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/journal/articles/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).

 

[Temeraroius]

If anyone else wants an answer to this, it's over in CD.

 

[jswilla]

A few questions for you. did you do all of your THC research from this one article? I have a test coming up and don't have time to read it - probably shouldn't even be on here right now. What happens before the glutamic acid is released and binds to the post-synaptic neuron? is the TCH responsible for increased glutamic acid release or something?
The inhibition of adenylate cyclase is a result of stimulation of a receptor that is coupled to an inhibitory G-protein.
Also, to my knowledge (masters in biomedical science and a first year med student) depolarization of a post-synaptic neuron doesn't open calcium channels. That happens at the presynaptic neuron once the depolarization reaches the axon terminal. I could be wrong though.
I'll be back on here in a few days after my test. Hopefully by then I will have found out some more info about this topic that I can share. Thanks for posting this. I've been thinking about it for a while but never really tried to get to the bottom of it.

 

[Temeraroius]

Haha, I mostly did it from wikipedia and the thread I made over in CD. THC has nothing to do with Glutamate release. THC simply does the same thing as Anandamide (which is created when glutamate is released). Glutamate is released by I dont know what. That one article only gave me the info on how the Anandamide is synthesized (from what and by what enzymatic action) in the post synaptic neuron.

 

[Tsukasa]

lul, well i'm a 17 year old too, with a weird interest in neurobiology and pharmacology.

Using my memory as a source, Theirs 2 cannabinoid discovered so far, THC binds to both of them. Their also more than 1 endocannabinoid. besides adandamine, theirs also 2-AG, Noladin Ether, NADA, and OAD. They are all eicosanoids which are synthesized from either omega-3 or omega-6 essential fatty acids.

I know that cannabinoids reduce GABA release in interneurons of the basolateral amygdala. (which paradoxically actually extinguishes the conditioned fear response somehow), it also does something similiar to 5-HT which may account for the psychedelic effect and deep contemplative thinking. The stimulating euphoria and adrenergic like effects are from release of dopamine and norepinephrine. Cannabis also reduces testosterone levels, which is responsible for the lack of motivation caused by it.

 

[Temeraroius]

It also does something similiar to 5-HT which may account for the psychedelic effect and deep contemplative thinking. The stimulating euphoria and adrenergic like effects are from release of dopamine and norepinephrine. Cannabis also reduces testosterone levels, which is responsible for the lack of motivation caused by it.

Could you go into a little more depth or hook me up with a source for that information. Does the DA and norepinephrine release happen simply because the inhibition (GABA release) is inhibited? Also some more depth on the 5-HT thing would be cool.

 

[Tsukasa]

^ I don't feel like looking around for sources now, but i'll be sure to find them tommorow.

I'd think that GABA and 5-HT inhibition is responsible for DA and NE release, since that's how i understand it works. They are like opposites in effect. inhibition of one leads to dis-inhibition of the other.

Recently, a group of Italian researchers succeeded in demonstrating that THC releases dopamine along the reward pathway, like all other drugs of abuse. Some of the mystery of cannabis had been resolved by the end of the 1990s, after researchers had demonstrated that marijuana definitely increased dopamine activity in the ventral tegmental area. Some of the effects of pot are produced the old-fashioned way after all--through alterations along the limbic reward pathway.

Recent data from animal studies reveal that, in common with various drugs of addiction (heroin, cocaine, nicotine and amphetamines), THC activates the release of the chemical messenger dopamine in some regions of the brain of rats (Pertwee Q 311, Wall Q 126). This is considered important as this pattern of dopamine release is thought to be associated with the rewarding properties of these drugs and hence may be related to their ability to cause dependence.

Also forgot to mention that THC also has effects on the opioid system too, which contributes mostly to the dopamine release, and is probably what is responsible for the physical relaxation, since it antagonizes GABA we know what isn't responsible.

Other recent scientific findings indicate a relationship between the cannabinoid system in the brain and the naturally occurring opioid system[8]. The ability of THC to trigger dopamine release in the rat brain is blocked by prior administration of naloxone, a drug that selectively blocks the actions of opiates in the brain. This suggests that some of the psychoactive effects of THC and other cannabinoids may be mediated indirectly through an ability to activate the opioid system (Pertwee Q 311). Recent studies have also shown that the administration of THC to animals enhances the pain-relieving effects of morphine and related opiates. Furthermore, administration of naloxone (the opiate-blocker) to animals previously treated repeatedly with a cannabinoid produced some physical withdrawal signs; conversely, administration of a cannabinoid antagonist to animals previously dependent on heroin elicited some (but not all) of the signs of opiate withdrawal (see Appendix 4, paragraph 8). On the other hand, although some of the actions of THC may involve activation of the opioid system, THC does not mimic morphine or heroin either in its effects on animals or in the subjective experience of human users.

