Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen

Abstract

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...

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