The serotonin transporter (SERT) is an integral membrane glycoprotein that is responsible for the reuptake of serotonin from the synapse. Drugs that inhibit the SERT are effective in several psychiatric disorders including depression. Recent studies have shown that the SERT can be regulated in vitro. Less is understood about its acute or chronic regulation in vivo. Different approaches have been used to address this issue, with inconclusive results. We have used in vivo chronoamperometry, a fast voltammetric technique, to demonstrate that there are areas in brain such as the CA3 region of the hippocampus, where the active clearance of exogenously ejected serotonin is primarily a function of SERT activity. This technique, then, is capable of generating rapid kinetic, quantitative measures of SERT function in vivo. In the proposed experiments, we will use this approach to study if long term administration of two different selective serotonin reuptake inhibitors (SSRIs), paroxetine and fluoxetine, produce a time-dependent subsensitivity of the SERT. The influence of treatment parameters such as route of administration, duration of administration, and drug-free washout period will be evaluated. Based on our preliminary data, we will explore if activation of terminal 5-HT1B autoreceptors alters the kinetics of SERT function in vivo. If so, then we will examine whether such a phenomenon impacts on any apparent regulatory effect of chronic SSRI treatment on SERT activity. In addition to examining the CA3 region, two other brain areas where the active clearance of 5-HT is due exclusively to the SERT will be studied. These experiments provide a new approach to study whether the SERT, a primary target for several types of antidepressants, is capable of being regulated either acutely or chronically in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH057001-01A1
Application #
2464988
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1998-05-01
Project End
2001-02-28
Budget Start
1998-05-01
Budget End
1999-02-28
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Bondi, Corina O; Rodriguez, Gustavo; Gould, Georgianna G et al. (2008) Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 33:320-31
Gould, Georgianna G; Brooks, Bryan W; Frazer, Alan (2007) [(3)H] citalopram binding to serotonin transporter sites in minnow brains. Basic Clin Pharmacol Toxicol 101:203-10
Gould, Georgianna G; Altamirano, Alfonso V; Javors, Martin A et al. (2006) A comparison of the chronic treatment effects of venlafaxine and other antidepressants on serotonin and norepinephrine transporters. Biol Psychiatry 59:408-14