 

[Doctor Abalaba]

You're a bit confused. Glutamate may stimulate endocannabinoid release, but THC substitutes for endocannabinoids. I doubt anandamine plays a huge role in the action of THC.
As for the monoamine systems, there are clear effects, but as with most pharmacological agents, differ depending on location. For example, in the frontal cortex, serotonin was uneffected, while dopamine turnover was increased (1). While another study, examining urine metabolites , didn't find any differences between dopamine, serotonin, and noradrenaline (2). It seems that there is a consistent increase in monoamine oxides, both in vitro and in vivo (3,4). Now the dopamine increase shouldn't be surprising, it is a rewarding experience. The question is, is the increase in MAO due to a direct effect of THC, or as a response to high DA levels.
With respect to THC and GABA. Endocannabinoids, and presumably THC, depress GABA signalling in the hippocampus, and yet again, paradoxically may be responsible for the decrease in memory-based processes (5). Moreover, the specific decrease in short term episodic memory may also be mediated by a decrease in ESPS by Glu (6). To further complicate the picture, different effects are mediated by acute versus chronic administration (7).
Not to be overlooked are the effects of THC on acetylcholine. There is a 'triphasic', u-shaped effect of THC on specific subtype nicotinic (α-sub-4 β-sub-2) receptors (6,8,9).
Well, I don't want to write a review, but before I go, I want to say one thing.
The methods used to study pharmacology have come a long way, and to a large degree are automated, so that at least the risk of human observational error is decreased. But do not forget many of the measures, for example, using antagonists, use some behavioral observations. These behaviors may be a product of a variety of neurochemical systems. On that same note, the antagonists used may have a high affinity for their respective receptor, but its not like they wont bind to other receptors. Moreover, the neurochemical or physiological assays of endogenous chemicals don't specify whether the changes are a direct result of THC or a downstream event. Basically, we understand what happens after THC enters the brain, but the specific mechanisms of action (note the pural noun) are poorly understood.

1- Jentsch, J. David; Andrusiak, Ericka; Tran, Anh; Bowers, Malcolm B.; Roth, Robert H.; Δ-9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: Blockade of dopaminergic effects with HA966. Neuropsychopharmacology, Vol 16(6), Jun 1997. pp. 426-432.
2- Taylor, David A.; Biphasic nature of the effects of !D-9-tetrahyrocannabinol on body temperature and brain amines of the rat. European Journal of Pharmacology, Vol 46(2), Nov 1977. pp. 93-99.
3-Banerjee, Anuradha; Poddar, Mrinal K.; Saha, Subhash; Ghosh, Jagat J.; Effect of D9-tetrahydrocannabinol on monoamine oxidase activity of rat tissues in vivo. Biochemical Pharmacology, Vol 24(15), Aug 1975. pp. 1435-1436.
4- Gawienowski, A.; Chatterjee, D.; Andersen, P.; Epstien, D.; Grant, W.; The effect of delta-9-tetrahydrocannabinol on monoamine oxidase activity in bovine eye tissues, in vitro. Invest Opthalmol Vis Sci, 24, 482-485, 1982
5- Kang-Park, Maeng-Hee; Wilson, Wilkie A.; Kuhn, Cynthia M.; Moore, Scott D.; Swartzwelder, H. Scott; Differential sensitivity of GABA-sub(A) receptor-mediated IPSCs to cannabinoids in hippocampal slices from adolescent and adult rats. ; Journal of Neurophysiology, Vol 98(3), Sep 2007. pp. 1223-1230.
6- Ranganathan, Mohini; D'Souza, Deepak Cyril; The acute effects of cannabinoids on memory in humans: A review. Psychopharmacology, Vol 188(4), Nov 2006. pp. 425-444.
7- Hoffman, Alexander F.; Oz, Murat; Yang, Ruiqin; Lichtman, Aron H.; Lupica, Carl R.; Opposing actions of chronic Δ-sup-9-tetrahydrocannabinol and cannabinoid antagonist on hippocampal long-term potentiation. Learning & Memory, Vol 14(1-2), Jan-Feb 2007. pp. 63-74.
8- Smith, Aaron D.; Dar, M. Saeed; Mouse cerebellar nicotinic-cholinergic receptor modulation of Δ-sup-9-THC ataxia: Role of the α-sub-4β-sub-2 subtype. Brain Research, Vol 1115(1), Oct 2006. pp. 16-25.
9-
Inhibition of hippocampal acetylcholine release after acute and repeated Δ-sup-9-tetrahydrocannabinol in rats. Carta, Giovanna; Nava, Felice; Gessa, Gian Luigi; Brain Research, Vol 809(1), Oct 1998. pp. 1-4.

