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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Brady, Linda S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Zhubi, A; Veldic, M; Puri, N V et al. (2009) An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. Schizophr Res 111:115-22
Rasmusson, Ann M; Pinna, Graziano; Paliwal, Prashni et al. (2006) Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry 60:704-13
Pinna, Graziano; Costa, Erminio; Guidotti, Alessandro (2004) Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids. Proc Natl Acad Sci U S A 101:6222-5
Puia, G; Mienville, J-M; Matsumoto, K et al. (2003) On the putative physiological role of allopregnanolone on GABA(A) receptor function. Neuropharmacology 44:49-55
Pinna, Graziano; Dong, Erbo; Matsumoto, Kinzo et al. (2003) In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc Natl Acad Sci U S A 100:2035-40
Costa, E; Auta, J; Grayson, D R et al. (2002) GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs. Neuropharmacology 43:925-37
Izzo, E; Auta, J; Impagnatiello, F et al. (2001) Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines. Proc Natl Acad Sci U S A 98:3483-8
Liu, W S; Pesold, C; Rodriguez, M A et al. (2001) Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc Natl Acad Sci U S A 98:3477-82
Dong, E; Matsumoto, K; Uzunova, V et al. (2001) Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci U S A 98:2849-54
Pinna, G; Uzunova, V; Matsumoto, K et al. (2000) Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol. Neuropharmacology 39:440-8

Showing the most recent 10 out of 29 publications