Using antagonism/agonism for potentially long-term beneficial effects through up/down regulation...

[Druidus]

I'm probably way off base here, but maybe someone can help me understand if or how this might work or if it is theoretically possible.

As I understand it, when we take drugs that affect the CNS, they either up- or down- regulate the neuroreceptors they target. So opioid/opiate drugs downregulate opiate receptors, dopamine centered drugs like amphetamine downregulate dopamine, GABAergics downregulate GABA. I know that sometimes these effects can last a long time, well after cessation of use of the drug. For example after chronic/long-term use of GABAergics like benzodiazepines/barbiturates, there is a very strong downregulation effect on the GABA system, and after cessation the GABA system stays in a changed state for quite some time, slowly moving back to a more neurotypical and homeostatic state. This results in a serious increase in anxiety until the CNS rebalanced itself. Would it, then, be possible to take a chemical that provokes anxiety through opposite effects compared to GABAergics in low doses, chronically, for eventual upregulation of GABA and reductions in anxiety and low-GABA symptoms? For instance, something like 4f-mph, which is fairly anxiogenic.

Could you take that or something like it at a rather low dose (not seeking the stimulant effects or "high") in order to have the CNS try to adapt to the chronic mild anxiogenic effects by upregulating GABA to try to reach a new homeostasis?

If it works I realize it wouldn't likely be permanent, but maybe could be used as a treatment every so often to upregulate GABA again when the previous effects were fading/waning. Wouldn't this be "safer", theoretically (with the right anxiogenic substance at the right dose) than using benzodiazepines themselves, as you wouldn't be risking long-term excessive GABA downregulation? Sure it would not be of immediate benefit, but if planned and done right, could something like this theoretically work? Has it been considered at all as a therapeutic avenue?

 

[jose ribas da silva]

I don't know how to answer your question but I can say that once on benzos always on benzos

 

[Nagelfar]

The first mention is of the opioid "receptor", which in fact is up-regulated: the effects are due to percentage of overall receptors being occupied, and when you add exogenous compounds that act as agonists, the body up-regulates the amount of receptors: cessation leaves a much smaller percentage occupied and the body slowly down-regulates to match the endogenous opioids produced by the body.

 

[Druidus]

I don't know how to answer your question but I can say that once on benzos always on benzos

I was on a ton of benzos when I was younger and I'm clean off them now, but it was extremely hard.

The first mention is of the opioid "receptor", which in fact is up-regulated: the effects are due to percentage of overall receptors being occupied, and when you add exogenous compounds that act as agonists, the body up-regulates the amount of receptors: cessation leaves a much smaller percentage occupied and the body slowly down-regulates to match the endogenous opioids produced by the body.

I understand the basic concept, but could it be used to one's benefit with something that is anxiogenic at low/micro doses to "trick" the body to upregulate GABA?

 

[Nagelfar]

I understand the basic concept, but could it be used to one's benefit with something that is anxiogenic at low/micro doses to "trick" the body to upregulate GABA?

I don't see why not. There's plenty of benefits (albeit, unrelated to the antagonism) to low dose naltrexone as the opioid system is concerned. The GABA system is just as differently complex, another could answer the question who has more knowledge than I about GABA.

 

[TheInvisibleStoner]

I was on a ton of benzos when I was younger and I'm clean off them now, but it was extremely hard.

How long clean? Are you still experiencing symptoms? I have gotten off them, but they change something where I had all kinds of fucked up panic attacks over the months and years.

But on them now since do need them I think. At least for now.

 

[Skorpio]

Something that may complicate this goal is that very few drugs have selective activity. It would be very hard to balance up regulation of multiple different systems to ameliorate tolerance to the effect.

Also, tolerance is much more complex than down regulation of the target receptor. Adaptations in vta circuit (one example which is key to reward) architecture will change the flavor of how an experience is rewarding in a way that cannot be simply overcome by increasing the magnitude of effect.

Tolerance is even complex beyond receptor levels in a subcellular context. Sustained signaling (such as pka signaling from a Gs coupled receptor such as dopamine d1 like receptors) will cause altered gene expression (such as through the phosphorylation of transcription factor CREB in this case). This altered gene expression can include changes as simple as 'em expression levels of elements in the cascade, but can include production of new regulatory factors that alter the dynamics or even second messenger routing of receptor activation.

While antagonist application will reverse some of these elements of tolerance, especially levels of receptors, some of these higher level circuit and pathway changes will not necessicarily cancel out. For example some antagonists can cause receptor internalization which decreases surface receptor expression.

 

[Jabberwocky]

I once was on hypomania induced by fluoxetine as soon as I started to take the drug. After 6 months or so, tolerance build so I quit it. But that left me thinking about how to induce hypomania again using fluoxetine.

So I started to take antipsychotics like risperidone, and a very strong one called levomepromazine which is like the anti-stimulant prototype, it has antidopaminergic, antiadrenergic, anticholinergic, antiserotonergic and antinoradrenergic activities, so basicly blocks every neurotransmitor that is needed for stimulation.

I start taking these drugs for some months gradually so I would not enter into a drug-induced depression and in hopes it would upregulate my receptors, and at anytime I would decide to be enter hypomania, i would just suddenly stop these drugs and introduce fluoxetine again. After a few months taking these antipsychotics, i decided to give a try with fluoxetine, and remove it all overnight and start taking only fluoxetine, but it did not work. I wasnt able to induce hypomania again. It would take 2 years to be able again to induce it but with other drugs.

In my opinion in theory this could be done, and I did regain sensitivity to fluoxetine again as it improved my mood, but it did not send me to hypomania state.