Andrea Gogos

The effect of estrogen on dopamine and serotonin receptor and transporter levels in the brain: An autoradiography study

The aim of the present study was to elucidate the effect of estrogen on dopaminergic and serotonergic regulation of prepulse inhibition (PPI) by measuring its effects on the density of dopamine transporters (DAT), dopamine D(1) and D(2) receptors, serotonin transporters (SERT), serotonin-1A (5-HT(1A)) and 5-HT(2A) receptors using radioligand binding autoradiography. Three groups of female Sprague-Dawley rats were compared: sham-operated controls, untreated ovariectomized (OVX) rats and OVX rats with a 17beta-estradiol implant (OVX+E). These groups were identical to our previous prepulse inhibition (PPI) studies, allowing comparison of the results. Results showed that in the nucleus accumbens, DAT levels were 44% lower in OVX rats than in intact controls. Estrogen treatment completely reversed the effect of OVX in this brain region to levels similar to those in intact controls. Dopamine D(2) receptor density was increased in OVX rats by 28% in the nucleus accumbens and 25% in the caudate nucleus compared to intact controls. Estrogen treatment reversed this increase and, in addition, reduced dopamine D(2) receptor levels by a further 25% and 20%, respectively, compared to intact control rats. There were no differences between the groups with respect to the densities of dopamine D(1) receptors, SERT, 5-HT(1A) receptors or 5-HT(2A) receptors. These results show effects of estrogen treatment on central indices of dopaminergic, but not serotonergic function. The observed changes do not provide a direct overlap with the effects of these estrogen treatment protocols on drug-induced disruptions of PPI, but it is possible that a combination of effects, i.e. on both DAT and dopamine D(2) receptor density, is involved. These data could also be relevant for our understanding of the potential protective effect of estrogen treatment in schizophrenia.

Greater superior than inferior parietal lobule activation with increasing rotation angle during mental rotation: An fMRI study

Mental rotation is a task known to activate the parietal cortical regions. The present study aimed to investigate whether there is differential activation of regions within the parietal lobe and to reveal functional subspecialisation of this region by examining the effects of increasing angle of rotation. Functional magnetic resonance imaging was performed in nine healthy female subjects whilst undertaking a parametric mental rotation task. The task comprised 6 alphanumeric characters presented in their normal or mirror-reversed orientation. Behaviourally, subjects showed increased reaction times with increased angle of rotation, with differential effects between the alphanumeric characters; numbers having greater reaction times than letters. BOLD signal increase was observed bilaterally in the middle occipital gyrus and medial frontal gyrus, in the right superior and inferior parietal lobules and in the left superior temporal gyrus. Parametric increases in activation with increasing angle of rotation were observed bilaterally in the superior and inferior parietal lobules and in the right medial frontal gyrus, with greater parametric effects in the superior parietal lobules compared to the inferior parietal lobules. Our findings suggest subspecialisation of the posterior parietal lobules during mental rotation, with differential responses in the superior and inferior regions.

Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF

Schizophrenia is a severe psychiatric disorder with a complex and variable set of symptoms. Both genetic and environmental mechanisms are involved in the development of the illness and lead to structural and neurochemical abnormalities in the brain. An intriguing facet of schizophrenia is sex differences, which have been described for nearly all features of the illness, including the peak age of onset, symptoms and treatment response. The ovarian hormone, estrogen, may be protective against schizophrenia and evidence is accumulating that estrogen may exert this effect via an interaction with brain-derived neurotrophic factor (BDNF). Both estrogen and BDNF have trophic effects on the developing brain and promote synaptic plasticity and maintain neurons well into adulthood. Major neurotransmitter systems including dopaminergic, serotonergic and glutamatergic pathways are modulated and supported by estrogen and BDNF. Despite their commonalities, estrogen and BDNF have mostly been examined independently but increasing evidence suggests an interaction between the two in brain regions pertinent to schizophrenia. This review will focus on the role of estrogen and BDNF in clinical and animal studies of schizophrenia. We include animal models of neurotransmitter dysfunction and genetic manipulation to show how estrogen may provide a protective effect in schizophrenia, including through mediating BDNF expression and activity. This posited estrogen-BDNF interaction could play a key role in modulating sex-dependent results reported in animal work as well as sex differences in clinical aspects of schizophrenia.

Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women.

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT1A receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

Estrogen Treatment Blocks 8-Hydroxy-2-dipropylaminotetralin- and Apomorphine-Induced Disruptions of Prepulse Inhibition: Involvement of Dopamine D1 or D2 or Serotonin 5-HT1A, 5-HT2A, or 5-HT7 Receptors

Prepulse inhibition (PPI) is a measure of sensorimotor gating and an endophenotype of schizophrenia. We have shown previously in rats that estrogen treatment prevents disruption of PPI by the 5-HT1A/5-HT7 receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D1 and D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors in these effects. Part 1 of this study investigated the ability of estrogen treatment to reverse PPI disruption induced by 8-OH-DPAT or the dopamine D1/D2 receptor agonist apomorphine. Part 2 of this study compared these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apomorphine on PPI. Female Sprague-Dawley rats were ovariectomized (OVX), and, where appropriate, they received silastic implants containing either a low (E20) or high dose (E100) of estrogen. Two weeks later, PPI was assessed using automated startle boxes. The disruption of PPI by either treatment with 8-OH-DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg) was similarly prevented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pretreatment with the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg) and the typical antipsychotic and dopamine D2 receptor antagonist haloperidol (0.25 mg/kg), but it was not reversed by pretreatment with the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.1 mg/kg), the 5-HT2A/2C receptor antagonist ketanserin (2 mg/kg), or the 5-HT7 receptor antagonist SB-269970 (10 mg/kg). Apomorphine-induced disruptions of PPI were reversed by haloperidol and SCH 23390 only. Estrogen may prevent disruptions of PPI induced by both 8-OH-DPAT and apomorphine by an action on dopamine D2 receptors downstream of 5-HT1A receptors.

