Compelling evidence now exists for estrogen's involvement in the regulation of mood and cognitive functions. Serum estrogen levels have been shown to play an important role in the expression of psychiatric disorders such as depression and schizophrenia. We have characterized the distribution of the estrogen receptors, ERalpha and ERbeta, in the human brain and showed a preferential limbic-related expression pattern for these transcripts. The ERalpha mRNA dominates in the amygdala and hypothalamus, suggesting estrogen modulation of autonomic and neuroendocrine as well as emotional functions. In contrast, the hippocampal formation, entorhinal cortex, and thalamus appear to be ERbeta-dominant areas, suggesting a role for ERbeta in cognition, non-emotional memory, and motor functions. The role of estradiol can also be examined in regard to its relationship to other neurotransmitter systems known to be linked to specific psychiatric disorders. Estradiol has been shown to regulate the serotonin (5-HT) system, which has been strongly implicated in affective disorders. We have studied a genetic animal model of depression, and found altered 5-HT receptor mRNA levels in discrete brain regions; many of the abnormalities are reversed by estradiol treatment, especially for the 5-HT(2A) receptor subtype. The norepinephrine (NE) system is, similar to serotonin, a target for antidepressant drugs, and projects to mesocorticolimbic structures implicated in mood disorders. We have recently observed that NE neurons in the human locus coeruleus (LC) express moderate levels of both ER transcripts. The possibility of estrogen's regulating LC function has been documented in animal studies. Results from our preliminary experiments have revealed that the ERbeta mRNA is decreased in persons committing suicide, a cause of death that is highly linked to affective disorder. Follow-up studies are currently under way with a much larger population to validate these results. Overall, the discrete anatomical organization of the ER mRNAs in the human brain provide evidence as to the specific neuronal populations in which the actions of ERs could modulate mood and thus underlie the neuropathology of psychiatric disorders such as depression.