Using tolerance wisely....?

[swilow]

This may be a rather stupid question, but I was thinking that if a GABA agonist such as diazepam ultimately leads to downregulation of receptors and thus increased excitatory action/ and anxiety in the brain. Obviously, this reaction is most apparent when withdrawing from the drugs.

I wonder if an inverse agonist, such as Ro15-4513 could be used for a period of time, leading to a tolerance towards glutaminergic excitement and thus decreased anxiety- would the 'withdrawl' symptoms from chronic use of such a drug be 'similar' to the actual anxiolytic properties of benzodiazepine? Would it be AT ALL therapeutically viable? I understand that the period where one would be using the drug could indeed be hellish and dangerous; but this idea just floated into my head. I am really only referring to the use of these drugs drugs to control diagnosed anxiety, not for recreation.

Please feel free to shoot this idea down in flames of wrath....I don't know much about Ro15-4513 at all, but some simple conjecturing just bought this forth. It would be kinda like withdrawing before starting treatment....Anyway. Yeah.

 

[Smyth]

The general idea is one that has merit.

Using NMDA antagonists to limit opioid tolerance is perhaps the best idea I have seen. Moreover methadone and ketobemidone already have NMDA antagonist properties, i.e. it is an intrinsic (built-in => inbuilt) activity.

Secondly, 5-HT2C ant/agonists both downregulate this receptor subtype upon chronic (>2 weeks) treatment. An oversensitive 5-HT2C subreceptor complex is therefore one of the hypotheses of depression. As it returns to a desensitized (downregulated) state, dopaminergic neurotransmission originating in the VTA is greatly disinhibited.

My knowledge of GABA is very limited, I understand that contrary to glutamate, GABA is the major inhibitory neurotransmitter.

I think that such theories could be valid. Are you suggesting that by taking pro-glutamatergic drugs, these systems would become downregulated and then there would be a anxiolytic net-effect, even though during the acute phase they may be anxiogenic?

Tell me more about "Ro15-4513" since it is some bogus code that is meaningless to me.

Also, do you have a particularly interesting paper to share to increase my general knowledge of this area?

 

[MattPsy]

Ro15-4513 is a weak partial GABA-A inverse agonist whcih was thought could be of use as a alcohol "antidote".

ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate

 

[Jamshyd]

My guess, and this is only a guess, is that although the body can easily produce less of a thing in favourable conditions, it would not e likely produce more. The body is inherently conservative.

So, while you can cause downregulation by using agonists, your best bet with the opposite is returning to "normal" rather than cause a dramatic upregulation, probably due to a rate-limiting process (negative-feedback).

This is all just an educated guess, and I could be wrong.

ps. I strongly recommend not fucking around with GABA antagonists, unless you're comfortable with seizures...

 

[Smyth]

The body is inherently conservative.

The body is inherently efficient, but I wouldn't call it inherently "conservative." For example, the body wont mind laboring large quantities of energy from mitochondria energy reserves in events that are perceived as being prosurvival (e.g. hunting or escape from predators).

Upregulation is the opposite of downregulation and is known to occur. For example, opiates cause an acute downregulation of cAMP and consequently CREB in the locus coreuleus (LC), but this becomes upregulated upon chronic dosing. So, the body is producing more of someting, in this case noradrenergic receptors.

Read some of these articles to gain insight into the molecular underpinnings of opiate addiction.

 

[fastandbulbous]

Partial inverse agonists have been considered as possible treatments for dementia & other cognitive illnesses as they promote potentiation/memory formation, but apparently they're not exactly wel;l tolerated because of their anxiogenic potential. The idea of administering a full inverse agonist comes under the heading of 'torture & psychological warfare' in my book!

 

[swilow]

^I guess my idea stems from the fact that 'treatment' for anxiety these days is the use of benzo's, which most people find amplifies their anxiety when coming off it. It is a needless trauma that resembles the symptoms of the inital disorder, and is one of the biggest causes of relapse. I would think, that in cases of intactable anxiety, that something that really hinders peoples ability to get of benzo's is the horrid withdrawal, which mimicks their illness....I think that an inverse agonist would be almost impossible to relapse on.

Anyway, this is is just a silly idea really.