Benzodiazepines and GABA-receptors

[Benzeneringz]

Benzodiazepines are a class of drugs used medically for their anxiolytic, anticonvulsive, sedative, and myorelaxant properties. Another property of the benzodiazepines, amnesia, is not sought after medically. Different benzodiazepines have different strengths and weaknesses, depending on their affinity for GABA(A) receptors. Let me discuss this in further detail.

GABA(a), GABA(b), and GABA(c)
Gamma-aminobutyric acid (GABA) is the most widespread inhibitory neurotransmitter found in the brain. GABA works by reducing the action potential of a cell which prevents it from firing. Drugs that work on GABA receptors include the barbiturates, benzodiazepines, baclofen, gabapetine (Neurotonin), imidazopyridines-zopiclone & zolpidem, GHB, valproate, and many more. There are three types of GABA-receptors: A, B, and C. The benzodiazepines bind to GABA(A), while baclofen (Lioresal) binds to GABA(B). Neuroactive steroids are thought to bind to GABA(C).

GABA(a) sub-receptors
There are five sub-receptors of the sub-receptor GABA(A). These subreceptors determine the actions of a benzodiazepine. For example, benzodiazepines with a high affinity for GABA(A) A1, also known as alpha-1, are highly sedating. Alpha-2 ligands are powerful anxiolytics. Each benzodiazepine has a slightly different affinity profile which makes each benzodiazepine unique!

What about zolpidem?
Zolpidem and related compounds (zaleplon, zopiclone, eszopiclone) are often referred to as 'non-benzodiazepine hypnotics' but are considered to have many properties in common with the benzodiazepines. This is easy to decipher. Zolpidem has little affinity for alpha-2,3,4,&5 subreceptors. It's primary binding to alpha-1 makes it a benzodiazepine-type sedative and nothing more. Anxiolytic and anticonvulsive properties only are apparent at 10-20the theraputic dose of 5-10 milligrams (1).

1. http://en.wikipedia.org/wiki/Zolpidem

Reputation Comments on this post:

	a lovely read!
	good info
	Benzodiazepines and GABA-receptors post just brilliant
	well composed info

[Forthesevenlakes]

great post explaining these drugs' pharmacology!

[imyourlittlebare]

gaba-b agonists such as baclofen or phenibut also relax. However, if there is too much activity at the gaba-a receptor they decrease the amount of GABA released and allow more glutamate release. GABA-C is in the eyes. I dont think that was mentioned. But yeah GABA-A sub receptors are a bitch and the subtypes. Then GABA-B its all so complicated. You have your benzo, your picrotoxin, barbituate, etc then you got your alpha 1-5 etc, GABA-B-1a 1b. They dont even know how alcohol works. They believe the reinforcing effect is GABA-A mediated but alot of the other effects are mediated GABA-B since GABA-B agonists are good for deterring drinking cravings and the GHB receptor causes similar alcohol reactions to a person.

Reputation Comments on this post:

-0 but please explaiin your posts more fully and be thorough. for example: gaba c is found throughout the BRAIN as we...

[soma]

Swim thinks one of the best buzzes is hitting gaba(a) with a nice, strong dose of benzos, and hitting gaba(b) with anything from baclofen to barbituates to gabapentin. He wouldn't suggest this to non-tolerant users, as the combo of downers could cause exponential increase of effects. He highly recommends that anyone attempting this combo titrate upward very slowly, until desired effects are achieved.

Does anyone know what receptor Carisoprodol binds to? I assume there is a gaba component somewhere, I can feel it

[riaahacker]

Originally Posted by soma

Swim thinks one of the best buzzes is hitting gaba(a) with a nice, strong dose of benzos, and hitting gaba(b) with anything from baclofen to barbituates to gabapentin. He wouldn't suggest this to non-tolerant users, as the combo of downers could cause exponential increase of effects. He highly recommends that anyone attempting this combo titrate upward very slowly, until desired effects are achieved.

Does anyone know what receptor Carisoprodol binds to? I assume there is a gaba component somewhere, I can feel it

Carisoprodol metabolizes into Meprobamate which is indeed a GABA(A) agonist.

[p4oloz]

Gabapentin, pregabalin don't works on GABA receptors.

[tyranny4u]

actually benzodiazepines work very different compared to barbiturates.
while barbiturates are "real agonists" on the GABA receptor, benzodiazepines
only work together with GABA and then the BD will cause that the "ionic
channel" (right expression used here?) will open for chloride more likely.
so benzodiazepines rather could be seen as "synergists" than "agonists".

barbiturates are not dependent of the presence of GABA to work.
that mechanism partial explains why barbiturates will "force" sleep, while
benzos "only" will activate sleep in humans. and it's mainly the part of the
safety of the benzos concering deadly overdoses.

tt will have more research on this if his time allows.

