrollable stressor e.g. restraint stress, elevated platform and forced swimming also show coping deficits for aversive but escapable situations [64, 65]. Chronic mild stress also causes behavioral changes in animals that parallels symptoms of depression [66, 67].


SEX RELATED DIFFERENCES IN ADAPTATION TO STRESS

Although learned helplessness is an established model for clinical depression and anxiety, and has been investigated for about 40 years, only few studies have used female animals in the learned helplessness paradigm. The female preponderance of depression is also, heretofore, not been consistently reflected in animal models (Table 1). Surprisingly, evidence from animal studies suggests that females are relatively resistant to the behavioral effects of an acute stress compared to males.

Exposure to inescapable foot shock disrupted shuttle box-escape performance of males, whereas, escape performance of females was unaffected [68]. Escape latencies increased in both males and females but the increases were greater in male rats [69]. In the elevated plus-maze also, exposure to inescapable foot shock resulted in suppression of “total number of arm entries” and “rearings” in males but not in females [70]. In addition “time on open arms” was reduced in both sexes, but this effect was stronger in males than in females. No sex based difference was found in learned helplessness behavior in another study [71] which reported that females to be more vulnerable than males to stress-induced elevations in homocysteine but not escape deficits.

Exposure to controllable stress (escapable foots hock) alleviated the expression of helplessness behavior in both females and males, but females learned to escape more rapidly than did males [72]. Moreover, modulation of controllability i.e exposure to inescapable foot shock produced helpless behavior in males but females were less likely to become helpless [72].

Male rats were more vulnerable to restraint stress than that of the female rats because open field behavior of female rats was less affected by a single 2h restraint stress than that of the male rats, though food intake was comparably decreased [73]. Male animals exhibited more immobility than females in the forced swimming test [3, 74-78] but young female rats were more vulnerable than males in an open space swim test [79].

Male rats were also more vulnerable to a mild lipopolysaccharide (LPS) challenge than that of female rats as assessed in both forced swim and open field test [80] because LPS challenge decreased open field activity in male but not female rats. LPS-treated female rats coped better with the stressful forced swimming procedure, as evidenced by an increase in swimming duration while in males swimming duration was not altered by LPS administration [80].

In striking contrast female but not male rats exhibited deficits of open field behavior after exposure to repeated restraint stresses [64, 73, 81, 82]. Female rats were more vulnerable to chronic mild stress as depicted by the disruption of sucrose intake and decreases of open field activity [66]. But in response to an additional forced swim test, females previously exposed to chronic mild stress, were found to cope better than males. The sex differences in helplessness behavior were not dependent on the presence of sex hormones in adulthood, because neither ovariectomy of females nor castration of males abolished those [83].

In general sex related studies on animal models show that female performance though better than males if exposed to an acute stressor but repeated or chronic exposure induces coping deficits to impair adaptation making female sex more vulnerable to depression. Data in Fig. (1) (Haleem unpublished data), similar to previously reported studies [64, 73, 81] show that male and female rats exposed to 2h restraint stress exhibited a decrease in open field activity monitored on the following day but the decreases were smaller and not significant in female rats. These differences were not attributable to the effects of entrained oestrus cycles in females as these were randomly distributed [73, 81]. Conversely, following repeated (2h/day for 5 days) exposure to restraint stress the deficits of open field exploration were present in female but not male rats (Fig. 1).


RAPHE-HIPPOCAMPAL SEROTONIN NEUROTRANSMISSION AND ADAPTATION TO STRESS

Early indications that central serotonin system may be involved in responses to stress came from studies on male rats demonstrating that acute stress procedures like immobilization, forced swimming and cold exposure increased brain 5-HT metabolism [84, 85]. Since then evidence has accumulated that 5-HT turnover is enhanced by following exposure to various stressors including exercise and foot shock although brain levels of 5-HT are not always altered [1, 4, 86-88]. It has been also shown that stress-induced increases of brain serotonin are caused by an increase in the availability of tryptophan [86, 88], the precursor of 5-HT, or an increase in the activity of tryptophan hydroxylase [89-92], the rate limiting enzyme of 5-HT biosynthesis. Microdialysis studies showed an increase in extracellular levels of serotonin [93-95] in different areas of the brain following exposure to different types of stressors.

A role of hippocampus in responses to stress, first reported from our laboratory [90], also emerged from studies on male rats. We found that acute exposure to an episode of 2h restraint stress increased 5-HT turnover in the hypothalamus, midbrain and cortex but the increases did not occur in the hippocampus [90]. Conversely, repeated daily exposure to 2h/day restraint, which produced behavioral adaptation, increased 5-HT turnover in the hippocampus only and not in other brain regions. It was suggested that an increase in serotonin neurotransmission via hippocampus is involved in adaptation to stress.

Later studies, performed on male animals, also consistently showed that hippocampus may mediate adaptation to severe inescapable stressor by the facilitation of serotonergic neurotransmission (Table 2). Acute exposure to an elevated platform enhanced 5-HT overflow in the prefrontal cortex but not dorsal hippocampus whereas repeated daily exposure to the same stressor increased extracellular 5-HT in the dorsal hippocampus but not the prefrontal cortex [65]. In another study rats received inescapable foot shock and were tested in a shuttle box 24 h later. Pre stressed animals exhibited impairment of escape responses. This effect was prevented by bilateral intra hippocampal injection of zimelidine, a serotonin reuptake blocker but not by desipramine, a noradrenaline reuptake blocker [96]. Neurogenesis in the dentate gyrus of the hippocampus was enhanced by the activation of serotonin receptors [97]. It was suppressed by stress and the suppression prevented by 5-HT-1A receptor agonists [98].

