1. ¹Psychobiology Research Group, Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, UK
2. ²Department of Psychiatry, Institute of Mental Health, University of British Columbia, Vancouver, British Columbia, Canada
3. ³Developmental Psychiatry Section, Department of Psychiatry, Cambridge University, Cambridge, UK

Correspondence: Dr SE Gartside, Psychobiology Research Group, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne, Tyne and Wear, NE2 4HH, UK. Tel: +44 191 222 7633; Fax: +44 191 222 5227; E-mail: sasha.gartside@ncl.ac.uk

Received 19 December 2008; Revised 20 April 2009; Accepted 22 April 2009; Published online 3 June 2009.

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.