Reputation Comments on this post:

Wrong information sorry bud. Look up your goods.

[eche05]

Benzodiazepines (alprazolam, diazepam, clonazepam, etc...) as well as the pill-encapsulated GABA both stimulate GABA receptors (gamma-amino-butyric acid (sp?)) Which relieves stress and eliminates excess neural firing.

[rocknroll714]

Nice article! This is a good read on the subject as well:

http://books.google.com/books?id=nJQ...GABA+receptors

Some info from the book and from my head..

The GABA-A receptor α1 subtype is the most widely distributed subtype in the brain and appears to primarily mediate the sedation and hypnotic effects of the benzos. α2 and α3 seem to be important for anxiety with the latter being somewhat less important. The α5 receptor is related to the cognitive and memory impairment of these drugs. The nonbenzodiazepines are a new class of GABA-A agonists which include the Z-drugs which are mainly selective for the α1 subtype and are used almost exclusively as highly effective hypnotics. New nonbenzodiazepines selective for the α2/α3 types are being developed as non-sedating and non-cognitive-impairing anxiolytics. Some of them have as high as 100x selectivity for α2/α3 over the other subtypes. None of them have made it onto the market in the US as of yet however. Furthermore antagonists/inverse agonists of some of the subtypes (especially the α5 subtype) are being developed as novel nootropics and Alzheimer's disease medications.

Reputation Comments on this post:

Good basic info to some degree, off on some others. But still, great post.

[imyourlittlebare]

Originally Posted by tyranny4u

actually benzodiazepines work very different compared to barbiturates.
while barbiturates are "real agonists" on the GABA receptor, benzodiazepines
only work together with GABA and then the BD will cause that the "ionic
channel" (right expression used here?) will open for chloride more likely.
so benzodiazepines rather could be seen as "synergists" than "agonists".

barbiturates are not dependent of the presence of GABA to work.
that mechanism partial explains why barbiturates will "force" sleep, while
benzos "only" will activate sleep in humans. and it's mainly the part of the
safety of the benzos concering deadly overdoses.

tt will have more research on this if his time allows.

no. Barbituates are the same. The reason it causes sleep is because its not very specific. It is a general CNS depressant. Benzos are more selective, and also only work on the alpha channels which may have something to do with it as well as benzos therapeutic dosage being low and lethal being very high so its very safe and not as depressing. They both work similarly. Help increase the chance that a chloride influx will happen having an inhibitory effect. This is a brief and simple, yet good explanation. Differences btwn the drugs are receptors, metabolism, and where it effects the CNS. THink of it this way, benzos are not used as anesthetics. No matter how high you go, it doesnt work. Barbs are. Thats bc they are general CNS depressants and work differently.

imyourlittlebare added 5 Minutes and 33 Seconds later...

Originally Posted by rocknroll714

Nice article! This is a good read on the subject as well:

http://books.google.com/books?id=nJQ...GABA+receptors

Some info from the book and from my head..

The GABA-A receptor α1 subtype is the most widely distributed subtype in the brain and appears to primarily mediate the sedation and hypnotic effects of the benzos. α2 and α3 seem to be important for anxiety with the latter being somewhat less important. The α5 receptor is related to the cognitive and memory impairment of these drugs. The nonbenzodiazepines are a new class of GABA-A agonists which include the Z-drugs which are mainly selective for the α1 subtype and are used almost exclusively as highly effective hypnotics. New nonbenzodiazepines selective for the α2/α3 types are being developed as non-sedating and non-cognitive-impairing anxiolytics. Some of them have as high as 100x selectivity for α2/α3 over the other subtypes. None of them have made it onto the market in the US as of yet however. Furthermore antagonists/inverse agonists of some of the subtypes (especially the α5 subtype) are being developed as novel nootropics and Alzheimer's disease medications.

yeah great info to know. The beta kind are very unique as well. Agonists dont have anxiolytic effects while the Alpha subunits have been linked to anxiety disorders, treatment, schizophrenia etc. There was a study that I site in my kava kava manuscript that I will have to put up for you guys that GABA-A benzodiazepine receptors, whether CNS or peripherally, are found less in people with true and pronounces anxiety disorders. However, it may be a fallacy just like the monoamine hypothesis. People think serotonin, norepinephrine, and dopamine cure depression bc they created MAO-I and tricyclics. They had to explain the anti-depressant effect so they made up that hypothesis. It has not been supported. Current support shows BDNF, specific brain areas such as Brodmanns Area 25, and the glutamanergic system is involved. Same might be with anxiety disorders. GABA may be involved to a degree, but overactive circuits in thalamic, cortical and in the amygdala can be to blame on top of neurotransmitter problems. Who knows? Were still learning.

imyourlittlebare added 4 Minutes and 37 Seconds later...