The synthesis and release of 5-HT in all brain regions including the hippocampus [20-22, 99] is under the control of an effective feedback mechanism involving the stimulation of 5-HT-1A receptors located on the soma and dendrites [100] of the serotonergic neurons in the raphe nucleus. 5-HT1B receptors located at the terminal ends of the serotonergic neurons [101] also control the release of 5-HT via a feedback mechanism [102]. Studies on the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants showed that repeated administration of these drugs increased 5-HT neurotransmission by either decreasing the sensitivity of presynaptic receptor or increasing the sensitivity of postsynaptic 5-HT-1A receptor in the dorsal hippocampus [13, 14, 16, 103]. Consequently it was suggested that a decrease in the function of the 5-HT in the hippocampus and an increased function of the 5-HT-1A receptor in the raphe nucleus coexist in depression.

Studies using learned helplessness model of anxiety/depression and chronic stress model of depression also support the role of 5-HT-1A receptor in adaptation to stress. Thus, rats adapted to repeated restrain stress schedule of 2h/day for 5 days exhibited a decrease in the sensitivity of somatodendritic 5-HT-1A [60, 104] and terminal 5-HT-1B [105] receptors: an effect similar to antidepressant like effect. It was suggested that a decrease in the negative feedback control due to desensitization of auto receptors increases the availability of 5-HT in terminal regions to help cope the stress demand and produce adaptation to stress (Fig 2). Conversely, exposure to inescapable but not escapable stressors sensitized serotonergic neurons in the raphe region to subsequent input [85]. Acute exposure to 2h restraint stress [106] as well as long term starvation [107] increased the responsiveness of somatodendritic 5-HT-1A receptor to decrease serotonin neurotransmission particularly via raphe-hippcampal pathway (Fig. 2). A decrease in the density of 5-HT-1A receptor in the hippocampus also occurred in rats exposed to restraint stress [98, 108, 109]. Rats exposed to different mild to moderate stressors every day, therefore making the daily stress exposure unpredictable exhibited a significant decrease in 5-HT-1A mRNA and 5-HT-1A receptor binding in the hippocampus [23].

It may be argued that a desensitization and super sensitization respectively of autoreceptors would be expected to increase and decrease the availability of 5-HT in all brain regions innervated by serotonergic neurons and not particularly in the hippocampus [90]. An explanation to this could be that postsynaptic 5-HT-1A receptors also control the synthesis and release of 5-HT via feedback mechanism. Hippocampus is enriched with 5-HT-1A receptor [110] and receives serotonergic innervations from median raphe [111]. Many innervated areas project back to raphe nuclei and these are interconnected [112]. It is therefore possible that postsynaptic 5-HT-1A receptors also alter the median raphe nucleus 5-HT neuronal firing [15]. It is also possible that the effects are mediated via stress-induced release of corticosteroid hormones. Hippocampus is enriched with high affinity mineralocorticoid receptors and lower affinity glucocorticoid receptors at which corticosteroids bind to alter 5-HT-1A receptor mediated responses, reviewed by Joel, [113].


SEX-DIFFERENCES IN RAPHE-HIPPOCAMPAL SEROTONIN NEUROTRANSMISSION

If facilitation of serotonin neurotransmission due to desensitization of somatodendritic 5-HT-1A receptor increasing the availability of 5-HT in the hippocampus mediates adaptation to stress, the sex differences of somatodendritic 5-HT-1A receptors become important. Sexual dimorphism in the serotonin was first reported in early 1960’s [114]. An increasing amount of later work supported the view that central serotonin metabolism synthesis and functional responses are greater in female than male rats [20, 115-117]. It was also observed that sex differences of 5-HT were particularly larger in the hippocampus [20].

Sex differences also occur in the regulation of serotonin neurotransmission via 5-HT-1A receptors [118]. Expression of serotonin-1A receptor messenger RNA was greater in males in the hypothalamus and amygdala, and less in males in the hippocampus [119]. The concentrations of 5-HT and 5-HIAA were greater in the hippocampus of female than male rats. The 5-HT-1A agonist 8-hydroxy-2 (di-n-propylamino) tetralin caused comparable decreases of 5-HT and 5-HIAA in both sexes in the hypothalamus, cortex and midbrain except the hippocampus where the decreases were twice as large in the females as in males [20]. It suggests that the sensitivity of 5-HT-1A receptors that control the availability of 5-HT in the hippocampus (Fig. 2) is greater in female sex.

A few studies have examined sex influence on the role of hippocampus in responses to stress. Female in proestrus exhibited greater density of dendritic spines in the area CA1 of the hippocampus than males [120]. In response to acute stressful event of intermittent shocks, spine density was enhanced in the male hippocampus but reduced in the female hippocampus. Effects of early experience on the dendritic structure of dentate gyrus were also sexually dimorphic [121]. Thus female rats raised in an enriched environment displayed increased dendritic bushiness relative to males raised in the same environment. Conversely, neonatal handling resulted in an increase in postsynaptic serotonin neurotransmission in the hippocampus of male rats but decreased it in females [122]. LPS treatment induced a female-specific enhancement of 5-HIAA levels in the hippocampus and some other regions [80].

In a study of sex influence and isolation housing on 5-HT-1A receptor binding female mice displayed lower postsynaptic 5-HT-1A receptor binding compared to males in the hippocampus. Subsequently, following 6 weeks isolation housing 5-HT-1A receptor binding was further increased in males but not in females [123]. Conversely, forced swimming was found to decrease 5-HT-1A receptor binding in the hippocampus of female but not male rats [124]. Serotonin-1A mRNA, protein and binding sites, were greater in the hippocampi of pre-pubertal female than male rats. These were decreased more by neonatal handling and the decreases were greater in female sex [122].

Sex related studies therefore show that male and female animals have different levels of serotonin neurotransmission via raphe- hippocampal pathway under unstressed condition, which can respond in opposite directions to the same stressor. Females have greater serotonin content but an exaggerated feedback control over raphe-hippocampal serotonin neurotransmission via 5-HT-1A receptors making this sex more vulnerable to depression.

