Integration of neural networks activated by amphetamine in females with different estrogen levels: A functional imaging study in awake rats

doi:10.1016/j.psyneuen.2015.02.022

Psychoneuroendocrinology

Volume 56, June 2015, Pages 200-212

https://doi.org/10.1016/j.psyneuen.2015.02.022 Get rights and content

Highlights

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Amphetamine-sensitized, ovariectomized rats receiving estradiol were subjected to fMRI in response to peripheral amphetamine.
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Hormone level-dependent responses to amphetamine were observed.
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Effects of different levels of hormone involved structures associated with schizophrenia.

Summary

Previous studies demonstrate that schizophrenia symptomatology in women is dependent upon estrogen levels. Estrogen has beneficial properties when administered in conjunction with antipsychotics, and estrogen also alters, in rats, dopamine neurotransmission, which is a common target of all antipsychotic medications, suggesting a possible interaction between the two. The aim of the current study was to investigate this possible interaction using functional magnetic resonance imaging in awake, female rats. Amphetamine-sensitized, ovariectomized rats receiving no, chronic low, or phasic high levels of estradiol replacement were used, and changes in blood-oxygen-level-dependent (BOLD) signal were recorded over time in response to an acute amphetamine injection. Increasing levels of estradiol enhanced BOLD activation in pathways previously known to be implicated in schizophrenia symptomatology, such as the mesocorticolimbic, habenular and olfactory pathways, as well as more widespread areas. We propose here the first comprehensive “amphetamine activation map” integrating brain regions where amphetamine-related BOLD activity is influenced by estrogen levels in sensitized female rats.

Graphical abstract

Introduction

Schizophrenia symptoms are exacerbated in women when estrogen (E) levels are low, and women experience an improvement in symptoms during pregnancy when E levels fluctuate (Riecher-Rossler et al., 1994, Seeman and Lang, 1990). Women also show a worsening of symptoms after giving birth and/or experiencing menopause as E levels fluctuate and/or decline (Castle and Murray, 1993, Hafner, 2003). Thus it is suggested that E may play a role in schizophrenia onset and development in women. Women are also differentially responsive to antipsychotics; it has been consistently shown that women are more responsive to typical antipsychotics, and women with schizophrenia require increasing doses of antipsychotics upon menopause in order to maintain remission of symptoms (Seeman and Lang, 1990). Yet, we still know surprisingly little about the neurobiological effects of E in this regard.

Sensitization to amphetamine (AMPH) in rodents is a phenomenon where repeated, intermittent exposure to AMPH leads to an increased behavioral response to subsequent lower doses of the drug and has been widely used as a rodent model of some of the neurochemical and behavioral aspects of schizophrenia (for review, see Featherstone et al., 2007, Schmidt and Beninger, 2006, Vezina, 1996). In addition, AMPH sensitization is sex-dependent, such that female rats show increased locomotor activation in response to acute and repeated injections of AMPH compared to males (Forgie and Stewart, 1994). Ovariectomized (OVX) female rats with E replacement show higher levels of AMPH-induced locomotor activity during induction of sensitization compared to no-E controls (Forgie and Stewart, 1994) and E enhances sensitization to cocaine (Hu and Becker, 2003). We have shown that AMPH-sensitized, OVX rats show different behavioral and dopamine responses to a challenge injection of AMPH depending on their E replacement levels. That is, the antipsychotic, haloperidol, is effective in reducing locomotor activity in only those rats with high E replacement (Madularu et al., 2014). Although AMPH sensitization is not the only model of mimicking some aspects of schizophrenia in rodents (i.e. sensitization of the mesocorticolimbic dopaminergic system), this approach was chosen here because one of the purposes of this study, namely the possible interaction between dopamine and estradiol in schizophrenia is best suited to this model and much has been published on AMPH-sensitized rats.

A recent functional magnetic resonance imaging (fMRI) study showed that the prefrontal cortex (PFC) and ventral tegmental area (VTA) of OVX rats receiving E replacement yield robust AMPH-induced blood-oxygen-level-dependent (BOLD) signal increases compared to those without E replacement (Sarvari et al., 2014). An earlier study reported that OVX rats, with and without E replacement, show increased BOLD activation in the PFC, VTA, and nucleus accumbens (NAcc) in response to cocaine, with those with E replacement showing lower positive BOLD changes compared to those without (Febo et al., 2005). On the other hand, repeated cocaine administration increases BOLD signal changes in the NAcc, VTA and hippocampus, but only in those with 17β estradiol (E2: the most potent E during reproductive years) replacement. While much is known about the involvement of the PFC, NAcc and VTA in AMPH-sensitization models, there has been little attention paid to the integrated neural networks associated with, and independent of, the mesocorticolimbic dopamine system.