Originally Posted by riaahacker

Carisoprodol metabolizes into Meprobamate which is indeed a GABA(A) agonist.

It does. But the weird thing is it was a failed experiment. Just because something is similar in action does not mean it will be the same. Some benzos are anti-epileptic meds while others arent. Meprobamate or however you spell it, if I remember correctly, has a crappy safety margin, and works alot on the thalamus, the relay center of the brain. Benzos still the safest when prescribed correctly and there are no pre-existing conditions. If you have GAD or panic disorder, typically the anxiolytic effect does not diminish over time with use of benzos. Its a fact wikipedia wont acknowledge but google scholar search the phenomenon

imyourlittlebare added 4 Minutes and 41 Seconds later...

Originally Posted by p4oloz

Gabapentin, pregabalin don't works on GABA receptors.

Yeah, they were good attempts by the US to copy the Russians ideas on phenibut and modify GABA to our advantage. Thats my opinion but heres facts. Works through L-type calcium channels. Recently shown to be involved in addiction to benzos, have anxiolytic properties, and these drugs gabapentin and pregabalin are the same more or less but one is cheaper and works less effectively (gabapentin). Anyway, its decreases the release of various neurotransmitters so very helpful for alot of things. However, its big on decreasing substance P release so very useful indeed. THats why it can take up to a week to work. To ...modulate the way your brain is working. Its a fairly safe drug. I think its funny they say on the commercials "lyrica can cause depression or suicidal thoughts" "lyrica can cause certain people to feel high"

[rocknroll714]

Originally Posted by imyourlittlebare

no. Barbituates are the same. The reason it causes sleep is because its not very specific. It is a general CNS depressant. Benzos are more selective, and also only work on the alpha channels which may have something to do with it as well as benzos therapeutic dosage being low and lethal being very high so its very safe and not as depressing. They both work similarly. Help increase the chance that a chloride influx will happen having an inhibitory effect. This is a brief and simple, yet good explanation. Differences btwn the drugs are receptors, metabolism, and where it effects the CNS. THink of it this way, benzos are not used as anesthetics. No matter how high you go, it doesnt work. Barbs are. Thats bc they are general CNS depressants and work differently.

imyourlittlebare added 5 Minutes and 33 Seconds later...



yeah great info to know. The beta kind are very unique as well. Agonists dont have anxiolytic effects while the Alpha subunits have been linked to anxiety disorders, treatment, schizophrenia etc. There was a study that I site in my kava kava manuscript that I will have to put up for you guys that GABA-A benzodiazepine receptors, whether CNS or peripherally, are found less in people with true and pronounces anxiety disorders. However, it may be a fallacy just like the monoamine hypothesis. People think serotonin, norepinephrine, and dopamine cure depression bc they created MAO-I and tricyclics. They had to explain the anti-depressant effect so they made up that hypothesis. It has not been supported. Current support shows BDNF, specific brain areas such as Brodmanns Area 25, and the glutamanergic system is involved. Same might be with anxiety disorders. GABA may be involved to a degree, but overactive circuits in thalamic, cortical and in the amygdala can be to blame on top of neurotransmitter problems. Who knows? Were still learning.

imyourlittlebare added 4 Minutes and 37 Seconds later...



It does. But the weird thing is it was a failed experiment. Just because something is similar in action does not mean it will be the same. Some benzos are anti-epileptic meds while others arent. Meprobamate or however you spell it, if I remember correctly, has a crappy safety margin, and works alot on the thalamus, the relay center of the brain. Benzos still the safest when prescribed correctly and there are no pre-existing conditions. If you have GAD or panic disorder, typically the anxiolytic effect does not diminish over time with use of benzos. Its a fact wikipedia wont acknowledge but google scholar search the phenomenon

Barbiturates are not the same. They bind to a distinct site on the GABA-A receptor complex unrelated to the benzodiazepine site. It is true however that barbiturates and benzodiazepines are similar and benzodiazepines are more selective, but it's important to establish that they work via different mechanisms.

