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Increasing evidence now suggest that estrogen may play a protective role against the onset and incidence of psychosis in schizophrenia. In women, the onset of schizophrenia occurs far later than it does in men and there is a peak incidence of the illness after menopause. 2-4 Moreover, estrogen supplements given together with antipsychotic drugs improve clinical outcomes. 6 One of the theories postulates that estrogen induces neurons in critical regions of the brain to respond favourably to dopamine in a manner not yet understood. This is consistent with the 'Dopamine Hypothesis' of schizophrenia, which postulates an overactivity of dopamine neurons or heightened responsiveness of D 2 receptors to dopamine or both may play an important role in positive symptoms of the illness. 7,8 Recent evidence from PET scan studies further suggests that reduced abundance or underfunction of D 1 D 5 receptors or both in the prefrontal cortex may link to the negative symptom of schizophrenia. 1 Taken together, it now appears that an overactivity of D 2 -like receptors and an underactivity of D 1 -like receptors or both may underlie the pathophysiology of the illness. This notion is substantiated by clinical observations as anti-psychotic drugs that block D 2 receptors are effective in alleviating positive symptoms, 9,10 whilst those enhancing the activity of D 1 -like receptors may improve negative symptoms. 11 Recently, we have reported that estrogen selectively augments the expression of D 5 receptors, a member of the D 1 -like receptor family, but not D 1 receptors, in central neurons. 5 Interestingly, D 5 receptors are constitutively active and play an important role in maintaining functional activities of the host cells through the cAMP pathway. 12 The possibility that this neurobiological effect of estrogen on D 5 receptors may affect critical regions of the brain and confer protection against psychosis in schizophrenia needs to be considered. However, besides estrogen, mammalian ovaries also produce another important ovarian steroid, progesterone. In women, progesterone and estrogen are produced and released from ovaries in a sequential manner during the menstrual cycle. The two steroids interact at many levels to induce neurophysiological changes pertinent to behavioural modification. 13,14 Unlike estrogen, the role of progesterone in modulating dopamine responsiveness in central neurons, however, remains elusive.Employing a well characterised long-term rat hypothalamic cell culture system, we have recently identified that atrial natriuretic factor (ANP)-producing neurons constitute a common convergent site for integration of ovarian steroid and dopamine actions. 5 In this system, estrogen induces the expression of progesterone receptors in ANP neurons and augments neuronal functions by increasing the expression of constitutively active D 5 receptors that generate cAMP in a ligand-independent manner. Adopting the same approach, we have now exploited our hypothalamic culture system to examine the effect of progesterone, a...

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...