Down regulation of 5HT2C antagonism of Prozac

[musique]

I'm thinking of starting a good anti-d that doesnt effect cognition or energy. I've read that besides Zoloft which at high dosages can have minimum DRI properties that Prozac can cause robust synthesis of Norepinephrine and dopamine to the pre-frontal cortex due to the 5HT2C antagonist ( unique to most ssri's) component. Does anyone know or have experience as to whether this effect rapidly minimizes once 5HT1, 5HT2 etc reaches full agonist and results in the regular dulling and apathetic effects as all the other SSRI's ?
I know that at 10 mgs~ low dose that the 5HT2C antagonist effects are very high, does this mean that at higher dosages it becomes mitigated and eventually ceases to have this effect?

I appreciate any and all input. thank's in advance

 

[kleinerkiffer]

Od - > N&PD

 

[musique]

Od - > N&PD

Huh ?

 

[Coolwhip]

The moderator has moved the thread from Other Drugs to Neuroscience and Pharmacology, where you will get better answers.

I don't have a lot of knowledge about this specific substance, its mechanism of action, or its efficacy, and I am not looking at the binding affinities, but I believe it has a higher affinity for said receptor than 5HT, so it should retain its antagonistic affect regardless of increased 5HT levels.

 

[musique]

Oh yeah, duhh! I frequent that sub-forum as well. I feel like a dumb ass lol..Thanks for your responses. I appreciate your thoughts

 

[Cotcha Yankinov]

Prozac is fully capable of causing emotional blunting in some people, especially at first, just like other SSRIs. With continued agonist (or even antagonist) stimulation of 5-HT2C, there will be receptor downregulation. There is also e.g. mirtazapine which has direct effects on 5-HT2C. It's 5-HT2C inverse agonism is known to have effects on dopaminergic systems via binding in medial prefrontal cortex.

I'm not sure just how appreciable Prozac's 5-HT2C antagonism really is. But with continued use of SSRIs, the 5-HT2A/5-HT2C receptors will downregulate and desensitize anyways. For what its worth, Prozac is thought to be one of the more "activating" SSRIs.

 

[asecin]

i read about "emotional blunting" but there is no definition of this. i dont understand it. does it mean you become emotionless worker bee of a type or what else in other terms?
im thinking, the government might have a very good use of such drugs on people if thats how i perceive it be

 

[Scrofula]

As a longtime SSRI-taker-person, sertraline specifically, "emotional blunting" is probably the best way to describe it. It means you have all the emotions you used to have, felt at the same situations, but they are less intense. Something that triggered despair only triggers some sadness now, but times that felt soaring high, are just happy. For me, right now, that's a good thing, and I'll sacrifice the highs. Other times it's not worth it.

Strangely, way back in college it had the opposite effect of the worker bee. My grades tanked. And I think it was because I lost some of the anxiety over them.

Your worker bees would just tell you to piss off, then go and do something that's alright, on an OK day.

 

[musique]

Prozac is fully capable of causing emotional blunting in some people, especially at first, just like other SSRIs. With continued agonist (or even antagonist) stimulation of 5-HT2C, there will be receptor downregulation. There is also e.g. mirtazapine which has direct effects on 5-HT2C. It's 5-HT2C inverse agonism is known to have effects on dopaminergic systems via binding in medial prefrontal cortex.

I'm not sure just how appreciable Prozac's 5-HT2C antagonism really is. But with continued use of SSRIs, the 5-HT2A/5-HT2C receptors will downregulate and desensitize anyways. For what its worth, Prozac is thought to be one of the more "activating" SSRIs.

Great explanation of the mechanism of action. Much thanks. I'm just wondering then, how would it maintain it's activation if the 5HT2C is antagonized? I mean it's more activating than zoloft/sertraline

 

[musique]

Scrofula, I agree. I have been on Zoloft before @ 100mgs/day and experienced just that. It's worth the blunting if you have racing thoughts that tremendously interfere with being productive and/or maintaining a normal lifestyle.
I'm thinking Prozac over Zoloft, Effexor for cognition and obv prozac is a hell of alot easier to come off of than Effexor if need be.

I felt the nicotinic antagonist effect( blunting of memory) of Wellbutrin for a week straight and decided to quit. I'm not sure if after a few weeks this effect would be mitigated or would it be remotely possible that it dissipates entirely ?