As for tolerance to the anxiolytic effects of benzos not occurring, that is quite a claim. Everything I've read and personally heard from others who've chronically taken benzos for anxiety problems indicates otherwise. You have any sources for this?

[imyourlittlebare]

hey guys any questions for me? Id love to help. Im going into behavioral pharmacology and just finished neuroscience/psychology degree with an emphasis on bio, evolutionary psychology and anthropology

imyourlittlebare added 2 Minutes and 32 Seconds later...

Originally Posted by rocknroll714

Barbiturates are not the same. They bind to a distinct site on the GABA-A receptor complex unrelated to the benzodiazepine site. It is true however that barbiturates and benzodiazepines are similar and benzodiazepines are more selective, but it's important to establish that they work via different mechanisms.

As for tolerance to the anxiolytic effects of benzos not occurring, that is quite a claim. Everything I've read and personally heard from others who've chronically taken benzos for anxiety problems indicates otherwise. You have any sources for this?

Its a basic thing dude its a barbituate vs benzo receptor. The difference isnt worth going into I was going over the basics.

Yes I have a lot of resources for everything. Let me get back on in say.... an hour when I have my flash drive?

Safety and Efficacy of Long-term Diazepam Therapy.
Primary Article
Southern Medical Journal. 73(12):1581-1584, December 1980.
BOWDEN, CHARLES L. MD; FISHER, JOHNNIE G. MD
Abstract:
Clinical evidence of withdrawal phenomena and efficacy was studied in 23 long-term users of diazepam (15 to 60 mg daily). No withdrawal reactions were observed in the ten patients who received placebo in a double-blind fashion for a two-week period. Changes in anxiety scores of both patients who received placebo and those who received diazepam suggest that the diazepam continued to be effective when used for one year or longer.


Theres a basic one for ya. Its small but you get the point. People with true anxiety disorders dont develop a tolerance for the anxiolytic effects. Most people get a tolerance to the sedative effects and think thats the anxiolytic effects occasionally. Thats my opinion since benadry has been used successfully to treat anxiety in certain people who seem to value the sedative and "drugged" feeling rather than treatment of the biological part of the illness. Most of this is fact. Some is ad lib. I shouldnt, I know, Im in a big hurry and GF pissed bc this site is a "Waste of time" cya later guys.

[rocknroll714]

Something a lot of people aren't aware of is that carisoprodol and meprobamate, in addition to their positive allosteric modulation of the GABA-A receptor, are also strong adenosine reuptake inhibitors and may exert their muscle relaxant effects and some of their other effects primarily through this action. I remember when I first tried carisoprodol.. there was just something different about it. It was really nice and made music sound fantastic. Quite different from the GABAergics I was used to like alcohol and benzos. I'd take it over them any day. Also, hydroxyzine, cyclobenzaprine, benzodiazepines, barbiturates, and alcohol, among many other drugs, are adenosine reuptake inhibitors as well to varying degrees with the benzos probably being the weakest of the lot. It has been suggested that the anticonvulsant, anxiolytic, and muscle relaxant effects of these drugs may be in part significantly mediated by this action. Personally I wouldn't be surprised if adenosine fully accounted for their muscle relaxation.

rocknroll714 added 10 Minutes and 26 Seconds later...

imyourlittlebare: You seem to act like you're pretty well-versed on the subject of GABA pharmacology. Would you care to take a look at this thread for me:

http://www.drugs-forum.com/forum/showthread.php?t=88908

Input would be very appreciated.

[imyourlittlebare]

Originally Posted by rocknroll714

Something a lot of people aren't aware of is that carisoprodol and meprobamate, in addition to their positive allosteric modulation of the GABA-A receptor, are also strong adenosine reuptake inhibitors and may exert their muscle relaxant effects and some of their other effects primarily through this action. I remember when I first tried carisoprodol.. there was just something different about it. It was really nice and made music sound fantastic. Quite different from the GABAergics I was used to like alcohol and benzos. I'd take it over them any day. Also, hydroxyzine, cyclobenzaprine, benzodiazepines, barbiturates, and alcohol, among many other drugs, are adenosine reuptake inhibitors as well to varying degrees with the benzos probably being the weakest of the lot. It has been suggested that the anticonvulsant, anxiolytic, and muscle relaxant effects of these drugs may be in part significantly mediated by this action. Personally I wouldn't be surprised if adenosine fully accounted for their muscle relaxation.

rocknroll714 added 10 Minutes and 26 Seconds later...

imyourlittlebare: You seem to act like you're pretty well-versed on the subject of GABA pharmacology. Would you care to take a look at this thread for me:

http://www.drugs-forum.com/forum/showthread.php?t=88908

Input would be very appreciated.

