Research
GABA Receptors

Investigator: Alessandro Guidotti, M.D.

The overall goal of our research project is to utilize the diversity of GABAA receptor structure and function to develop via new strategies safer and more effective neuroactive drugs capable of acting as modulators of GABAA receptor function. The present proposal if 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 GABAA receptors. The hypothesis of the proposed studies is that an alteration of the brain content of neurosteroids active at GABAA receptors occurs as a consequence of acute or protracted fluoxetine, or other antidepressant treatments. The focus on fluoxetine (Prozac), other serotonin reuptake inhibitors (SSRIs), and allopregnanolone (ALLO), which in nanomolar concentrations with nongenomic action positively modulates GABAA receptor function, and also decrease the brain content of 5a-dehydroprogesterone (5a-DHP), which also in nanomolar concentrations with genomic action (via progesterone receptors) may control GABAA receptor subunit gene expression.

We propose a systematic investigation of the action of SSRIs and other antidepressants drugs and antidepressant treatments on brain neurosteroids biosynthesis with the following Specific Aims: 1) To establish the onset and the duration of changes in ALLO and 5a-DHP content in various rat brain regions,brain microdialysates, and plasma following acute or long-term administration of fluoxetine and other antidepressant treatments; 2) To determine of the 3a-hydroxysteroid oxydoreductase enzyme is a target for fluoxetine's action on neurosteroid biosynthesis; 3) To determine if 5HT (serotonin) plays a role in the regulation of neurosteroid biosynthesis elicited by fluoxetine and other SSRIs; and 4)To study if neurosteroids alter GABAA receptor subunit expression following long-term antidepressant treatment.

Additional evidence that neruosteroids alterations are causally associated with antidepressant drug treatment would enable a completely new insight into the development of more efficacious antidepressants by focusing on their neurosteroidal action.