A structural explanation for ERalpha/ERbeta SERM discrimination.

Many NRs have multiple subtypes that possess distinct expression patterns and that regulate distinct target genes. Antagonists generated through the addition of bulky side chains to agonist scaffolds are limited to being antagonistic on one or more subtypes of a particular NR. The passive antagonism mechanism, as revealed in our studies through direct comparison of the two THC-ER LBD complexes, suggests a new approach to achieving NR antagonism. Compounds could be designed to selectively stabilize the inactive conformations of certain NR subtypes and the active conformations of others. Such ligands are likely to exert novel biological and therapeutic effects.

Influence of the ventral hippocampal formation on plasma vasopressin, hypothalamic-pituitary-adrenal axis, and behavioral responses to novel acoustic stress.

The ventral hippocampal formation (vHF) seems to constrain diverse responses to psychological stimuli, and disruption of this function may underlie severe neuropsychiatric diseases. In particular, the ventral subiculum inhibits hypothalamic-pituitary-adrenal axis (HPA) activity following psychological, but not systemic, stressors. Despite the difficulty in interpreting such HPA responses, they have been relied upon to further characterize vHF function, because increased HPA axis activity is implicated in neuropsychiatric disturbances, and reliance on behavioral and cognitive data is even more problematic. Plasma arginine vasopressin (pAVP), which is inhibited by psychological stimuli and is also implicated in diverse neuropsychiatric diseases, provides a less ambiguous measure of CNS function. To test if its inhibition by psychological stress is also mediated by the vHF, we conducted two studies. In the first, pAVP and behavioral responses to novel acoustic stress were assessed in rats with bilateral excitotoxic lesions of the ventral subiculum and the ventral hippocampus. The subiculum lesions blocked the fall in pAVP and enhanced escape behaviors, whereas the hippocampal lesions produced responses intermediate to those in the subiculum-lesioned and control rats. In the second study, the pAVP response was similarly blocked by small lesions restricted to those vHF subfields which project to the neuroendocrine hypothalamus, compared to the response in animals with lesions in other vHF subfields. These results indicate that discrete projections from the vHF inhibit the pAVP response to psychological stimuli, and suggest that pAVP may provide a reliable probe of vHF activity.

Anterior medial temporal lobe volumes in polydipsic schizophrenic patients with and without hypo-osmolemia: a pilot study.

The volume of certain brain structures, particularly those in the anterior medial temporal lobe, may be reduced to a greater extent in hyponatremic/hypo-osmolemic polydipsic schizophrenics than other schizophrenic patients. To explore if volume reduction is specific to this particular brain region, and if it is fundamentally associated with polydipsia, we imaged the anterior hippocampi/subicula and adjacent temporal lobes in normal males (n = 10) and polydipsic schizophrenic patients with (n = 7) and without (n = 6) hypo-osmolemia. Bilateral hippocampal/subicular (p < .01), but not temporal lobe (p < .30), volumes were diminished in the hypo-osmolemics relative to the other two groups, who resembled each other on these measures. No recognized or putative factor could explain these findings. Thus anterior medial temporal lobe structures appear to be preferentially diminished in hypo-osmolemic polydipsic schizophrenics. Additional studies are needed to more precisely define these anatomic differences and their relationship to these patients' impaired water excretion and severe mental illness.

Influence of the hippocampus/subiculum on antidiuretic hormone levels during stress.

The hippocampus/subiculum has been hypothesized to restrain hypothalamically mediated neuroendocrine responses to psychological stressors. While psychological stress has been observed to restrict plasma vasopressin (AVP) secretion, the role of these brain structures has not been examined. We subjected rats with bilateral aspiration of the hippocampus and controls with bilateral aspiration of the overlying neocortex to a 45 s swim stress. Plasma AVP and relevant AVP stimuli were measured at 30 min intervals for 90 min following the stressor. Immediately following the stressor, AVP levels were similar in the two groups, and then rose in hippocampal-lesioned animals to a greater extent than in the controls. None of the measured AVP stimuli could account for this difference. We conclude that rats with hippocampal lesions demonstrate increases in plasma AVP following psychological stress.