Cannabinoids control memory through mitochondria

Cannabinoids control memory through mitochondria
Cannabinoids and memory
(Medical Xpress)—Few classes of drugs have galvanized the pharmaceutical industry in recent times like the cannabinoids. This class of molecules includes not only the natural forms, but also a vast new treasury of powerful synthetic analogs with up to several hundred times the potency as measured by receptor activity and binding affinity. With the FDA now fast tracking all manner of injectables, topicals, and sprays promising everything from relief of nebulous cancer pain to anti-seizure neuroprotection, more than a few skeptics have been generated.

What inquiring minds really want to know, beyond the thorny issue of how well they actually work, is how do they work at all? If you want to understand what something is doing in the cell, one useful approach is to ask what it does to their . With drug companies now drooling over the possibility of targeting drugs and treatments directly to these organelles by attaching mitochondrial localization sequences (MLS) or other handler molecules, answers to this kind of question are now coming into focus.

But even with satisfactory explanations in hand, there would still be one large hurdle standing in the way of cannabinoid medical bliss: Namely, even if a patient can manage to avoid operating vehicles or heavy machinery throughout the course of their treatment, how do they cope with the endemic collateral memory loss these drugs invariably cause?

A recent paper published in Nature neatly ties all these subtleties together, and even suggests a possible way out of the brain fog by toggling the sites of cannabinoid action between mitochondria and other cellular compartments. By generating a panel of cannabinoid receptor and second messenger molecules with and without the appropriate MLS tags or accessory binding proteins, the authors were able to directly link cannabinoid-controlled mitochondrial activity to memory formation.

One confounder in this line of work is that these MLSs are very fickle beasts. The 22 or so leader amino acids that make up their 'code' is not a direct addresses in any sense. While the consensus sequences that localize protease action or sort nuclear, endoplasmic reticulum, and plasma membrane proteins generally contain clearly recognizable motifs, any regularities in the MLSs have only proven visible to a computer. That is not to say that MLSs are fictions—they clearly do work—but their predictable action is only witnessed whole once their 3-dimensional vibrating structures are fully-conformed.

The authors availed themselves of two fairly sophisticated programs called Mitoprot and PSQRT to remove any guesswork in identifying a potential MLS in CN1 cannabinoid receptors. CN1s had been previously associated by immunohistochemical methods to what we might call the mitochondrial penumbra, but their presence there may have been purely incidental. This in silico analysis theoretically confirmed the presence of a putative MLS in CB1 and encouraged them to carry out further manipulations of this pathway.

Namely, the researchers took a mouse with the mitochondrial mtCB1 receptor knocked out, and then added modified versions back using viral vectors. When they applied the synthetic cannabinoid ligands (known as WIN55,212 and HU210 ) they found that mitochondrial respiration and mobility, and subsequently memory formation, remained largely intact in animals without the MLS in their receptor.

The researchers were then able to look further downstream using the same general strategy of controlling localization of the second messenger molecule protein kinase A (PKA). By fusing a constitutively active mutant form of PKA to an MLS and putting it inside using an adenovirus they were able to trace the signal cascade into the heart of the complex I of the respiratory chain.

The presence and origin of full G-protein receptor signal pathways in mitochondria is now more than just an academic question. Exactly how retroviruses and other molecular agents of sequence modification managed to re-jigger gene duplicated backups of proteins like CN1 to add alternatively spliced MLS tags is still shrouded in mystery.

Our ability to now harness these same slow evolutionary processes in real time, and bend them to our needs, will undoubtedly have implication well beyond the cannabinoid market. Together the results above suggest the tantalizing possibility of preserving some of the desired benefits of while eliminating the unintended consequences like memory loss or full blown amnesia.


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More information: Etienne Hebert-Chatelain et al. A cannabinoid link between mitochondria and memory, Nature (2016). DOI: 10.1038/nature20127

Abstract
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

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Citation: Cannabinoids control memory through mitochondria (2016, November 18) retrieved 23 February 2019 from https://medicalxpress.com/news/2016-11-cannabinoids-memory-mitochondria.html
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Nov 18, 2016
Not sure what operating heavy machinery has to do with this. Excepting THC, there does not appear to be any psychoactive effect to the 60+ cannabinoids in cannabis. Pure synthesized THC has been around for decades --- patients don't like it: someone heavily dosed with THC is not going to be operating anything except the remote control from the sofa --- they will be immobilized. My guess is that heavy machine operators have used marijuana and gone to work for decades now; the absence of evidence of a resulting holocaust on the highways and construction sites of this country suggest it's not as big a risk as is portrayed by the propagandists fighting a rear-guard action against drug reform.

Nov 18, 2016
Cannabis laws were written by Congressional alcoholics.

Nov 18, 2016
patients don't like it: someone heavily dosed with THC is not going to be operating anything except the remote control from the sofa


You're thinking of CBD or Cannabidiol. Someone on pure synthetic THC will be having anxiety attacks and psychotic paranoia.

CBD is the anti-psychotic, "stoner" part of cannabis that makes you slump down and eat a bunch. THC is the part that makes you come up with weird associations and conspiracy theories about "the man". They're both about 50/50 present in pot, depending on the strain - hence the "upper/downer" difference between indica and sativa.


Nov 19, 2016
patients don't like it: someone heavily dosed with THC is not going to be operating anything except the remote control from the sofa


You're thinking of CBD or Cannabidiol. Someone on pure synthetic THC will be having anxiety attacks and psychotic paranoia.

CBD is the anti-psychotic, "stoner" part of cannabis that makes you slump down and eat a bunch. THC is the part that makes you come up with weird associations and conspiracy theories about "the man". They're both about 50/50 present in pot, depending on the strain - hence the "upper/downer" difference between indica and sativa.


CBD is non-psychoactive, and does not get you 'stoned'. THC affects some users by making them less anxious, some have paranoia. The effects include 'relaxation' in most descriptions of being stoned. This is not yet understood, but the studies done are mostly with people that have reported anxiety in the past.

Nov 20, 2016
CBD is non-psychoactive, and does not get you 'stoned'.


it's called non-psychoactive because it doesn't get you high. However:

Cannabidiol has been found to be an antagonist at the putative cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[27] Cannabidiol has also been shown to act as a 5-HT1A receptor partial agonist,[28] an action which may be involved in its antidepressant,[29][30] anxiolytic,[30][31] and neuroprotective[32][33] effects.


Antidepressant and anxiolytic are psychoactive effects. The latter means "antipanic". In other words, it tends to suppress the anxiety caused by THC in combination, leaving you just stoned and hungry rather than paranoid.

This is not yet understood, but the studies done are mostly with people that have reported anxiety in the past.


When you administer healthy subjects pure THC in a clinical setting, most of them will display effects similiar to schitsophrenia.

Nov 20, 2016
Not sure what operating heavy machinery has to do with this.


The heavy machinery part is because of the lapses in memory formation and learning caused by cannabis. You become absent minded and foolhardy because you forget even your own mistakes, which causes a Dunning-Kruger effect where you believe you're doing much better than you actually are because you fail to recognize when things are going wrong, which makes you dangerous around machines.


Nov 20, 2016
the pharmaceutical industry being galvanized in 99% of the reason cannabis is still illegal.

Maybe now that sanity has returned to Washington? Naw. Cannabis should be a States' Rights issue, not some all encompassing mandate from the fetid swamps of the Federal district.

Nov 20, 2016
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