Abnormal activation of amino-acid receptors is hypothesized to play a role in the etiology of psychiatric disorders, and to contribute to brain damage associated with neurodegenerative diseases such as Alzheimer's and Parkinson's, seizures, and stroke. Neuroactive steroids can exert profound modulatory effects on glutamate receptors, raising the possibility that endogenous neurosteroids may play a role in regulating excitatory synaptic activity in the CNS, or that abnormal steroid levels could contribute to CNS pathology. Studies of steroid modulation of excitotoxicity raise the prospect that steroid negative modulators may be clinically useful as neuroprotective agents, and reveal that endogenous positive modulators may sensitize neurons to excitotoxic neurodegeneration. Understanding the mechanisms of steroid actions on the CNS may lead to new strategies for the treatment of such disorders. Regardless of their physiological role, neuroactive steroids offer a novel pharmacologic approach to regulating the activity of excitatory amino acid receptors in the CNS.

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