I'm good with strict diet etc so I'm seriously considering MAO ~ Nardil or maybe Parnate as well

 

[Cotcha Yankinov]

Great explanation of the mechanism of action. Much thanks. I'm just wondering then, how would it maintain it's activation if the 5HT2C is antagonized? I mean it's more activating than zoloft/sertraline

5-HT2C antagonism (or desensitization) seems to be leading to an increase in the excitability of some dopamine and norepinephrine cells. 5-HT2C has many functions (it is apparently the most populous serotonin receptor) but 5-HT2C are expressed on dopamine/norepinephrine cells and can regulate those cell's firing.

 

[musique]

5-HT2C antagonism (or desensitization) seems to be leading to an increase in the excitability of some dopamine and norepinephrine cells. 5-HT2C has many functions (it is apparently the most populous serotonin receptor) but 5-HT2C are expressed on dopamine/norepinephrine cells and can regulate those cell's firing.

Sorry Cotcha, I meant if the antagonism down regulates eventually according to you, how would it keep working as an activating anti-d ? Is there a totally seperate mechanism of action at work that you know of.
Also I sustained a small bleed in my basal ganglia many years ago and it's common to experience symptoms of apathy, abulia, lack of sustained spontaneous activation/movement, depression, ocd, non verbal tourettes and slight anxiety. Do you know of any meds that can be helpful for this? I'm currently trying ropinirole which has shown me in literature to be effective with people with much larger lesions than myself. It works as agonist on D2+D3 . I use Addy and dex occasionally only for mental clarity and focus with energy doing mental tasks NOT athletics etc where my heart rate goes up. The bleed was from hypertension, unknown to me, as all my doctor visits in 20 years showed normal blood pressure BUT because of my stenosed aortic valve, the systolic spikes during workouts. The icing on the cake was using anabolics which raised my hemoglobin and hematocrit and a pre-wokout drink with very high undisclosed amounts of caffeine mixed with L-tyrosine. Even though I took only 1 scoop which is a minimum and cycled it~ 4 weeks on, 2 -3 weeks off it was still the coffin's nail for me.
I guess I'm asking if you could recommend an anti-D in any class to help with focus , energy and cognition which few would you suggest? Much thanks in advance.

 

[Cotcha Yankinov]

Sorry if I wasn't clear - one way to think about this is that the 5-HT2C receptors can inhibit DA/NE cells, and continued agonist or even antagonist binding will downregulate 5-HT2C, leaving less 5-HT2C receptors to exert an inhibitory tone on those DA/NE cells.

If there are issues with dopamine release, the dopamine receptors (expressed elsewhere on non-dopaminergic cells) can still be activated by a direct agonist but that may lose a lot of the subtlety of natural release of DA. Normally cells fire in specific patterns/directions to mediate specific signals, but a DA agonist isn't spatially/temporally selective.

Dopamine releasing agents depend upon intact dopamine cells to mediate dopamine efflux. In other words, if the dopamine releasing cells have been damaged, then a dopamine releasing agent will be a poor releaser of dopamine (while a direct DA agonist can still bind to whatever receptors are left). This means that dopamine releasing agents (amphetamine) and direct agonists can have very different effects and different therapeutic uses.

There actually seems to be a limited variety of antidepressants. Aside from SSRIs there are basically SNRIs, TCAs, mood stabilizers, atypical antidepressants (mirtazapine, which although is sedating at first can be activating at higher doses), and oddball or two like Buspar and Wellbutrin. Mindfulness meditation can also be very helpful though.

 

[musique]

Ahhh! I see, so is the Atypical once labeled to Prozac a marketing ploy to an extent? As it seems that it doesnt matter if 5HT2C is an antagonist like touted with Prozac or Valdoxan etc..OR an agonist like in most other SSRI's ..the point is once down regulation occurs, and that's inevitable, it will no longer possess an inhibition and more dopamine/norepinephrine cells will be firing.

Yes this applies to me, as the minor bleed in the right head of Caudate nucleus still caused necrosis to numerous dopaminergic cells and neurons. My understanding that the caudate nucleus contains high amounts of mostly dopaminergic and Gabaergic cells.
Therefore a Dopamine agonist such as what I've started lately ~ Requip or agents like pramipexole, dostinex, lisuride etc.. will be more beneficial than amps.

Whats your opinion on the various MAO inhibitors such as Nardil, Parnate and Manerix(moclobomide) ? You seem very knowledgeable in various areas of Neuroscience. Not just from here but I've read some of your other posts and replies. Is this your field of study/profession or mostly self interest with tonnes of reading and research ?

