Confirmation that there is a difference between Seroxat/Paxil and other SSRIs - yeah is that why they got off so easily ?

“Interestingly, one SSRI, paroxetine (Paxil), retains its normal powerful action on the transporter, revealing that — at a molecular level — different antidepressants interact with the transporter in different ways,” Blakely said.




The researchers are now evaluating chronic administration of SSRIs to determine how much the transporter contributes to the more clinically relevant, delayed effects of these drugs, as well as for the side effects experience with antidepressant medications.

http://seroxatsecrets.wordpress.com/2011/02/19/confirmation-that-there-is-a-difference-between-seroxatpaxil-and-other-ssris/

Seroxat Prescriptions Decline 2001 to 2003 – An Analytical Study by Graham Aldred


Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter



Brent J. Thompsona,1, Tammy Jessena, L. K. Henrya,2, Julie R. Fielda, Karen L. Gambleb,3, Paul J. Grescha, Ana M. Carneiroa, Rebecca E. Hortonc, Peter J. Chisnella, Yekaterina Belovaa, Douglas G. McMahonb,d, Lynette C. Dawsc,e, and Randy D. Blakelya,d,f,4

+ Author Affiliations



Departments of aPharmacology and

bBiological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232;

cDepartment of Physiology, University of Texas Health Sciences Center, San Antonio, TX 78229;

dCenter for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232;

eDepartment of Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229; and

fDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232

Edited* by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved January 7, 2011 (received for review August 14, 2010)



Abstract

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]–targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., “ecstasy”), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.



Footnotes

4To whom correspondence should be addressed. E-mail: randy.blakely@vanderbilt.edu. Author contributions: B.J.T., T.J., L.K.H., J.R.F., K.L.G., P.J.G., A.M.C., D.G.M., L.C.D., and R.D.B. designed research; B.J.T., T.J., L.K.H., J.R.F., K.L.G., P.J.G., A.M.C., R.E.H., P.J.C., and Y.B. performed research; B.J.T., L.K.H., K.L.G., P.J.G., A.M.C., D.G.M., L.C.D., and R.D.B. analyzed data; and B.J.T., T.J., L.K.H., J.R.F., K.L.G., P.J.G., A.M.C., D.G.M., L.C.D., and R.D.B. wrote the paper.

↵1Present address: Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229.

↵2Present address: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, Grand Forks, ND 58203.

↵3Present address: Department of Psychiatry and Behavioral Sciences, University of Alabama at Birmingham, Birmingham, AL 35233.

The authors declare no conflict of interest.

↵*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1011920108/-/DCSupplemental.