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Thread: The GABA(A) Receptor Complex and Benzodiazepines

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    The GABA(A) Receptor Complex and Benzodiazepines 
    #1
    Bluelighter kokaino's Avatar
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    We all know that benzos work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and therefore has a calming effect on many of the functions of the brain.

    The GABA(A) receptor complex has many different subunits, which in turn have isoforms or otherwise known as subtypes (α1-6, β1-4, γ1-3, δ, ε, θ, and ρ1-2). Different benzodiazepines (BZD) have different affinities for GABA(A) receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. Only three of the subunits (α, β, and γ) are benzodiazepine sensitive. The α (alpha) subunit has 6 subtypes, but only α1, α2, α3, and α5 are BZD sensitive. The β (beta) subunit has 4 subtypes, but only the β3 subtype is BZD sensitive. The γ (gamma) subunit has 3 subtypes, but only the γ2 subtype is BZD sensitive.

    Subunits from only one class (α) or two classes (α and β) can form functional GABA receptors under experimental conditions, but subunits from three classes (α, β, and γ) are needed for full receptor function. These three subunits also compose most of the GABA(A) receptors in the mammalian brain.


    The Alpha (α) subunit

    The most important subunit is the "alpha" (α) and its subtypes isoforms (α1,2,3,and 5). The alpha subunit is responsible for mediating most of the effects of the benzos. All benzos bind to this subunit but they also all have different affinitie levels to the different subtypes.

    α1 subtype: Sedation, respiratory depression, sleep, ataxia, motor-impairment, amnesia, anti-convulsive, and reinforcing behavior.

    α2 subtype: Anxiolysis, disinhibition

    α3 subtype: Anxiolysis, anti-convulsive, muscle relaxation

    α5 subtype: Learning and memory, amnesia, minor sedation

    α3 & α5 subtype: Sensorimotor information processing

    The Beta (β) and Gamma (γ) subunits

    γ2 subtype: Physical dependence, respiratory depression

    β3 subtype: Anti-convulsive, minor sedation, muscle relaxation, various other reactions related to respiration. This receptor subtype is a barbiturate receptor.

    Benzos affinity to the GABA(A) receptors

    High α1 affinity: midazolam, triazolam, flunitrazepam, temazepam, lormetazepam, nitrazepam, brotizolam, nimetazepam, loprazolam, and flutoprazepam.

    Low to Moderate α1 affinity: wide range of 1,4 benzodiazepines including diazepam, estazolam, flurazepam, oxazepam, lorazepam, alprazolam, bromazepam, camazepam, quazepam (highly selective affinity), clonazepam, medazepam, nordazepam, chlordiazepoxide (very weak affinity), clorazepate, and most other benzo as all benzos are α1 agonists with varying degrees of affinity levels. Also included here are the nonbenzodiazepine "z-drugs" such as zolpidem, zaleplon, zopiclone, and eszopiclone which are all highly selective of the α1 subtype receptor but with only weak to moderate affinity.

    High α2 affinity: diazepam, clonazepam, bromazepam, lorazepam, alprazolam, camazepam, nitrazepam, loprazolam, lormetazepam, and flutoprazepam.

    Moderate α2 affinity: oxazepam, prazepam, phenazepam, temazepam, flunitrazepam, halazepam, midazolam, and other less commonly known benzos.

    Weak α2 affinity: triazolam, chlordiazepoxide (stronger affinity for α3), brotizolam, quazepam, tetrazepam (stronger affinity for α3), and a few others.

    High α3 affinity: diazepam, clonazepam, temazepam, lorazepam, tetrazepam, flunitrazepam, nimetazepam, phenazepam, and bromazepam.

    Moderate α3 affinity: alprazolam, adinazolam, estazolam, chlordiazepoxide, clorazepate, and flurazepam.

    High γ2 affinity (these benzos are the most physically addictive): temazepam, brotizolam, triazolam, alprazolam, lorazepam, loprazolam, midazolam, flunitrazepam, clonazepam, lormetazepam, flutoprazepam, nitrazepam, nimetazepam, and estazolam

    Low to moderate γ2 affinity: diazepam, chlordiazepoxide, oxazepam, and most other benzos.

    High β3 affinity: mostly the hypnotics (nitrazepam, temazepam, triazolam, etc)

    Low to moderate β3 affinity: diazepam, alprazolam, most other benzos.


    Source of all this info is this book which I purchased. It has A LOT of more useful info. It's worth its price.
    Last edited by kokaino; 06-02-2011 at 19:20.
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    #2
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    Captain.Heroin's Avatar
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    My hopes are blighted, my heart is broken, my life a burden, everything around me is sad and mournful; earth has become distasteful to me, and human voices distract me. It is mercy to let me die, for if I live I shall lose my reason and become mad.
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    Awesome, thank you! I am adding this to the OD Directory.
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    #3
    Bluelighter
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    Awesome thread, thank you.
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    #4
    Bluelight Crew NeighborhoodThreat's Avatar
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    ^^Seconded, this is really awesome information! Thanks CH for adding to the directory!
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    #5
    Bluelighter Starshowers's Avatar
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    Thank you for this. Excellent.
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    #6
    Bluelighter Nagelfar's Avatar
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    What in the benzo class has "the highest" affinity for γ2?

    Also are there any specific ligands for γ2?
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    #7
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    This is off-topic but can someone please tell me why I never see anything about an a4 receptor?

    Edit: I'd probably look into buying the book if it didn't just center around GABA. Thanks though.
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    #8
    Bluelighter
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    nice work, man, thanks. really informative.
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    #9
    I agree w/ everyone in applauding you work, but I'f I may make a suggestion:

    Add a table of contens at the beginig, or a glossary/index at the end.

    Whenever I find great informv posts like this, they are often so visually challanging I ignore them
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    #10
    Bluelighter phatass's Avatar
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    interesting !
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    #11
    from this can anyone speculate why even large doses of clonazolam are much worse at stopping trips, getting rid of headaches, and at the same time gives less of that destructive brain frying feeling while tapering, compared to etizolam and others?
    clonazolam has much higher antianxiety effects and sedation, yet it seems it doesn't "comfort" a certain subtype that calms certain brain activity down nearly as much as etizolam. Etizolam would remove any negative feeling in my head(headache, overexcitaton-wise) but clonazolam doesn't unless you take a much higher dose. Yet clonazolam certainly feels like it should.. given every other aspect surpassses etizolam
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