It is worth considering that serotonin functions are modulated by corticosteroids [113, 125, 126] while stress-induced [81] as well as 5-HT-1A agonist-induced [82] increase of plasma corticosterone, the principal corticosteroid secreted by the rat adrenal gland, are greater in female than male rats suggesting an important role of circulating corticosteroids in the sex related differences of raphe hippocampal serotonin neurotransmission in adaptation to stress. Influence of MAO-A genotype on 5-HT-1A receptor availability or polymorphic variations of 5-HT transporters [108] may well be involved in these sex differences of 5-HT-1A expression.

5-HT-1A receptor dependent responses are also modulated by estrogen. Thus, acute estrogen treatment prevented 5-HT1A receptor-induced disruption of Prepulse inhibition in healthy women [127]. Although, estrogen treatment to ovariectomized rats had no effect on the number or affinity of 5-HT1A binding sites labeled with [3H]8-OH-DPAT but 5-HT1A-mediated inhibition of adenylate cyclase selectively increased in the hippocampus [128]. A role of glutamate receptors in the sex related differences of adaptation to stress is also possible because antidepressant like activity of chromium chloride in the forced swim test in mice was inhibited by antagonists of glutamate receptors as well as antagonists of 5-HT-1A receptors [129].


POSSIBLE CLINICAL RELEVANCE

There is wealth of clinical evidence supporting sex difference in 5-HT-1A receptor function. Investigations have also been made to show that variation in 5-HT-1A expression is genetically mediated [130, 131].

Age related sexual dimorphism of 5-HT-1A receptor binding potential was initially observed in various brain tissues obtained from autopsy subjects. In this study men exhibited a significant age dependent decrease in the dissociation constant (Kd) for 5-HT-1A receptor binding in the occipital cortex; in women maximum binding capacity (Bmax) decreased with aging in the parietal cortex and hippocampus [132].

Parsey et al. [133] did not find an age related decrease in 5-HT-1A binding potential in healthy men or women. However, they found higher 5-HT-1A binding potential in the dorsal raphe and many forebrain regions of women than men. Conversely, 5-HT-2 receptor binding capacity was higher in healthy men than healthy women [134]. Staley et al. [135] observed higher 5-HT transporter availability in healthy women than men, but lower 5-HT transporter availability in depressed women than depressed men [136]. Javanovic et al. [137] also observed that compared to healthy men healthy women had significantly higher 5-HT-1A receptor but lower 5-HT transporter binding potential in a wide array of cortical and subcortical brain regions but in the follicular phase, women did not differ from men in the 5-HT1A receptor binding [138].

Several strands of evidence have emerged that specifically implicate 5-HT-1A receptors in depression and therapeutic effects of antidepressant drugs. Men and women patients with major depression exhibited attenuation of 5-HT-1A receptor mediated neuroendocrine and hypothermic responses reflecting a decrease in the effectiveness of postsynaptic and somatodendritic 5-HT-1A receptors respectively [46, 139, 140]. A decrease in 5-HT-1A binding potential has been also observed in the multiple brain areas including raphe region of men and women patients with major depression and bipolar disorder [141-143]. In another study, patients with major depression who have never been exposed to medication were found to have higher 5-HT-1A receptor binding compared to the depressed patients with a history of medication and control [133] suggesting the 5-HT-1A binding potential to be affected by medication. Higher 5-HT1A binding potential in the raphe and hippocampus in bipolar depressed males but not in bipolar depressed females has been also reported [68].

Currently the most common class of effective antidepressants is SSRIs that acts by selectively blocking the high affinity reuptake of serotonin. Approximately 78% of the prescribed SSRIs are given to women [5], while some studies indicate that sex may moderate the response to antidepressants with women exhibiting a preferential response to SSRIs compared to TCAs. Investigations addressing gender differences in response to SSRI (sertraline) and imipramine treatment in male and female patients with chronic depression have reported that premenopausal women had a favorable response to sertraline than to imipramine [17, 144]. Postmenopausal women exhibited similar response to the two medications and men exhibited a more favorable response to impramine than to sertraline. Martenyi et al. [145] compared treatment efficacy of SSRI (fluoxetine) and SNRI (maprotiline) in men and women patients of unipolar depression. They found a significant difference between treatment groups in females but not in males. Amongst females the difference was significant in women aged <44 years but not >44 years suggesting that women in their reproductive period are more responsive to SSRIs than SNRIs. In a recent study, Young et al. [146] have reported that women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.


CONCLUSION

The evidence accumulated in the present article suggests that raphe hippocampal serotonin neurotransmission and its regulation by 5-HT-1A receptors has an important role in the sex related differences of adaptation to stress. Greater 5-HT neurotransmission via postsynaptic 5-HT-1A receptors in the hippocampus makes female sex more resistant to an acute stressor. On the other hand, greater efficacy of feedback control over 5-HT synthesis and release mediated via 5-HT-1A receptors could impair adaptation making the female sex more vulnerable to repeated and/or chronic stressors. In the quest to understand the mechanism of sex related differences in adaptation to stress, the role of raphe-hippocampal serotonin neurotransmission and its regulation by 5-HT-1A receptors can only be a small part of a big picture. The mechanisms through which estrogen and glucocorticoids can modulate serotonin neurotransmission and functional polymorphisms in the 5-HT transporter gene are also worth considering for an understanding of sex related differences of adaptation to stress. Despite heightened complexity it implies that the issue of sex related differences of brain function is not less important because it may provide ways to understand novel mechanisms of brain function.


ACKNOWLEDGEMENT

The author would like to thank Higher education Commission, Pakistan Science Foundation and Karachi University for providing research grants.