In terms of the interaction between E, dopamine and antipsychotics; the animal literature is divergent. On the one hand, E enhances dopamine release in response to AMPH (Becker, 1990, Becker and Cha, 1989, Peris et al., 1991), which would theoretically worsen schizophrenia symptoms. On the other, it improves behaviors similar to those observed in schizophrenia when combined with antipsychotics (Almey et al., 2013, Kulkarni et al., 2001, Madularu et al., 2014). Thus, it is important to examine widespread brain activation in response to AMPH under different E2 treatments to help clarify this issue.

With the advent of fMRI in awake animals it is now possible to offer a global perspective of changing brain function with high temporal and spatial resolution. When combined with 3D-segmented and annotated brain atlases as well as computational analysis, it is possible to reconstruct distributed and integrated neural circuits, or “finger prints” of brain activity (Ferris et al., 2014). To this end, here we use fMRI to corroborate previous findings on E-dependent effects of AMPH. Moreover, we can report the changing pattern of activation from 172 brain areas, showing a clear delineation of neural circuits involved in learning and memory, motivation and olfaction. This experiment was carried out in awake, OVX, female rats that had been sensitized to AMPH and had either no, low constant, or low constant plus phasic high E2 replacement.

Section snippets

Animals

Twenty-seven Sprague Dawley rats (Charles River Laboratories, Wilmington, MA, USA) weighing 200–250 g (approx. 2–3 months old) were purchased already OVX and were pair-housed in cages located in a 21 °C with a 12-h light-dark cycle (lights off at 19:00 h), with ad libitum access to food and water. Testing, injections, surgical procedures and imaging were performed during the dark phase of the diurnal cycle, in semi-dark conditions. All procedures were conducted in accordance with the National

Results

The positive BOLD changes as a percentage of the total ROI volume (i.e. Normalized # of voxels = (# acticated voxels × 100)/(total # of voxels)) for No E2, Low E2 and High E2 groups in response to an AMPH challenge (0.25 mg/ml IP). The ROIs are ranked with respect to their significance as determined by Kruskal–Wallis analysis (see Table 1, Table 2; also Supplemental Tables 1–4).

Based on previous studies on male rats receiving acute AMPH (Graybiel et al., 1990, Lin et al., 1996, Nguyen et al., 1992, Orzi

Discussion

Ovariectomized rats receiving different levels of E2 were sensitized to AMPH over four consecutive days, and BOLD activation in response to an AMPH challenge was recorded. Analysis revealed an overall effect of hormone replacement, such that rats receiving high E2 showed the greatest BOLD activation in areas previously associated with AMPH. Furthermore, these areas comprise neural systems previously associated with schizophrenia, or schizophrenia-like symptoms in animal models. The chief scope

Role of funding sources

W.G.B. is supported by Natural Sciences and Engineering Research Council of Canada (NSERC). C.F.F. is supported by the National Institutes of Health (grant number 1P01HD075750-1).

Conflict of interest

C.F.F. and P.K. have financial interests in Ekam Solutions, the company that developed the 3D segmented atlas and analytical tools used in this study. C.F.F. has financial interest in Animal Imaging Research, the company that developed the RF electronics and animal holder used for awake animal imaging. All other authors report no other biomedical financial interests or potential conflicts of interest.

Acknowledgements

We would like to thank Dr. Dave Mumby for feedback on earlier versions of the manuscript.

References (69)

S. Akhondzadeh et al.
Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2003)
L. Becerra et al.
CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw
Neuroimage
(2011)
J.B. Becker
Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis
Neurosci. Lett.
(1990)
J.B. Becker et al.
Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis
Behav. Brain Res.
(1989)
M.E. Brevard et al.
Changes in MRI signal intensity during hypercapnic challenge under conscious and anesthetized conditions
Magn. Reson. Imaging
(2003)
M. Dadda et al.
Early differences in epithalamic left–right asymmetry influence lateralization and personality of adult zebrafish
Behav. Brain Res.
(2010)
R.E. Featherstone et al.
The amphetamine-induced sensitized state as a model of schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2007)
M.L. Forgie et al.
Effect of prepubertal ovariectomy on amphetamine-induced locomotor activity in adult female rats
Horm. Behav.
(1994)
C.R. Genovese et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002)
W. Gong et al.
Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum
Brain Res.
(1996)

A.A. Grace

Gating of information flow within the limbic system and the pathophysiology of schizophrenia

Brain Res. Brain Res. Rev.

