The endocannabinoid system is a fascinating and complex system. It has received little attention until relatively recently, where it is now becoming clear that it is a vital and important regulatory system in our CNS. Often associated with marijuana and then routinely ignored, the endocannabinoid system has been recently shown to play a critical role in regulating and protecting neurons, modulate mood, stimulate stem cell differentiation and inhibit nicotine addiction. Details and corresponding papers after the jump.

What is the endocannabinoid system?

The endocannabinoid system includes cannibanoid receptors, endocannabinoids and enzymes. Endocannabinoids, such as 2-AG, are cannabinoid receptor agonists. Their discovery, however, is the result of the widely prevalent recreational drug known as marijuana. Marijuana’s active chemical is Tetrahydrocannabinol (THC), which is also a cannabinoid receptor agonist and bestows recreational users with a mildly euphoric psychoactive experience. Marijuana mainly binds to the CB1 cannabinoid receptor. THC is an exogenous agonist, meaning it is not produced by the body. This prompted the search for an endogenous agonist (produced internally). Searching revealed 2-AG, AEA, and a few other cannabinoid agonists. While it was clear our body has a use for cannabinoids, their role remains relatively unclear.

These agonists bind to cannabinoid membrane receptors in the body, CB1 and CB2. CB1 is mainly located in the central nervous system although also found peripherally as well. CB1 has been located in the olfactory bulb, neocortex, pyriform cortex, hippocampus, amygdala, basal ganglia, thalamic and hypothalamic nuclei, cerebellar cortex and brainstem nuclei. CB1 is a G-Protein Linked Receptors (GPLR) and is one of the most prevalent GPLR’s in the CNS. CB1 has been shown to inhibit the adenyl cyclase pathways and voltage-dependent presynaptic calcium channels, affect inwardly rectifying potassium channels and various MAP kinases. Receptor density varies among the different brain regions and shows no correlation between density and influence. It is widely believed that CB1 regulates GABA release and can be found near GABAergic cells.

CB2 is also a GPLR but is found predominantly in the peripheral system. It has been shown recently that CB2 is minorly located in the CNS as well. CB2 has an immunological role and can be linked to imflammation, especially in the CNS.

A third receptor, GPR55, has recently been discovered and is theorized to also be a cannabinoid receptor.

Role in Synaptic Plasticity

Cannabinoids are increasingly being regarded as important receptors in synaptic plasticity. Because of CB1’s inhibitory response and localization on the presynaptic end of synapses, it is believed that cannabinoids function as local retrograde modulators. Essentially, they are believed to help maintain homeostasis in the brain and keep neurons from over-exciting themselves. Neurons that over exert themselves can suffer from excitotoxicity which is fatal. In one study, mice were altered to lack the expression of CB1 and then stimulated with kainic acid, a excitotoxin. These mice suffered seizures. In vitro, neurons lacking CB1 showed a lowered threshold for kainic acid induced excitability. In wildtype mice, kainic acid administration raised anandamide (cannabinoid agonist) concentrations and triggered various neuronal protective mechanisms. These protective mechanisms were not triggered in mice lacking CB1, showing that CB1 is clearly used to help protect neurons from over-exciting themselves.

One of the interesting aspects of the endocannabinoid system is that it is mainly a retrograde system. Cannabinoid receptors are located presynaptically. Activation of classic post synaptic receptors releases cannabinoid compounds that move backwards across the synaptic cleft. Once bound to the receptor, the the presynaptic cell is inhibited or even prevented from releasing more post-synaptic bound transmitters. This type of plasticity has been shown to be both long term and short term, as well as occurring at both inhibitory and excitory synapse junctions.

CB receptors play an obvious role in fear and anxiety. CB-knockout mice have provided some excellent data on CB’s role in anxiety. CB-KO mice demonstrate increased anxiety at all times, especially in high stress environments. Knockout mice also appear to receive decreased benefits from anti-anxiety medication such as bromazepam and buspirone, indication that CB receptors play a crucial role in the action of anxiolytic medication. Mice administered with CB1 antagonists showed similar anxiety results. Administration of CB1 agonists, however, completely reversed anxiety-induced behavior. Interestingly, the anxiolytic benefits of the CB1 agonist were only seen in mice habituated to the test environment. Mice performing the test for the first time (running a maze) showed normal signs of stress. It was only after they had become familiar with the environment did the anti-anxiety effects of the CB1 agonist kick in. Clearly, CB receptors play a crucial role in the regulation of mood and anxiety in mammals.