REFERENCES
1. Andrews MH,Matthews SG. Programming of the Hypothalamo-Pituitary-Adrenal Axis: Serotonergic InvolvementStressYear: 20047527
2. Jans LA,Riedel WJ,Markus CR,Blokland A. Serotonergic vulnerability and depression: assumptions, experimental evidence and implicationsMol. PsychiatryYear: 20071252254317160067
3. Vigod SN,Stewart DE. Emergent research in the cause of mental illness in women across the life spanCurr. Opin. PsychiatryYear: 20092239640019276809
4. Bebbington P,Dunn G,Jenkins R,Lewis G,Brugha T, Farrell M,Meltzer H. The influence of age and sex on the prevalence of depressive conditions: report from the National Survey of Psychiatric MorbidityInt. Rev. PsychiatryYear: 200315748312745313
5. Kessler R C. Epidemiology of women and depressionJ. Affect. DisorderYear: 200374513
6. Kornstein SG,Schatzberg AF,Thase ME,Yonkers KA,McCullough JP,Keitner GI,Gelenberg AJ,Ryan CE,Hess AL,Harrison W,Davis SM,Keller MB. Gender differences in chronic double and major depressionJ. Affect. DisorderYear: 200060111
7. De Vries GJ. Sex differences in adult and developing brain: Compensation, compensation, compensationEndocrinologyYear: 20041451063106814670982
8. Hoyer D,Hannon JP,Martin GR. Molecular pharmacological and functional diversity of 5-HT receptorsPharmacol. Biochem. BehavYear: 20027153355411888546
9. Christiansen L,Tan Q,Iachina M,Bathum L,Kruse TA,McGue M,Christensen K. Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomlogy in an elderly populationBiol. PsychiatryYear: 20076122323016806099
10. McMahon FJ,Buervenich S,Charney D,Lipsky R,Rush AJ,Wilson AF,Sorant AJ,Papanicolaou GJ,Laje G,Fava M,Trivedi MH,Wisniewski SR,Manji H. Variation in the gene encoding the serotonin-2A receptor is associated with outcome of antidepressant treatmentAm. J. Hum. GenetYear: 20067880481416642436
11. Niesler B,Kapeller J,Hammer C,Rappold G. Serotonin type 3 receptor genes: HTR3A, B, C, D, EPharmacogenomicsYear: 2008950150418466097
12. Savitz J,Lucki I,Drevets WC. 5-HT-1A receptor function in major depressive disorderProg. NeurobiolYear: 200988173119428959
13. Artigas F,Bel N,Casanovas JM,Romero L. Adaptive changes of the serotonergic system after antidepressant treatmentsAdv. Exp. Med. BiolYear: 199639851598906240
14. Barton CL,Hutson PH. Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: evidence for the involvement of both 5-HT-1A and 5-HT1B/D autoreceptorsSynapseYear: 199131131910025679
15. Blier P,de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HT-1A agonist gepirone: electrophysiological studies in the rat brainSynapseYear: 198714704802905533
16. Gardier AM,Wurtman RJ. Persistent blockade of potassium-evoked serotonin release from rat frontocortical terminals after fluoxetine administrationBrain ResYear: 19915403253301711396
17. Kornstein SG,Schatzberg AF,Thase ME,Yonkers KA,McCullough JP,Keitner GI,Gelenberg A,Davis SD,Harrison WH,Keller MB. Gender differences in treatment response to sertraline versus imipramine in chronic depressionAm. J. PsychiatryYear: 20001571445145210964861
18. Lesch KP,Gutknecht L. Focus on the 5-HT-1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogeneticsInt. J. NeuropsychopharmacolYear: 2004738138515683551
19. Sharp T,Boothman L,Raley J,Queree P. Important measures in the post recent discoveries in 5-HT neuron feedback controlTrends Pharmacol. Sci.Year: 20072862963617996955
20. Haleem DJ,Kennett GA,Curzon G. Hippocampal 5-HT synhesis is greater in females than in males and is more decreased by 5-HT-1A agonist 8-OH-DPATJ. Neural TransmYear: 19907993101
21. Hutson PH,Dourish CT,Curzon . Neurochemical and behavioral evidence for mediation of the hyperphagic action of 8-OH-DPAT by cell body autoreceptorsEur. J. PharmacolYear: 19861293473522430815
22. Sharp T,Bramwell SR,Hjorth S,Grahame-Smith DJ. Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysisBr. J. PharmacolYear: 1989989899972574066
23. Lopez JF,Chalmers D,Little KY,Watson SJ. Regulation of 5-HT-1A receptor, glucocorticoid mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depressionBiol. PsychiatryYear: 1998435475739564441
24. McEwen BS. Stress and hippocampal plasticityAnn. Rev. NeurosciYear: 19992210512210202533
25. McEwen BS. The neurobiology of stress: from serendipity to clinical relevanceBrain ResYear: 200088617218911119695
26. Anisman H. Cascading effects of stressors and inflammatory immune system activation: implication for major depressive disorderRev. Psychiatr. NeurosciYear: 200934420
27. Bale TL. Stress sensitivity and the development of affective disordersHorm. BehavYear: 20065052953316901485
28. Gilbert G,Gilbert J,Irons C. Life events, entrapments and arrested anger in depressionJ. Affect. DisorderYear: 200479149160
29. Jabbi M,Korf J,Ormel J,Kema IP,Den Boer JA. Investigating the molecular basis of major depressive disorder etiology, A functional convergent genetic approach. Stress, neurotransmitter and hormonesAnn. NY. Acad. SciYear: 20081148425619120090
30. Kendler KS,Kuhn J,Prescott CA. The relationship of neuroticism, sex and stressful life events in the prediction of episodes of major depressionAm. J. PsychiatryYear: 200416163163615056508