Thanks very much for your deep insights. I'm looking forward to more of your brilliance and lucidity

 

[Cotcha Yankinov]

That would be interesting if Prozac was once thought of as atypical. But yes, its always important to differentiate between the acute and chronic effects of SSRIs, the chronic effects can be very different than the acute. SSRIs can even reduce serotonin cell firing when given acutely (due to autoreceptor activation, but autoreceptors desensitize with chronic dosing).

With regards to the caudate injury, is the injury thought to have interrupted to projections from the substantia nigra? If there is a deficit of dopamine release onto the caudate in someone then I suppose that may be taken as a rationale for trial of a direct agonist..

The MAOIs can have some side effects but some people that don't have success with SSRIs can have success with them from what I've heard anecdotally.

I've just self educated so take everything I say with a grain of salt

 

[musique]

That would be interesting if Prozac was once thought of as atypical. But yes, its always important to differentiate between the acute and chronic effects of SSRIs, the chronic effects can be very different than the acute. SSRIs can even reduce serotonin cell firing when given acutely (due to autoreceptor activation, but autoreceptors desensitize with chronic dosing).

With regards to the caudate injury, is the injury thought to have interrupted to projections from the substantia nigra? If there is a deficit of dopamine release onto the caudate in someone then I suppose that may be taken as a rationale for trial of a direct agonist..

I believe that the "injury" has exerted a degree of volume loss to the Caudate head which in turn effects the efferent projections from the ventral medial aspect to the PFC. The lesion is abutting the lateral ventricle and is around 8mm in all aspects( Axial, coronal and Sagital) I have included 2 axial slices for easier understanding via visualization. Both a very High res ( research grade) 3T T1 (1mm slice) which does not over exaggerate the lesion's dimensions because there is no gradient blooming from the blood products ( Hemosiderin/ferritin) in contrast to the 2nd img which is also run on the same High res scanner and is a SWI sequence which is the best we have for discovering the slightest amount of signal drop off from Blood products etc..However there is slight blooming due to this sequence being devised from a Gradient echo foundation.

I'm wondering if Dopamine agonists can hitch a ride on the existing dopamine/gaba cells and projections to the PFC and to a lesser extent some serotonergic and acetylcholine cells. Efferent compromise would cause slowness, memory retrieval difficulties, robust spontaneous activation of movement and motivational loss and attentional defecits. Afferent compromise from PFC to Caudate ( the inhibitory loop) is most likely causing anxiety, ocd, insomnia and racing thoughts.

[/URL] [/IMG]

 

[Cotcha Yankinov]

Have you tried neurofeedback? It seems to be able to help people with traumatic brain injury and stroke. Unfortunately any drug is going to have very different effects than endogenous release of transmitters.

 

[musique]

No, what could that do as far as Motivation, energy and cognitive improvement ?

 

[asecin]

after going through this about prozac, ive tried one of my leftover pills today for serious depression issue and as expected 1 pill would not do anything, and it takes a week or so for antidepressant effect, YET, the side effects were pronounced IMMEDIATELY, wow! this has to be the antidepressant of the century, take it for weeks to feel anything, takes one single pill, a single day of use to get all the negatives! AMAZING! whoever came up with this crap is a genius!!! think about the profit, taking how many pills for how many weeks to work and how much you would spend, or the insurances as it is currently with the generics.

 

[musique]

after going through this about prozac, ive tried one of my leftover pills today for serious depression issue and as expected 1 pill would not do anything, and it takes a week or so for antidepressant effect, YET, the side effects were pronounced IMMEDIATELY, wow! this has to be the antidepressant of the century, take it for weeks to feel anything, takes one single pill, a single day of use to get all the negatives! AMAZING! whoever came up with this crap is a genius!!! think about the profit, taking how many pills for how many weeks to work and how much you would spend, or the insurances as it is currently with the generics.

You seem like a negative person in general sooo..Think about all the millions or lives were saved from this efficacious treatment and have you looked at large patient studies and confirmed how many people get adverse effects that drop out of treatment? a lot less than some medications such as Effexor etc..If there was so many unbearable adverse effects as opposed to the remission rates of MDD or other hard to treat maldaptive disorders , would it be the top dispensing SSRI via placebo?

This thread isn't about your ONE day placebo effect with a left over SSRI or Love it or hate it in genral. Have the decency to start a new thread and Not Hijack and dirty up my thread. I hope the Mods see this and remove and if not in a few days I will be contacting them and kindly ask.