Steroids‐Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Abstract

SUMMARYIntroduction: Dopamine cell loss is well documented in Parkinson's disease and dopamine hypofunction is proposed in certain depressive states. At the opposite, dopamine hyperactivity is an enduring theory in schizophrenia with extensive supporting evidence. Aims: This article reviews the sex differences in these diseases that are the object of many studies and meta-analyses and could be explained by genetic differences but also an effect of steroids in the brain. This article then focuses on the extensive literature reporting on the effect of estrogens in these diseases and effects of the other ovarian hormone progesterone as well as androgens that are less documented. Moreover, dehydroepiandrosterone, the precursor of estrogens and androgens, shows effects on brain dopamine neurotransmission that are reviewed. To investigate the mechanisms implicated in the human findings, animal studies are reviewed showing effects of estrogens, progesterone, and androgens on various markers of dopamine neurotransmission under intact as well as lesioned conditions. Discussion: For possible future avenues for hormonal treatments in these central nervous system diseases, we discuss the effects of selective estrogen receptor modulators (SERMs), the various estrogen receptors and their specific drugs as well as progesterone drugs. Conclusion: Clinical and experimental evidence supports a role of steroid-dopamine interactions in the pathophysiology of schizophrenia, depression and Parkinson's disease. Specific steroidal receptor agonists and SERMs are available for endocrine and cancer treatments and could find other applications as adjunct treatments in central nervous system diseases.

Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1

“…This is consistent with previous finding in MPTP mice and in 6-hydroxydopamine lesioned rats, reporting a lack of protection of DA neurons with ERb agonists (D'Astous et al, 2004;Baraka et al, 2011). Whereas ERb does not show a protective role on dopaminergic neurons, this receptor mediates many of the neuromodulatory effect of 17b-estradiol on dopaminergic neurons, including modulation of dopaminergic activity and preservation of the phenotype of DA neurons (Sanchez et al, 2010). Thus, it is possible that some effects of ERb activation resulted from an interplay between ERb and GPER1.…”

The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia

“…For example, testosterone levels dramatically increase and peak during adolescence and then progressively decrease with age (Wilson 1996), which mimics the pattern for the onset of schizophrenia. The exact mechanism of action of sex hormones in schizophrenia remains unknown, but we suggest that they modulate neurotransmitter systems implicated in schizophrenia, such as the serotonin and dopamine systems (Gogos et al 2010b;Sanchez et al 2010).…”

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

“…First, given that PROG is a neuromodulator [17], we have differentiated the neuroprotective versus neuromodulatory effect of PROG on the DA system, by investigating and comparing the effect of PROG in intact, nonlesioned mice with that in MPTP-treated mice with measures of DA, DA transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). In a second experiment, we investigated if high doses of PROG had the capacity to protect dopaminergic neurons that had been exposed to MPTP in male mice.…”