Corticosteroid modulation of the mesocorticolimbic dopamine system :implications for bipolar disorder.

Abstract

There is evidence that dopaminergic dysfunction plays a role in the symptoms of bipolar disorder although the precise abnormality is unclear. In addition clysregulation of corticosteroid secretion characterised by a flattened diurnal circadian rhythm has been observed across mood states in bipolar disorder. As a result it has been hypothesised that corticosteroid hypersecretion underlies the dopaminergic dysfunction. Here the endocrine regulation of mesocorticolimbic doparninergic neurotransmission was investigated with the hope of bettering our understanding of the pathology of bipolar disorder. Immunocytochemical studies established that around half of dopaminergic neurones in the ventral tegmental area (VTA) express the low affinity glucocorticoid receptor (GR), whilst all of these neurones express the high affinity mineralocorticoid receptor (MR). This indicated that corticosteroids can directly modulate dopaminergic neuronal function. By administering corticosterone to rats in their drinking water a flattened circadian profile of corticosteroid secretion similar to that seen in bipolar disorder was modelled. In situ hybridisation histochemistry in the VTA revealed that corticosterone treatment increased the transcription of mRNA for tyrosine hydroxylase, the vesicular monoamine transporter and the D2 receptor, whilst decreasing expression of the 5-HT2c receptor and the GluRl subunit of the AMPA receptor. In vivo microdialysis in the medial prefrontal cortex demonstrated increased doparnine release under both basal and stimulated conditions in corticosterone treated animals. This effect did not appear to be the result of altered D2 autoreceptor function or a change in the firing rate of cloparninergic neurones. In light of the in situ hybridisation data it is hypothesised that flattening the diurnal profile of corticosteroid secretion increases prefronto-cortical doparnine release by upregulating dopamine synthesis and vesicular uptake. These studies demonstrate that corticosteroid dysrhythmia of the type seen in bipolar disorder can alter doparninergic neurotransmission and furthermore they indicate specific aspects of dopaminergic function which might be altered. Thus circadian rhythm abnormalities in the HPA axis may play a role in the aetiology of bipolar disorder via clysregulation of dopaminergic neurotransmission.