31. Keller MC,Neale MC,Kendler KS. Association of deifferent adverse life events with distinct pattern of depressive symptomsAm. J. PsychiatryYear: 20071641521152917898343
32. Bromberger JT,Kravitz HM,Matthews K,Youk A,Brown C,Feng W. Predictors of first life time episodes of major depression in midlife womenPsychol. MedYear: 200939556418377672
33. Kessler RC. The effects of life events on depressionAnn. Rev. PsycholYear: 1997481912149046559
34. Oquendo M,Ellis S,Greenwald S,Malone K,Weissman M,Mann J. Ethnic and sex differences in suicide rates relative to major depression in the United StatesAm. J. PsychiatryYear: 20011581652165811578998
35. Kessler R,McGonagle K,Swartz M,Blazer D,Nelson C. Sex and depression in the National Comorbidity Survey, I: Life-time prevalence, chronicity and recurrenceJ. Affect. DisordYear: 19932985968300981
36. Ernst C,Angst J. The Zurich Study XII: Sex differences in depression: Evidence from longitudinal epidemiological dataEur. Arch. Psychiatry Clin. NeurosciYear: 19922412222301576178
37. Kendler KS,Thrornton LM,Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesisAm. J. PsychiatryYear: 20001571243125110910786
38. Maciejewski P,Prigerson H,Mazure C. Sex differences in event-related risk for major depressionPsychol. MedYear: 20013159360411352362
39. Mazure C,Maciejewski P. The interplay of stress, gender and cognitive styleArch. Women Ment. HealthYear: 2003658
40. Silverstein B. Gender differences in the prevalence of clinical depression: The role played by depression associated with somatic symptomsAm. J. PsychiatryYear: 199915648048210080570
41. Payne JL. The role of estrogen in mood disorder in womenIntern. Rev. PsychiatryYear: 200315280290
42. Lewinsohn PM,Rohde P,Seeley JR,Baldwin CL. Gender differences in suicide attempts from adolescence to young adulthoodJ. Am. Acad. Child Adolesc. PsychiatryYear: 20014042743411314568
43. Piggot A. Gender differences in the epidemiology and treatment of anxiety disordersJ. Clin. PsychiatryYear: 199960Suppl 18 415
44. Chourbaji S,Zacher C,Sanchis-Sequra C,Dormann C,Vollmayr B,Gass P. Learned helplessness: validity and reliability of depressive like states in miceBrain Res. Brain Res. ProtocYear: 200516707816338640
45. Maier SF,Watkin LR. Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotrophin releasing factorNeurosci. Biobehav. RevYear: 20052982984115893820
46. Shapira B,Newman M E,Gelfin Y,Lerer B. Blunted temperature and cortisol response to ipsapirone in major depression: lack of enhancement by electroconvulsive therapyPsychoneuroendocrinologyYear: 20002542143810818278
47. Willner P. The validity of animal model of depressionPsychopharmacologyYear: 1984831166429692
48. Maier SF. Learned helplessness and animal models of depressionProg. Neuropsychopharmacol. Biol. PsychiatryYear: 198484354466385140
49. Seligman M E,Beagley G. Learned helplessness in the ratJ. Comp. Physiol. PsycholYear: 1975885345411150935
50. Overmier JB,Seligman M E. Effects of inescapable shock upon subsequent escape and avoidance respondingJ. Comp. Physiol. PsycholYear: 196763 28336029715
51. Seligman M E,Maier S F. Failure to escape traumatic shockJ. Exp. PsycholYear: 196774196032570
52. Miller WR,Seligman ME. Depression and learned helplessness in manJ. Abnorm. PsycholYear: 1975842282381169264
53. Gambarana C,Scheggi S,Tagliamonte A,Pierluigi T,De Montis MG. Animal models for the study of antidepressant activityBrain Res. Brain Res. ProtocYear: 20017112011275519
54. Petty F,Davis LL,Dabel D,Kramer GL. Serotonin dysfunction disorders: a behavioral neurochemistry perspectiveJ. Clin. PsychiatYear: 1996571116
55. Drugan RC,Ryan SM,Minor TR,Maier SF. Librium prevents the analgesic and shuttlebox escape deficits typically observed following inescapable shockPharmacol. Biochem. BehavYear: 1984217497546542677
56. Maier SF,Kalman BA,Sutton LC,Wiertelak EP,Watkin LR. The role of the amygdale and dorsal raphe nucleus in mediating behavioral consequences of inescapable shockBehav. NeurosciYear: 19931073773888484901
57. Maier SF,Kalman B A,Grahn R E. Chlordiazepoxide microinjected in the region of the dorsal raphe nucleus eliminates the interference with escape responding produced by inescacapable shock whether administered before inescapable shock or escape testingBehav. NeurosciYear: 19971081211308192838
58. Short KR,Maier SF. Stressor controllability, social interaction and benzodiazepine systemsPharmacol. Biochem. BehavYear: 1993458278358415822
59. Vollmayr B,Henn F A. Learned helplessness in the rat: improvements in the validity and reliabilityBrain Res. Brain Res. ProtocYear: 200181711522522
60. Haleem DJ. Serotonergic mechanism of antidepressant action and adaptation to stressJ. Coll. Physician Surg. PakYear: 19999139146
61. McArthur R,Borsini F. Animal models of depression in drug discovery: a historical perspectivePharmacol. Biochem. BehavYear: 20068443645216844210
62. Rupniak NM. Animal models of depression challenges for a drug development perspectiveBehav. PharmacolYear: 20031438539014501252
63. Willner P,Mitchell PJ. The validity of animal model of predisposition to depression BehavPharmacolYear: 200213169188
64. Kennett GA,Dickinson SL,Curzon G. Enhancement of some 5-HT dependent behavioral responses following repeated immobilization in ratsBrain ResYear: 1985330252263