 

[Temeraroius]

Wow, thank you very much. Lots of great info there.

 

[lenses]

Glutamate release would fuck you shit up and cause major neurotoxicity.

 

[Temeraroius]

Glutamate release would fuck you shit up and cause major neurotoxicity.

False. Too much does though. When theres too much extra GLU around it causes too much Ca++ ions to enter through your NMDA receptors but a little (enough to depolarize the post-synaptic neuron) is aight.

 

[PsychedelicPeptide]

Here's some newer papers with good ideas on how marijuana acts on CB receptors to look into:

Mol Cell Endocrinol. 2008 Apr 16
Signaling via CNS cannabinoid receptors.
Mackie K.

Department of Psychological and Brain Sciences, Indiana University

Because of the prominent psychoactive effects of cannabis and its preparations, much research has focused on the actions of cannabinoids, the primary psychoactive components of cannabis, on neuronal function. A convergence of research has identified (1) cannabinoid receptors, (2) endogenous compounds that activate these receptors (endocannabinoids), and (3) drugs that interact with these receptors and the proteins that synthesize and degrade the endocannabinoids. This review will first consider how endogenous cannabinoids signal through cannabinoid receptors and the various forms of synaptic plasticity mediated by endocannabinoids. Next the interactions between exogenous cannabinoids such as Delta9-tetrahydrocannabinol and endocannabinoids and endocannabinoid-mediated plasticity will be examined. Finally, a model will be presented that can explain the prominent psychoactivity of these plant-derived cannabinoids.

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

J Neuroendocrinol. 2008 May;20
Cannabinoid receptors: where they are and what they do.
Mackie K.

Department of Psychological and Brain Sciences, Indiana University

The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endocannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB(1) and CB(2), although additional receptors may be involved. CB(1) receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of cannabinoids. CB(2) receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.

Expert from the 1st paper:

Somewhat surprisingly, in examining DSE, MSE, and
endocannabinoid-mediated LTD, we found that increasing concentrations
of THC antagonized all three forms of plasticity
(Straiker and Mackie, 2005, 2007) (and R. Kellogg, Mackie,
and Straiker, unpublished observations). Interestingly, longterm
treatment with THC caused desensitization of cannabinoid
responses (Straiker and Mackie, 2005). Thus, while occupancy
of CB1 receptors by THC antagonizes endocannabinoid inhibition
of neurotransmission in autaptic cultures, THC still
stimulates CB1 receptors sufficiently to set in motion the cellular
machinery necessary for desensitization. This appears to
be an example of functional selectivity or biased agonism inCB1
receptor signaling (Urban et al., 2007). Thus, at least from the
cell culture results it appears that a major action of THC is to
antagonize endogenous cannabinoid signaling. Does this mean
that the psychoactivity of THC and cannabis are simply due to
the antagonism of endocannabinoid signaling? This is not the
case because the indiscriminant antagonism of CB1 receptors
by the CB1 antagonist rimonabant generally does not mimic the
effects of THC (Le Foll and Goldberg, 2005; Navarro et al.,
2001). (However, it is important to note that CB1 antagonism
can produce reward as assayed by conditioned place preference,
indicating the complex nature of the interactions of the endocannabinoid
and reward systems (Cheer et al., 2000).) More
likely the psychoactivity of cannabis is due to complex interactions
of THC (and related compounds) as a partial agonist
with CB1 receptors, in part through the antagonism of high
efficacy endocannabinoids (e.g., 2-AG) and the mimicking of
low efficacy endocannabinoids such as anandamide. Additional
support for this notion comes from experiments with human
volunteers where even sustained high doses of rimonabant only
slightly attenuate the subjective measures of cannabis-induced
psychoactivity (Gorelick et al., 2006; Huestis et al., 2001).

6. Conclusions and perspectives

The past 20 years have seen the emergence of the endocannabinoid
system from the receptors “hijacked” by cannabis
to a complex neuromodulatory system involved in processes as
diverse as cognition, reinforcement, energy balance and reproduction.
Endocannabinoids mediate several forms of synaptic
plasticity, an action that may underlie their varied psychoactive
and behavioral actions. In addition to the diverse processes
influenced by the endocannabinoid system, it is becoming
increasingly apparent that the pharmacology of this system is
highly complex. In particular, multiple endocannabinoids target
the CB1 cannabinoid receptor leading to varied physiological
effects. The divergent routes of synthesis and degradation of the
different endocannabinoids enrich the diversity of these effects.
The interactions between endocannabinoid-mediated plasticity
and THC are similarly complex, with substantial evidence
supporting an antagonist relationship between THC and the
well-studied forms of synaptic plasticity.

To me it sounds like THC may be an allosteric modulator of CB1 receptors, rather than a pure antagonist like rimonabant.