Posted by Brainbeard on July 28, 2009, at 14:39:27
In reply to Re: Do SSRI's cause dopamine depletion » SLS, posted by morganpmiller on June 5, 2009, at 23:17:28
> Hi I'm new to this board. You guys know that Zoloft is a Serotonin and Dopamine reuptake inhibitor, especially at doses of 100 and more?
> It has far more dopamine reuptake inhibition than Wellbutrin.
Yeah, but the gap between a drug's receptor affinities is what matters. Although sertraline's (Zoloft's) affinity for the dopamine reuptake pump is greater than that of bupropion (Wellbutrin), it is still 100 to 250 times smaller than sertraline's affinity for the serotonin reuptake pump. This means, as Dr. Preskorn argues, that 'the physician would have to increase the dose (ie, the concentration) of sertraline 100 times higher than that needed to inhibit the serotonin uptake pump before a comparable effect would be achieved on the dopamine uptake pump.' (Quoting from his online book: http://www.preskorn.com/books/ssri_s3.html)
Affinity ratios thus have to be seen 'within the context of the actual affinity of the drug for a secondary SOA [Site Of Action] relative to its affinity for its primary SOA and relative to the clinically relevant concentration needed to produce the desired clinical effect.'
Preskorn has also written a column with a subheading titled: 'Is sertraline an inhibitor of dopamine uptake?' Discussing this question, Preskorn concludes that 'it is quite doubtful that sertraline has any meaningful effect on dopamine uptake at concentrations typically achieved at its recommended dosing range, 50-200 mg/day.' (http://www.preskorn.com/columns/9909.html, scroll down)
Discussing other pharmacological data that support this view, he further concludes that 'While this does not absolutely rule out an effect of sertraline on dopamine uptake at concentrations usually achieved on its recommended dosing range, it places the burden of proof on the proponent of such a theory.'
Interestingly, Preskorn mentions a patient who used sertraline 300-400mg several times a day to achieve a stimulant high.
I do think that Preskorn underestimates the effects that even mild inhibition of the dopamine reuptake pump apparently has for many people. Alternatively, if Preskorn is entirely right, the stimulating effects of (higher doses of) Zoloft may be due to a different, yet unknown mechanism.
It is interesting that Zoloft is a derivative of tametraline, a norepinephrine and dopamine reuptake inhibitor. Quoting from the (excellent) Wikipedia article on sertraline (http://en.wikipedia.org/wiki/Sertraline):'in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline.'
I like to think that this chemical origin might contribute to Zoloft's stimulant profile in some intangible way.
poster:Brainbeard
thread:883495
URL: http://www.dr-bob.org/babble/neuro/20090701/msgs/909008.html