65. Storey JD,Robertson DA,Beattie JE,Reid IC,Mitchell SN,Balfour DJ. Behavioral and neurochemical responses evoked by repeated exposure to an elevated open platformBehav. Brain ResYear: 200616622022916150498
66. Dalla C,Antoniou K,Drossopoulou G,Xagoraris M,Kokras N,Sfikakis A,Papadopoulou-Daifoti Z. Chronic mild stress: are females more vulnerable?NeuroscienceYear: 200513570371416125862
67. Mineur YS,Beizung C,Crusio WE. Effects of unpredictable chronic mild stress on anxiety and depression like behavior in miceBehav. Brain ResYear: 200675435017023061
68. Steenbergen HL,Heinssbroek RPW,Van Harren F,Van de Poll N E. Sex dependent effects of inescapable shock administration on behavior and subsequent escape performance in ratsPhysiol. BehavYear: 1989457817872780848
69. Heinsbroek RP,Van Haaren F,Van de Poll NE,Steenbergen HL. Sex differences in the behavioral consequences of inescapable foot shocks depend on time since shockPhysiol. BehavYear: 1999149 12571263
70. Steenbergen H L,Heinsbroek R P,Van Hest A,Van de Poll N E. Sex-dependent effects of inescapable shock administration on shuttle box-escape performance and elevated plus-maze behaviorPhysiol. BehavYear: 1990485715762075210
71. Setnik B,de Souza F G,d’Almeida A,Nobrega JM. Increased homocysteine levels associated with sex and stress in the learned helplessness model of depressionPharamacol. Biochem. BehavYear: 200477155161
72. Shors TJ,Mathew J,Sisti HM,Edgecomb C,Beckoff S,Dalla C. Neurogenesis and helplessness are mediated by controllability in males but not in femalesBiol. PsychiatryYear: 2007624879517306770
73. Kennett GA,Chaouloff F,Marcou M,Curzon G. Female rats are more vulnerable than males in an animal model of depression: the possible role of serotoninBrain ResYear: 19863824164213756525
74. Alonso SJ,Castellano MA,Rodriguez M. Sex differences in behavioral despair: relationship between behavioral despair and open field activityPhysiol. BehavYear: 19914969722017482
75. Barros HM,Ferigolo M. Ethopharmacology of imipramine in the forced swimming test: gender differencesNeurosci. BiobehavYear: Rev.1998, 23279286
76. Contreras CM,Lara-Morales H,Molina-Hernandez M,Saavedra M,Arrelin-Rosas G. An early lesion of the lateral septal nuclei produces changes in the forced swim test depending on genderProg. Neuropsychopharmacol. Biol. PsychiatryYear: 199519127712848868209
77. Marvan ML,Chavez-Chavez L,Santana S. Clomipramine modifies fluctuations of forced swimming immobility in different phases of the rat estrous cycleArch. Med. ResYear: 19962783868867373
78. Marvan ML,Santana S,Chevez LC,Bertran M. Inescapable shocks attenuate fluctuations of forced swimming immobility in different phases of the rat estrous cycleArch. Med. ResYear: 1997283693729291632
79. Sun M-K,Alkon DL. Differential gender related vulnerability to depression induction and converging antidepressant responses in ratsJ. Pharmacol. Exp. TherYear: 200631692693216227471
80. Pitychoutis PM,Nakamura K,Tsonis PA,PapadopoulouDaifoti Z. Neurochemical and behavioral alterations in an inflammatory model of depression: Sex differences exposedNeuroscienceYear: 20091591216123219409213
81. Haleem DJ,Kennett G A,Curzon G. Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesisBrain ResYear: 19884583393472463050
82. Haleem DJ,Kennett GA,Whitton PS,Curzon G. 8-OH-DPAT increases corticosterone but not other 5-HT-1A dependent responses more in femalesEur. J. PharmacolYear: 19891644354432527755
83. Dalla C,Edgecomb C,Whetstone AS,Shors TJ. Females do not express learned helplessness like males doNeuropsychopharmacologyYear: 2008331559156917712351
84. Bliss EL,Ailion J,Zwangziger J. Metabolism of norepinephrine, serotonin and dopamine in rat brain with stressJ. Pharmacol. Exp. TherYear: 19681641221344387046
85. Curzon G,Green AR. Effects of immobilization on rat brain tryptophan pyrrolase and brain 5-hydroxytryptamine metabolismBr. J. PharmacolYear: 1969376896975348471
86. Chaouloff F,Berton O,Mormede P. Serotonin and stress NeuropsychopharmacologyYear: 19992128S32S10432486
87. Curzon G,Joseph MH,Knott PJ. Effects of immobilization and food deprivation on rat brain tryptophan metabolismJ. NeurochemYear: 197219196719745047857
88. Kennett GA,Joseph MH. The functional importance of increased brain tryptophan in the serotonergic responses to restraint stressNeuropharmacologyYear: 19812039436164003
89. Dunn AJ. Foot shock -induced changes in brain catecholamines or indoleamines are not mediated by CRF or ACTHNeurochem. IntYear: 200037616910781846
90. Haleem DJ,Parveen T. Effects of restraint on rat brain regional 5-HT synthesis rate following adaptation to repeated restraintNeuroReportYear: 19945178517887827332
91. Shimizu ,Oomura Y,Kai Y. Stress-induced anorexia in rats mediated via serotonergic mechanism in the hypothalamusPhysiol. BehavYear: 1989468358412628995
92. Singh VB,Onaivi ES,Phan TH,Boadle-Biber MC. The increase in rat cortical and midbrain tryptophan hydroxylase activity in response to acute and repeated sound stress are blocked by bilateral lesions of the central nucleus of the amygdaleBrain ResYear: 199053049502271952