(2000)

H. Hafner

Gender differences in schizophrenia

Psychoneuroendocrinology

(2003)

T. Hamamura et al.

Amphetamine sensitization augments amphetamine-induced Fos expression in the lateral habenula

Brain Res.

(1997)

E.A. Heerey et al.

Decision-making impairments in the context of intact reward sensitivity in schizophrenia

Biol. Psychiatry

(2008)

J.A. King et al.

Procedure for minimizing stress for fMRI studies in conscious rats

J. Neurosci. Methods

(2005)

G.F. Koob et al.

Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system

Behav. Brain Res.

(1981)

L.C. Kopala et al.

Olfactory deficits in neuroleptic naive patients with schizophrenia

Schizophr. Res.

(1993)

J. Kulkarni et al.

Estrogen – a potential treatment for schizophrenia

Schizophr. Res.

(2001)

L. Lecourtier et al.

Habenula lesions alter synaptic plasticity within the fimbria-accumbens pathway in the rat

Neuroscience

(2006)

S.R. Lindheim et al.

Behavioral stress responses in premenopausal and postmenopausal women and the effects of estrogen

Am. J. Obstet. Gynecol.

(1992)

P.J. Moberg et al.

Olfactory dysfunction in schizophrenia: a qualitative and quantitative review

Neuropsychopharmacology

(1999)

J. Peris et al.

Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [³H]dopamine release

Brain Res.

(1991)

M.G. Quinlan et al.

Use of cognitive strategies in rats: the role of estradiol and its interaction with dopamine

Horm. Behav.

(2008)

M. Sarvari et al.

Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats

Brain Res.

(2014)

B. Shurman et al.

Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task

Schizophr. Res.

(2005)

J.L. Silverman et al.

Evidence for the involvement of ERbeta and RGS9-2 in 17-beta estradiol enhancement of amphetamine-induced place preference behavior

Horm. Behav.

(2007)

L.W. Swanson

The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat

Brain Res. Bull.

(1982)

C.G. Van Eden et al.

Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level

Neuroscience

(1987)

A. Almey et al.

Medial prefrontal cortical estradiol rapidly alters memory system bias in female rats: ultrastructural analysis reveals membrane-associated estrogen receptors as potential mediators

Endocrinology

(2014)

A. Almey et al.

Estrogen receptors are found in glia and at extranuclear neuronal sites in the dorsal striatum of female rats: evidence for cholinergic but not dopaminergic colocalization

Endocrinology

(2012)

A. Almey et al.

Deficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment

Front. Behav. Neurosci.

(2013)

E. Brailoiu et al.

Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system

J. Endocrinol.

(2007)

A. Breier et al.

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

Arch. Gen. Psychiatry

(1992)

D.J. Castle et al.

The epidemiology of late-onset schizophrenia

Schizophr. Bull.

(1993)

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Integration of neural networks activated by amphetamine in females with different estrogen levels: A functional imaging study in awake rats

Highlights

Summary

Graphical abstract

Introduction

Section snippets

Animals

Results

Discussion

Role of funding sources

Conflict of interest

Acknowledgements

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neuroimage

Neurosci. Lett.

Behav. Brain Res.

Magn. Reson. Imaging

Behav. Brain Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Horm. Behav.

Neuroimage

Brain Res.

Brain Res. Brain Res. Rev.

Psychoneuroendocrinology

Brain Res.

Biol. Psychiatry

J. Neurosci. Methods

Behav. Brain Res.

Schizophr. Res.

Schizophr. Res.

Neuroscience

Am. J. Obstet. Gynecol.

Neuropsychopharmacology

Brain Res.

Horm. Behav.

Brain Res.

Schizophr. Res.

Horm. Behav.

Brain Res. Bull.

Neuroscience

Medial prefrontal cortical estradiol rapidly alters memory system bias in female rats: ultrastructural analysis reveals membrane-associated estrogen receptors as potential mediators

Endocrinology

Estrogen receptors are found in glia and at extranuclear neuronal sites in the dorsal striatum of female rats: evidence for cholinergic but not dopaminergic colocalization

Endocrinology

Deficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment

Front. Behav. Neurosci.

Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system

J. Endocrinol.

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

Arch. Gen. Psychiatry

The epidemiology of late-onset schizophrenia

Schizophr. Bull.