Glucocorticoid modulation of dopamine mediated effects on hypothalamic atrial natriuretic factor neurons

Abstract

Keywords: dopamine receptor subtypes; atrial natriuretic factor producing neurons; glucocorticoid; primary neuron cultures Dopamine (DA) plays an important role in cognition, neuroendocrine functions and psychosis. 1,2Whilst stress adversely affects some of these functions, its neurobiological basis remains unclear. 3 In the rat hypothalamus, a concurrent activation of D 5 and D 2 receptors by dopamine produces a biphasic effect on the function of atrial natriuretic factor (ANF) neurons. Severe stress may precipitate the onset of schizophrenia or aggravate the symptoms of the illness.3 In stress, the hypothalamus-pituitary-adrenal axis is activated and it results in an elevated level of circulating adrenal glucocorticoids or stress hormones.5 Whereas the neurobiological basis of this stress-induced adversity in schizophrenia remains elusive, the possibility that high levels of plasma glucocorticoids may unfavourably affect the responsiveness of important neurons in critical regions of the brain to dopamine needs to be considered. According to the 'Dopamine Hypothesis' of schizophrenia, overactivity of dopamine neurons or heightened responsiveness of D 2 receptors to dopamine or both play an important role in the positive symptoms of the illness.1,2 Recent evidence from PET scan studies, however, suggests that a reduced abundance or an underfunction of D 1 /D 5 receptors or both in the prefrontal cortex may link to the negative symptom of schizophrenia.6 Taken together, it now appears that an overactivity of D 2 -like receptors and an underactivity of D 1 -like receptors or both may contribute to the pathophysiology of the illness. This is consistent with clinical observations as anti-psychotic drugs that block D 2 receptors are effective in alleviating positive symptoms 7,8 whereas those enhancing the activity of D 1 -like receptors may improve negative symptoms. 9 Recently, we have reported that D 5 receptors and D 2 receptors co-exist in hypothalamic neurons producing atrial natriuretic factor or ANF.10 Interestingly, dopamine, the common intrinsic ligand of D 5 and D 2 receptors, induces a biphasic response from the neurons, which involve an intricate interaction of the two receptors. 4 Whilst low concentrations of DA produce an opposing effect between the two receptors resulting in a functional inhibition, high levels of DA augment neuronal functions through a synergistic interaction of D 5 and D 2 receptors. It suggests that typical functions of these DA responsive neurons may involve a delicate balance between D 2 and D 5 receptor interaction in accordance with the availability of DA. A disruption of this equilibrium consequent to an augmented number of D 2 receptors or a reduced abundance of D 5 receptors induced presumably by some pathophysiological conditions, such as stress, may lead to a compromise in the functional integrity of these neurons. We here present evidence that glucocorticoids suppress D 5 receptor-mediated effects thereby adversely affecting the responsiveness of ANF neurons to dopamine b...

Dopamine Inhibits Mitochondrial Motility in Hippocampal Neurons

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Higher stress response and altered quality of life in schizophrenia patients with low membrane levels of docosahexaenoic acid

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