93. Adell A,Casanovas JM,Artigas F. Comparative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areasNeuropharmacologyYear: 1997367357419225300
94. Fujino K,Yoshitake T,Inoue O,Ibii N,Kehr J,Ishida J,Nohata H,Yamaguchi M. Increased serotonin release in mice frontal cortex and hippocampus induced by acute physiological stressorsNeurosci. LettYear: 2002320919511849771
95. Shimizu N,Take S,Hori T,Oomura Y. In vivo measurement of hypothalamic serotonin release by intracerebral microdialysis: Significant enhancement by immobilization stress in ratsBrain Res. BullYear: 1992287277341377587
96. Joca SR,Zanelati T,Guimaraes FS. Post stress facilitation of serotonergic, but not noradrenergic neurotransmission in the dorsal hippocampus prevented learned helplessness development in ratsBrain ResYear: 20061087677416624257
97. Jason JR,Jacobs BL. 5-HT-1A receptor antagonist administration decreases cell proliferation in the dentate gyrusBrain ResYear: 200295526426712419546
98. Gould E. Serotonin and hippocampal neurogenesisNeuropharmacologyYear: 1991212 Suppl 46S51S
99. Hjorth S,Auerbach SB. Further evidence for the importance of 5-HT-1A autoreceptors in the action of selective serotonin reuptake inhibitorsEur. J. PharmacolYear: 19942602512557988652
100. Verge D,Daval G,Patey A,Gozlan H,Mestikawy E,Hamon M. Presynaptic 5-HT autoreceptors on serotonergic cell bodies and/or dendrites but not terminals are of the 5-HT-1A subtypeEur. J. PharmacolYear: 19851134634642931289
101. Engel G,Gothert M,Hoyer D,Schlicker E,Hillenbrand K. Identity of inhibitory presynaptic 5-hydroxytryptamine autoreceptors in the rat brain cortex with 5-HT-1B binding sitesNaunyn-Schmiedeberg s Arch. PharmacolYear: 198633217
102. Adell A,Celada P,Artigas F. The role of 5-HT-1B receptors in the regulation of serotonin cell firing and release in the rat brainJ. Neuro chemYear: 200179172182
103. Blier P,Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorder and painJ. Psychiatry NeurosciYear: 200126374311212592
104. Haleem DJ. Attenuation of 8-OH-DPAT-induced decreases in 5-HT synthesis in brain regions of rats adapted to a repeated stress scheduleStressYear: 1999312312910938574
105. Haleem DJ,Saify ZS,Siddiqui S,Batool F,Haleem M A. Pre and post synaptic responses to 1-(1-naphthylpiperazine) following adaptation to stress in ratsProg. Neuro-psychopharmacol. Biol. PsychiatryYear: 200226149156
106. Haleem D J,Samad N,Perveen T,Haider S,Haleem M A. Role of serotonin-1A receptors in restraint -induced behavioral deficits and adaptation to repeated restraint stress in ratsInt. J. NeurosciYear: 200711724325717365111
107. Haleem DJ. Exaggerated feedback control over 5-HT and hyperactivity in a rat model of anorexia nervosaAppetiteYear: 200952445018721836
108. Mickey BJ,Ducci F,Hodgkinson CA,Langenecker S A,Goldman D,Zubieta J-K. Monoamine oxidase a genotype predicts human serotonin-1a receptor availability in vivoJ. NeurosciYear: 20082811354 1135918971477
109. Wellman CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administrationJ. NeurobiolYear: 20014924525311745662
110. Azmitia EC,Gannon PJ,Kheck NM,Azmitia PM. Cellular localization of 5-HT-1A receptors inn primate brain neurons and glial cellsNeuropsychopharmacologyYear: 19961435468719028
111. Patel TB,Azmitia EC,Zhou FC. Increased 5-HT-1A receptor immunoreactivity in the rat hippocampus following 5, 7 dihydroxytryptamine lesions in the cingulum bundle and fimbria fornixBehav. Brain ResYear: 1996733193238788527
112. Jacobs B L,Azmitia E C. Structure and function of the brain serotonin systemPhysiol. RevYear: 1992721652291731370
113. Joels M. Functional actions of corticosteroids in the hippocampusEur. J. PharmacolYear: 200858331232118275953
114. Kato R. Serotonin content of rat brain in relation to sex and ageJ. NeurochemYear: 19605202P14404741
115. Carlsson M,Svensson K,Erriksson E,Carlsson A. Rat brain serotonin: Biochemical and functional evidence for a sex differenceJ. Neural. TransmYear: 1985632973132415675
116. Rosecrans JA. Differences in brain area 5-hydroxyrtyptamine turnover and rearing behaviour in rats and mice of both sexesEur. J. PharmacolYear: 197093793825440309
117. Simon A,Volicer L. Neonatal asphyxia in the rat: greater vulnerability of males and persistent effects on brain monoamine synthesisJ. NeurochemYear: 197626893900946815
118. Mendelson SD,McEwen BS. Autoradiogrphic analysis of the effects of restraint-induced stress on 5-HT-1A, 5-HT-1C and 5-HT2 receptors in the dorsal hippocampus of male and female ratsNeuroendocrinologyYear: 1991544544611749460
119. Zhang L,Ma W,Barker JL,Rubinow DR. Sex differences in expression of serotonin receptors (subtypes 1A and 2A) in rat brain: a possible role of testosteroneNeuroscienceYear: 19999425125910613515
120. Shors TJ,Chua C,Falduto J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampusJ. NeurosciYear: 2001216292629711487652
121. Juraska JM. Sex differences in ‘cognitive regions’ of the rat brainPsychoneuroendocrinologyYear: 1991161051091961834
122. Stamatakis A,Mantelas A,Papaioannou A,Pondiki S,Fameli M,Stylianopoulou F. Effects of neonatal handling on serotonin-1A subtype receptors in the rat hippocampusNeuroscienceYear: 200614011116533571