The effect of low estrogen state on serotonin transporter function in mouse hippocampus: a behavioral and electrochemical study.

Defects in serotonergic transmission, including serotonin transporter (SERT) function, have been implicated in depression, anxiety disorders and some aspects of schizophrenia. The sex steroid hormone estrogen is known to modulate functional SERT activity, but whether it is up- or down-regulated is unclear. The aim of the present study was to examine the effect of a low estrogen state in mice on the behavioral effect of drugs acting through the SERT, serotonin uptake kinetics and SERT density in the hippocampus. We compared control mice, ovariectomized (OVX) C57BL/6J mice and aromatase knockout (ArKO) mice that are unable to produce estrogen. Fluoxetine treatment, but not fenfluramine treatment, significantly increased prepulse inhibition (PPI), a measure of sensorimotor gating, in C57BL/6J mice. The effect of fluoxetine was greater in OVX compared to sham-operated mice. In ArKO and J129 wild-type mice, fluoxetine increased PPI to the same extent while fenfluramine increased PPI more in ArKO mice compared to controls. Measurement of the time-course for diffusion and reuptake of exogenous serotonin in the CA3 region of the hippocampus showed that, in OVX mice, the fluoxetine-induced slowing of signal decay after application of serotonin was enhanced when compared to sham-operated controls. Similarly, in ArKO mice, the effect of fluoxetine was enhanced, suggesting that SERT function was greater than in J129 wild-type controls. Measurement of SERT density by [3H]-citalopram autoradiography, revealed an 18% decrease in hippocampus of OVX mice compared to intact controls. SERT density was also significantly reduced in nucleus accumbens (26%) but not in other regions, such as the raphe nuclei. Together, these results suggest that a low estrogen state increases SERT activity in the hippocampus despite an apparent reduction in SERT density. The behavioral consequences of these changes depend on the model of estrogen state used.

Gender differences in prepulse inhibition (PPI) in bipolar disorder: men have reduced PPI, women have increased PPI

Prepulse inhibition (PPI) is a measure of sensorimotor gating or information processing. Few studies have examined PPI in bipolar disorder (BD); two studies reported a PPI disruption and two reported no change. There are gender differences in PPI and within the clinical profile of BD, which may explain some of these discrepancies. Thus, the effect of gender on PPI in BD was the focus of the current study. Euthymic BD patients (14 male/15 female) were compared to age- and IQ-matched healthy control participants (16 male/16 female). Assessment of PPI included 21 pulse-alone trials (115 dB) and a total of 42 prepulse-pulse trials (seven of each prepulse: 74, 78, 86 dB) at two stimulus onset asynchrony levels (SOA: 60, 120 ms). There was a group x SOA and a group x gender interaction, reflecting that men with BD showed reduced PPI compared to control males at the 60-ms SOA (3% in BD vs. 26% in controls), but not the 120-ms SOA. In contrast, women with BD had significantly increased PPI compared to female controls at the 120-ms SOA (49% in BD vs. 29% in controls), but not the 60-ms SOA. Compared to control participants BD patients showed changes in PPI, which are gender-dependent; male BD participants had reduced PPI, whereas female BD participants had increased PPI. This gender difference highlights the need to consider men and women with BD as two distinct groups, at least in PPI studies.

Use of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to investigate group and gender differences in schizophrenia and bipolar disorder

Objective: Gender differences exist in schizophrenia and bipolar disorder (BD), therefore the aim of the present study was to clarify the role of gender in cognitive deficits in these disorders. Methods: Cognitive performance was examined in schizophrenia (24M: 14F) and BD (16M: 24F) patients compared with age-, IQ- and gender-matched control participants (21M: 22F). The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess five cognitive domains: immediate memory/learning, visuospatial ability, language, attention, and delayed memory, which are summed to provide a Total score. Results: In comparison to controls, schizophrenia patients showed deficits on all domains, while BD patients had impaired immediate memory/learning, language and Total score. Schizophrenia patients showed deficits compared to BD in the Total score, immediate and delayed memory and visuospatial ability. The Total and domain scores were not different in men and women across or within groups. There were gender effects on four of the 12 individual cognitive tasks, in which female patients outperformed male patients. Further, there were gender differences across groups for three of the individual tasks: female schizophrenia patients showed poorer story memory and story recall compared to male schizophrenia patients; female BD patients had enhanced figure copy performance compared to male BD patients. Conclusions: The RBANS highlighted the cognitive deficits in schizophrenia and BD patients compared to controls and also each other. There were no overall gender differences in cognition.

Castration reduces the effect of serotonin-1A receptor stimulation on prepulse inhibition in rats

This study examined the interaction between hormones and serotonin-1A (5-HT1A) receptor modulation of prepulse inhibition (PPI) of the acoustic startle response. Male and female rats were gonadectomized; some castrated rats received testosterone- or estrogen-filled implants. Rats were randomly injected with saline or 0.02 or 0.50 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist. All rats showed a dose-dependent disruption of PPI in response to 8-OH-DPAT. In untreated castrated rats, this disruption was significantly reduced (33% compared with 78% in sham-operated rats). Testosterone treatment reversed this reduction, but estrogen was less effective. Ovariectomized and sham-operated rats showed similar PPI in response to 8-OH-DPAT. These data suggest that the effect of 8-OH-DPAT on PPI in male rats depends on circulating hormone levels, particularly testosterone.

A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiols underlying protective mechanisms is also substantially discussed, with particular focus on estradiols impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.