THC Mechanism of Action (NOT - "Dude why does weed get you high?")

[Temeraroius]

So, pretty much every explanation Ive been able to find in journal articles, wikipedia etc. has me pretty confused. It is to my understanding that the endocannabinoid system works as follows...

1. Glutamic acid binds to the post-synaptic neuron (NMDA receptor) and depolarizes it by opening ligand gated ion chanels and letting in Ca++ etc.

2. The depolarized post-synaptic neuron releases the endocannabinoid anandamide (which is explained in further detail near the bottom of the 3rd page here http://www.supportiveoncology.net/jo...es/0204305.pdf).

3. The anandamide then binds to the CB1 receptor on the pre-synaptic neuron (through retrograde signaling).

4. Those endocannabinoids then decrease GABA release through DSI (depolarization induced suppression of inhibition).

First of all, do I have any of this wrong? I'm confused as to weather or not the anandamide binding to the CB1 receptor depolarizes the pre-synaptic neuron (is the "D" in DSI refering to the depolarization of the post synaptic neuron by the glutamate or that of the pre-synaptic neuron due to anandamide?).

Second of all, Ive read that CB1 agonists such as anandamide and THC inhibit adenyl cyclase (which has SOMETHING to do with G-coupled protein action I THINK), where is this occuring?.

Is it that the CB1 receptors (which are G-protein bound) are agonized by either anandamide or THC, then the G-protein inhibits adenyl cyclase (and is adenyl cyclase part of the g-protein)? Also, when the CB1 receptor is antagonized, are any ion channels opened (this could be answered by my depolarization question)?

Finally, is it right to assume that THC does the same thing I described in steps 1-4 without including steps 1 and 2 (which is simply the trigger of creation/release of anandamide)?

Sorry, I know that I am asking for a lesson in basic neuron/receptor function as well as specific circumstantial explanations but I would really like to figure this out. Obviously I am no neurologist, I'm simply a 17 year old who is fascinated by neuroscience and cant take any legit classes yet (woohoo college next year).

(Sorry to cross-post this between ADD and CD but I figured it wouldn't hurt as some people here might know it but not frequent ADD)

 

[Temeraroius]

Okay this is probably too much science for CD so if the mods wanna close it, its totally cool with me. Ripping bowls is more fun than answering this stuff anyway (not that I dont wanna learn it though).

 

[ItchyRichy]

this is actually really interesting, ive always wanted to know more about this.

 

[Temeraroius]

Start out by reading the wiki pages on THC, CB1, Anandamide, Glutamate, and DSI; specifically the sections on mechanism of action (and anything that those raise questions about). I dont know how much you know in terms of neuroscience but if you know anything about how synapses work you should start to catch on. It's all really cool stuff.

 

[Coolio]

This belongs in Advanced Drug Discussion since it's about pharmacology.

 

[me0307]

i've actually have always wanted to learn about how exactly thc affects the brain

although...never realy had the motivation to learn it all

all i know is - it gets you high...and its fun.

 

[ranunky]

I'm studying the cannabinoid system in one of my modules this semester and although we haven't covered it yet, the lecture slides are online already.

I took some slides from it for you:

as you can see there are references in some of the slides.

Here is a review of the endocannabinoid system and possible theraputic strategies - http://www.megaupload.com/?d=728O9VV2

--------------

now to answer your questions one by one:

1. You seem to have it correct. Although step 4 may be different depending on what kind of cells we're talking about - not sure. I can't find anything about how it modulates GABA but it definately inhibits presynaptic neurotransmitter release as I go into later on...

2. Adenylyl cyclase is the most common downstram effector protein for G-protein coupled receptors (not G-coupled protein receptors!). There is a receptor, on the EC side it interacts with the ligand. On the IC side it is coupled to a membrane bound G protein. It's a receptor, coupled with a G protein. As a side note, you're far from the first person to get this mixed up, most people I know, including myself called them GCPRs at first until we realised what we were thinking didn't make any sense! Stimulation of the receptor induces a conformational change in the G protein, the G protein loses the GDP molecule it's associated with and a GTP molecule takes its place. The now active G-protein now dissociates from the GPCR and bumps into adenylyl cyclase, a membrane bound enzyme. Adenylyl cyclase converts ATP to cAMP blah blah blah downstream events et. cetera.

Oh yeah there's three subunit to a G protein, alpha, beta and gamma. The alpha dissociates from the beta gamma part at some point when the G protein is active I'm not exactly sure when, it's before it reaches adenylyl cyclase anyway. There are two types of alpha subunit, Ga(s) and Ga(i). One stimulates adenylyl cyclase, one inhibits it. The The CB1 receptor is a GPCR coupled with an inhibitory G protein. It inhibits cAMP production in the same neuron as the CB1 receptor, ie. the presynaptic neuron.

3. "Is it that the CB1 receptors (which are G-protein bound) are agonized by either anandamide or THC, then the G-protein inhibits adenyl cyclase (and is adenyl cyclase part of the g-protein)?" Yes (no)

4. Also, when the CB1 receptor is antagonized, are any ion channels opened (this could be answered by my depolarization question)?

No. You need to get some basics down on antagonism: When a receptor is antagonised, this means that the ligand binding site is occupied, but the appropriate conformational change for signal transduction is not induced. i.e. NO EFFECT on the cell.


5. Finally, is it right to assume that THC does the same thing I described in steps 1-4 without including steps 1 and 2 (which is simply the trigger of creation/release of anandamide)?
Yes, THC directly agonises the CB1 receptor, nothing fancy like stimulating release of endocannabinoids or anything like that.

Good luck in college mate, you're gonna do well, you know a shit ton more than I did at your age!

EDIT: I missed a q - "I'm confused as to weather or not the anandamide binding to the CB1 receptor depolarizes the pre-synaptic neuron (is the "D" in DSI refering to the depolarization of the post synaptic neuron by the glutamate or that of the pre-synaptic neuron due to anandamide?). "

I'm not sure if anandamide binding does depolarise the cell, but the D in DSI refers to the glutamic action.
EDIT2: anandamide binding inhibits depolarisation

When the CB1 receptor is agonised, the betagamma subunits of the Gi protein (remember them?) directly inhibit voltage depandant Ca++ chanells and stimulate inwardly rectifying K+ chanells resulting in a lower probability of glutamate being released.

 

[Temeraroius]

Wow Ranuky, thank you soo much, that clears a TON up. I'm glad i posted this in CB, 40 views and no answers in AD.

 

[MyDoorsAreOpen]

Ranunky, what kind of academic program are you in? I'm a first year medical student, and you know your cell signaling pathways better than I do, that's for sure! (I haven't taken neuro yet -- just cell -- including neuron -- physiology).

 

[FrostyMcFailure]

In hippocampus, CB1 is localised eclusively to a subset of presynaptic GABA-containing neurons, suggesting a major function of hipp campal endocannabidoids is to regulate GABA release.

That does explain A LOT. Great thread!

 

[ranunky]

MDAO: I'm in my third year majoring in pharmacology. I learned the basics of these receptors last year in "Pharmacology I" then last semester I learned them in detail in a module called "cell signalling". The module I took the slides from is called "Drugs of Abuse", fun stuff indeed !

 

[MyDoorsAreOpen]

I'm taking Pharm next year. The guy who teaches it actually interviewed me for my school, and we spent most of the interview shooting the shit about nootropics.

 

[thujone]

great topic to bump