123. Schiller L,Jahkel M,Oehler J. The influence of sex and social isolation housing on pre and postsynaptic 5-HT-1A receptorsBrain ResYear: 20061103768716814751
124. Bellido I,Gomez-Luque A,Garcia-Carrera P,Rius F,de la Cuesta FS. Female rats show an increased sensibility to the forced swim test depressive-like stimulus in the hippocampus and frontal cortex 5-HT1A receptorsNeurosci. LettYear: 200335014514814550915
125. Goel N,Bale TL. Examining the intersection of sex and stress in modeling neuropsychiatric disordersJ. NeuroendocrinolYear: 20092141542019187468
126. Haleem DJ. Repeated corticosterone treatment attenuates behavioral and neuroendocrine responses to 8-hydroxy-2-di-n-propylamino tetralin in ratsLife SciYear: 199251225230
127. Gogos A,Nathan PJ,Guille V,Croft RJ,van den Buuse M. Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy womenNeuropsychopharmacologyYear: 20063188588916237386
128. Clarke WP,Saul MS. Estrogen effects on 5-HT1A receptors in hippocampal membranes from ovariectomized rats: functional and binding studiesBrain ResYear: 19905182872912143962
129. Piotrowska A,Mtynie K,Siwek A,Dybata M,Opoka W,Poleszak E,Nowak G. Antidepressant like effects of chromium chloride in the mouse forced swim test: involvement of glutamatergic and serotonergic receptorsPharmacol. RepYear: 20086099199519211994
130. David SP,Murthy NV,Rabiner EA,Munafo MR,Johnstone EC,Jacob R,Walton RT,Grasby PM. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humansJ. NeurosciYear: 2005252586259015758168
131. Parsey RV,Oquenda MA,Ogden RT,Olvet DM,Simpson N,Huang YY,Van Heertum R,Arango V,Mann JJ. Altered serotonin-1A binding in major depression: a [carbonyl-C-11] WAY100635 positron emission tomography studyBiol. PsychiatryYear: 20065910611316154547
132. Palego L,Marazzi D,Rossi A,Giannaccini G,Naccarato AG,Lucacchini A,Cassano GB. Apparent absence of aging and gender effects on serotonin-1A receptors in human neocortex and hippocampusBrain ResYear: 199775826329203529
133. Parsey R V,Oquenda M A,Simpson N R,Ogden R T,Van Heertum R,Arango V,Mann J J. Effects of sex age and aggressive traits in man on brain 5-HT-1A receptor binding potential measured by PET using [C-11]WAY-100635Brain ResYear: 200294517318212414100
134. Biver F,Lotstra F,Monclus M,Wikler D,Damhaut P,Mendlewicz J,Goldman S. Sex difference in 5-HT-2 receptor in the living human brainNeurosci. LettYear: 199620425288929969
135. Staley JK,Krishnan-Sarin S,Tamagnan G,Fujita M,Seibyl JP,Maciejewski PK,O’Malley S,Innis RB. Sex differences in beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and non smokersSynapseYear: 20014127528411494398
136. Staley J K,Sanacora G,Tamagnan G,Maciejewski P K,Malison R T,Berman R M,Vythilingam M,Kugaya A,Baldwin RM,Seibyl JP,Charney D,Innis R B. Sex differences in diencephalon serotonin transporter availability in major depressionBiol. PsychiatryYear: 200659404716139815
137. Jovanovic H,Lundberg J,Karlsson P,Cerin A,Saijo T,Varrone A,Halldin C,Nordstrom A L. Sex differences in the serotonin-1A receptor and serotonin transporter binding in the human brain measured by PETNeuroimageYear: 2008391408141918036835
138. Stein P,Savli MW,Mitterhauser M,Fink M,Spindelegger C,Mien L-K,Moser U,Dudczak R,Kletter K,Kasper S,Lanzenberger R. The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C] WAY-100635Eur. J. Nucl. Med. Mol. ImagingYear: 2008352159216818542956
139. Cowen PJ,Power AC,Anderson IM. 5-HT-1A receptor sensitivity in major depression: A neuroendocrine study with buspironeBr. J. PsychiatryYear: 19941643723798199791
140. Lesch KP. 5-HT-1A receptor responsitivity in anxiety disorder and depressionProg. Neuropsychopharmacol. Biol. PsychiatryYear: 1991157237331763190
141. Drevets WC,Frank E,Price JC,Kupfer DJ,Greer PJ,Mathis C. Serotonin type-1A receptor imaging in depressionNucl. Med. BiolYear: 20002749950710962258
142. Sargent PA,Kjaer KH,Bench C J,Rabiner AE,Messa C,Meyer J,Gunn RN,Grasby PM,Cowen P J. Brain serotonin-1A receptor binding measured by positron emission tomography with WAY-100635: effects of depression and antidepressant treatmentArch. Gen. PsychiatryYear: 20005717418010665620
143. Sullivan GM,Ogden RT,Oquendo MA,Kumar JS,Simpson N,Huang YY,Mann JJ,Parsey RV. Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depressionBiol. PsychiatryYear: 20096622323019278673
144. Thase ME,Entsuah R,Cantillon M,Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: Sex-Age InteractionsJ. Women's HealthYear: 200514609616
145. Martenyi F,Dossenbach M,Mraz K,Metcalfe S. Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double blind trial of antidepressants with serotonergic and norepinephrinergic reuptake inhibition profileEur. NeuropsychopharmacolYear: 20011122723211418283
146. Young EA,Kornstein SG,Marcus SM,Harvey AT,Warden D,Wisniewski SR,Balasubramani GK,Fava M,Trivedi MH,Rush AJ. Sex differences in response to citalopram: A STAR*D reportJ. Psychiat. ResYear: 20094350351118752809

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Keywords: Keywords Raphe, hippocampus, sex related differences, stress 5-HT-1A receptors, serotonin, depression..

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