title: Profound changes in dopaminergic neurotransmission in the prefrontal cortex in response to flattening of the diurnal glucocorticoid rhythm: implications for bipolar disorder.
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 microg/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 D(2) 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.
authors.affiliation: Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: Gareth O
authors.initials: GO
authors.lastname: Minton
authors.forename: Allan H
authors.initials: AH
authors.lastname: Young
authors.forename: Richard
authors.initials: R
authors.lastname: McQuade
authors.forename: Graeme
authors.initials: G
authors.lastname: Fairchild
authors.forename: Colin D
authors.initials: CD
authors.lastname: Ingram
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gartside
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D016642:Bupropion / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects*; D003345:Corticosterone / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D017551:Microdialysis / Q000379:methods; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013469:Sulpiride / Q000378:metabolism / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D016642:Bupropion; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D011188:Potassium; D004298:Dopamine; D003345:Corticosterone