Profound changes in dopaminergic neurotransmission in the
prefrontal cortex in response to flattening of the diurnal
glucocorticoid rhythm: implications for bipolar disorder
Profound changes in dopaminergic neurotransmission in the
prefrontal cortex in response to flattening of the diurnal
glucocorticoid rhythm: implications for bipolar disorder
Patients with bipolar disorder have abnormalities in glucocorticoid secretion, dopaminergic neurotransmission, and prefrontal cortical function. We hypothesized that the flattening of the diurnal glucocorticoid rhythm, commonly seen in bipolar disorder, modulates dopaminergic neurotransmission in the prefrontal cortex (PFC) leading to abnormalities in prefrontally mediated neurocognitive functions. To address this hypothesis, we investigated the effects of a flattened glucocorticoid rhythm on (i) the release of dopamine in the PFC and (ii) the transcription of genes in the ventral tegmental area (VTA) coding for proteins involved in presynaptic aspects of dopaminergic neurotransmission. Male rats were treated for 13–15 days with corticosterone (50??g/ml in the drinking water) or vehicle (0.5% ethanol). Corticosterone treatment resulted in marked adrenal atrophy and flattening of the glucocorticoid rhythm as measured by repeated blood sampling. Animals treated with corticosterone showed markedly enhanced basal dopamine release in the PFC as measured by microdialysis in the presence of a dopamine reuptake inhibitor. Depolarization-evoked release was also enhanced, suggesting that the corticosterone effect on basal release did not result from an increase in the neuronal firing rate. Local blockade of terminal D2 autoreceptors failed to normalize release to control values, suggesting that the enhanced release was not because of reduced autoreceptor sensitivity. In situ hybridization histochemistry showed that mRNAs coding tyrosine hydroxylase and the vesicular monoamine transporter 2 were elevated in the VTA of corticosterone-treated rats. Our data show that flattening of the glucocorticoid rhythm increases dopamine release in the PFC possibly as a result of increased synthesis and vesicular storage. This provides a mechanistic explanation for prefrontal dysfunction in bipolar and other affective disorders associated with glucocorticoid dysrhythmia.
2265-2274
Minton, Gareth O.
e406ab31-7da1-47fe-bf60-3f5d267e222a
Young, Allan H.
9f9548bb-7449-4a2a-a70a-3aad78d2c454
McQuade, Richard
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Fairchild, Graeme
f99bc911-978e-48c2-9754-c6460666a95f
Ingram, Colin D.
e54d40c4-e782-47a7-b88f-255fe7a3d27f
Gartside, Sarah E.
45b98467-44b5-4657-b71d-824851420af0
September 2009
Minton, Gareth O.
e406ab31-7da1-47fe-bf60-3f5d267e222a
Young, Allan H.
9f9548bb-7449-4a2a-a70a-3aad78d2c454
McQuade, Richard
f015119a-d26e-4670-8afd-3dadab6e2135
Fairchild, Graeme
f99bc911-978e-48c2-9754-c6460666a95f
Ingram, Colin D.
e54d40c4-e782-47a7-b88f-255fe7a3d27f
Gartside, Sarah E.
45b98467-44b5-4657-b71d-824851420af0
Minton, Gareth O., Young, Allan H., McQuade, Richard, Fairchild, Graeme, Ingram, Colin D. and Gartside, Sarah E.
(2009)
Profound changes in dopaminergic neurotransmission in the
prefrontal cortex in response to flattening of the diurnal
glucocorticoid rhythm: implications for bipolar disorder.
Neuropsychopharmacology, 34 (10), .
(doi:10.1038/npp.2009.53).
Abstract
Patients with bipolar disorder have abnormalities in glucocorticoid secretion, dopaminergic neurotransmission, and prefrontal cortical function. We hypothesized that the flattening of the diurnal glucocorticoid rhythm, commonly seen in bipolar disorder, modulates dopaminergic neurotransmission in the prefrontal cortex (PFC) leading to abnormalities in prefrontally mediated neurocognitive functions. To address this hypothesis, we investigated the effects of a flattened glucocorticoid rhythm on (i) the release of dopamine in the PFC and (ii) the transcription of genes in the ventral tegmental area (VTA) coding for proteins involved in presynaptic aspects of dopaminergic neurotransmission. Male rats were treated for 13–15 days with corticosterone (50??g/ml in the drinking water) or vehicle (0.5% ethanol). Corticosterone treatment resulted in marked adrenal atrophy and flattening of the glucocorticoid rhythm as measured by repeated blood sampling. Animals treated with corticosterone showed markedly enhanced basal dopamine release in the PFC as measured by microdialysis in the presence of a dopamine reuptake inhibitor. Depolarization-evoked release was also enhanced, suggesting that the corticosterone effect on basal release did not result from an increase in the neuronal firing rate. Local blockade of terminal D2 autoreceptors failed to normalize release to control values, suggesting that the enhanced release was not because of reduced autoreceptor sensitivity. In situ hybridization histochemistry showed that mRNAs coding tyrosine hydroxylase and the vesicular monoamine transporter 2 were elevated in the VTA of corticosterone-treated rats. Our data show that flattening of the glucocorticoid rhythm increases dopamine release in the PFC possibly as a result of increased synthesis and vesicular storage. This provides a mechanistic explanation for prefrontal dysfunction in bipolar and other affective disorders associated with glucocorticoid dysrhythmia.
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Published date: September 2009
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Local EPrints ID: 156021
URI: http://eprints.soton.ac.uk/id/eprint/156021
PURE UUID: 2cb439f6-0ad2-4fcf-82a8-a89728530a6b
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Date deposited: 01 Jun 2010 16:22
Last modified: 14 Mar 2024 01:42
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Author:
Gareth O. Minton
Author:
Allan H. Young
Author:
Richard McQuade
Author:
Graeme Fairchild
Author:
Colin D. Ingram
Author:
Sarah E. Gartside
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