A recent paper has some interesting new data regarding CB1/CB2 in murine embryonic stem cells. During differentiation of hematopoietic (blood cell stem cells, multipotent) CB1 and CB2 receptors are expressed. When treated with an endocannabinoid antagonists (AM251 and AM630) the stem cells suffered significant death, indicating that cannabinoids are an important part of the survival of hematopoietic cells. Cannabinoid agonist THC induced increased differentiation as well as increased creation of embryoid bodies.

Cannibanoid antagonists may help those with Parkinson’s Disease (PDF). Parkinson’s is a degenerative disease most often associated with the degradation of motor control. The loss of muscle control is attributed to insufficient dopamine creation in the brain. Typical treatment includes medication to supplement dopamine levels in the form of a dopamine precursor L-Dopa. Treatment like this is only somewhat effective. Only roughly 2% of the supplemental L-Dopa makes it into the necessary neurons, the rest is metabolized elsewhere. This causes a wide range of side effects. Furthermore, supplementation increases L-Dopa levels, signaling the brain to stop producing its own L-Dopa. Dopamine agonists are used as well but suffer the same similar side effects and eventual down-regulation of receptors.

Cannabinoid receptors, however, may help with treatment. In addition to influence on GABA and glutamate, it appears CB1 acts presynaptically with dopaminergic neurons. When cannabinoid antagonist CE¹ was administered to Parkinson’s monkeys, no visible anti-Parkinson’s effect was observed. When co-administered with classic Parkinson’s L-Dopa treatment, however, there was marked increase in anti-Parkinson’s effect as well as increase in duration. The method of action is still largely unknown but it can be concluded that the CB1 receptor activity regulates the dopaminergic neurons in a way that is favorable.

1 - CE, selective cannabinoid antagonist (1-[7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-
a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide
benzenesulfonate)

An agonist this time, anandamide, may help nicotine addicts (PDF). Anandamide is an interesting and complex cannabinoid agonist. Anandamide is not only a agonist for CB1/CB2 but has also shown to influence Ca²⁺, Na⁺ and K⁺ channels not associated with CB1/CB2 pathways. It also appears to bind with 5-HT₃ and nicotinic Acetylcholine (ACh) receptors. Certain ACh receptors bind easily with nicotine and are speculated to be the cause of nicotine’s addictive property. The α4β2 ACh receptor in particular was scrutinized in this study. It was found that anandamide bound with this receptor and inhibited ion currents mediated by the receptor.

Interestingly, THC did not bind to α4β2 ACh, conclusively showing that the effects from anandamide were independent of CB1/CB2 action. It is believed that anandamide binds extracellularly but because of the ease with which fatty acids (like anandamide) can traverse cell membranes, it is uncertain if anandamide simply diffuses across the membrane as its method of action. Regardless, it appears this selective antagonist for α4β2 ACh decreases the addictive qualities of nicotine by inhibinting ion channel functionality.

Ironically, here is a study that shows similar behavior, although in the reverse order. In this study, researchers studied the effects of blocking α7 nicotine receptors to stop cannabis addiction. It was shown that inhibiting α7 nicotine receptors that mice self-administered cannabinoid agonists less often. They also observed that there were decreased THC-induced dopamine levels.

Combining the last two studies, I would hazard a guess that the addictive properties of the nicotine receptors are independent of either nicotine or cannabis. Instead, I would theorize that these receptors trigger releases in dopamine which in turn reinforce the behavior by granting pleasure. Drugs aimed at these receptors may prove useful in finding anti-addictive medication, particularly useful for drugs like nicotine, heroin or cocaine.

Lastly, I’ll leave you with a study that produced some very pretty images of CB1 distribution in the both monkeys and humans. Below is one of showing the distribution of CB1 throughout the human brain. Click for big.