Id love to. Heres a quick abstract of many of the studies ive seen. Psychiatr Serv 54:1006-1011, July 2003
© 2003 American Psychiatric Association

[top]Other Articles

[top] Lack of Relationship Between Long-Term Use of Benzodiazepines and Escalation to High Dosages

Stephen B. Soumerai, Sc.D., Linda Simoni-Wastila, Ph.D., Cara Singer, B.A., Connie Mah, M.S., Xiaming Gao, M.A., Carl Salzman, M.D. and Dennis Ross-Degnan, Sc.D. OBJECTIVE: The objective of this study was to determine whether long-term benzodiazepine use is associated with dose escalation. METHODS: The authors examined changes in dose and the frequency of dose escalation among new and continuing (at least two years) recipients of benzodiazepines identified from a database containing drug-dispensing and health care use data for all New Jersey Medicaid patients for 39 months. Independent variables included age; Medicaid eligibility category; gender; race or ethnicity; neighborhood socioeconomic variables; chronic illnesses, such as schizophrenia, bipolar illness, panic disorder, and seizure disorder; and predominant benzodiazepine received. Logistic regression analyses were conducted to determine the association between the independent variables and escalation to a high dosage (at least 20 diazepam milligram equivalents [DMEs] per day for elderly patients and at least 40 DMEs per day for younger patients). RESULTS: A total of 2,440 patients were identified, comprising 460 new and 1,980 continuing recipients. Seventy-one percent of continuing recipients had a permanent disability. Among all groups of continuing recipients, the median daily dosage remained constant at 10 DMEs during two years of continuous use. No clinically or statistically significant changes in dosage were observed over time. The incidence of escalation to a high dosage was 1.6 percent. Subgroups with a higher risk of dose escalation included antidepressant recipients and patients who filled duplicate prescriptions for benzodiazepines at different pharmacies within seven days. Elderly and disabled persons had a lower risk of dose escalation than younger patients. CONCLUSION: The results of this study did not support the hypothesis that long-term use of benzodiazepines frequently results in notable dose escalation.

Along with this, I also wanted to comment on adenosine. Adenosine is an inhibitory neurotransmitter (well almost NT, not quite there yet with research but it probably is it just hasnt met the qualifications). Coffee inhibits adenosine activity which is why when people quit, they get so tired. Their bodies compensate and adenosine levels, on top of decreased activity of other NTs, causes sleepiness. Peripherally, I dont know if I would agree, respectfully, since this is a debate. Pharmacologically, people with anxiety disorders have been shown to have less than average peripheral GABA-A benzo receptors if I remember correctly. Ill look up the article but I believe its through the inhibition in the CNS that causes muscle relaxation. You decrease activity of afferent and efferent neurons, you decrease neuronal activity, you decrease cerebellum activity indirectly, you get the muscle relaxation. Thats why I think buspirone doesnt have rhabdomyolic effects. At least in theory it makes sense. Let me check out that thread. Do me a favor though? A. I love debating so I dont want to offend anyone I love good discussions. B. Could you send me how to upload articles so I dont waste space with abstracts? Thanks dude.

[imyourlittlebare]

and according to a message given to me. There is stuff called GABA-C receptors that exist. But GABA-A receptors which are inhibitory and GABA-B which are disinhibitory are enough to worry about without worrying about sensory and perception. There maybe correlational studies on GABA-C and stuff but I have not heard any major breakthroughs yet. PS. also, barbituates also effect the GAMMA subunit of the GABA-A receptor. So theres the clarification I needed maybe? I dont know.

Tolerance and benzos is actually linked to l-calcium channel activity and NR2B receptor activity. But what a lot of people dont realize is that people with true GAD, and under the watch of a doctor, and not using for sedative effects (which are mediated by alpha 1 subunit linked to alcoholism and the worst effects of benzos and ambien), most people do not increase their dosage at all. People just cant increase their dosage at will, keep open communications with their health care providers, and consider other therapy options along with benzos or take a break. And dont drink on benzos. Tolerance will go up fast. Read how alcohol decreases GABA levels and the terrible effects it has on the CNS.

2009 kava shown not to cause liver damage, be effective at reducing anxiety and depression, not be addicting in anyway, improve cognitiion and work on a lot of stuff but mainly GABA-A non benzo receptor and decrease reuptake of norepinephrine. Consider it. Not together though. Also, kava decreases want and desire to drink through mediation of another receptor but thats for another thread.......