The overall goal of our research project is to utilize the diversity of GABAalpha receptor structure and function to develop via new strategies safer and more effective neuroactive drugs acting as modulators of GABAalpha receptor function capable of anticonvulsant, anxiolytic, and antipanic action without eliciting tolerance or physical dependence. The present proposal is the continuation of an ongoing project aimed at understanding and further defining the role of """"""""neurosteroids"""""""" in drug- induced positive and negative allosteric modulation of GABA action at GABAalpha receptors. The hypothesis of the proposed studies is that an increase of the GABAalpha receptor-active neurosteroid allopregnanolone (ALLO) elicited by fluoxetine or other SSRIs may be associated with the antidysphoric, anxiolytic, and anticonvulsant actions of this class of drugs. Because ALLO and related steroids acting at GABAalpha receptors play a putative role in modulating anxiety, mood, and cognitive behavior, to validate our hypothesis we need to establish whether the effect of SSRIs on neurosteroids is class-specific or whether other major classes of psychotherapeutic agents that act on mood and cognition (i.e., antidepressants, typical and atypical antipsychotics, benzodiazepines, cognition enhancers) alter neurosteroid biosynthesis and release. The focus on fluoxetine (Prozac), other serotonin reuptake inhibitors (SSRIs), and neurosteroids stems from our original observation that fluoxetine and other SSRIs increase the brain content of allopregnanolone (ALLO), which in nanomolar concentrations with nongenomic action positively modulates GABAalpha receptor function, and also decreases the brain content of 5alpha-dihydroprogesterone (5alpha- DHP), which also in nanomolar concentrations with genomic action (via progesterone receptors) may control GABAalpha receptor subunit gene expression. We propose a systematic investigation of the action of fluoxetine, other SSRIs, and other antidepressant and psychotherapeutic agents on brain neurosteroid biosynthesis and release with the following Specific Aims: (1) establish the onset and the duration of changes in ALLO and 5alpha- DHP content in various rat brain regions and microdialysates following administration of fluoxetine or other SSRIs; (2) determine if the increase of ALLO elicited by SSRIs is specific for this class of drugs; (3) establish if there is a correlation between the increase in brain and microdialysate ALLO content and the behavioral effects that reveal the strength of the underlying GABAergic transmission; (4) determine if the 33alpha-hydroxysteroid oxidoreductase enzymes are the target for fluoxetinee's action on neurosteroid treatment; and (5) study if neurosteroids alter GABAalpha receptor subunit expression following long-term fluoxetine treatment. Additional evidence that neurosteroid alterations are causally associated with SSRI drug treatment would enable a completely new insight into the development of safer and more efficacious antidepressants by focusing on their neurosteroidal actions.
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