Marijuana & the CNS Flashcards
3 ballot measures in Ohio, Nov
Issue 1 – Creates a bipartisan redistricting commission to draw state legislative districts
Issue 2 – Prohibits initiatives that would create market monopolies
Issue 3 – Legalizes both recreational and medical marijuana
Possibilities:
Anyone at least 21 years old with a valid state license could use, possess, grow, cultivate and share up to eight ounces of homegrown marijuana and four flowering marijuana plants
Anyone at least 21 years old (with or without a license) using marijuana recreationally could purchase, possess, transport, use and share up to one ounce of marijuana
Anyone with a certified debilitating medical condition could use medicinal marijuana
What are the active compounds in marijuana?
~500 natural components
THC: tetrahydrocannabinol
CBD: cannabidiol
CB1 & CB2
- Part of the endocannabinoid system
* G-protein coupled receptors
CB1 / CB2 Receptors
- from google
Cannabinoids interact with receptors. Many receptors exist in the body, but cannabinoids interact specifically with 2 types.
The two types of cannabinoid receptors are CB1 and CB2. Both are found throughout the body, but are most common in the Brain and Immune System. When cannabinoids activate CB1 or CB2 receptors, they change the way the body functions.
CB1 receptors are Responsible for Marijuana’s Psychoactive effects.
They are present in many areas of the brain and play a role in memory, mood, sleep, appetite, and pain sensation.
CB2 receptors are Responsible for Marijuana’s Anti-Inflammatory Effects.
They are found in immune cells and work to reduce inflammation. Inflammation is an immune response and is believed to be a factor in many diseases and conditions.
THC: tetrahydrocannabinol
*from google
Tetrahydrocannabinol, is the chemical responsible for most of Marijuana’s Psychological effects. It acts much like the cannabinoid chemicals made naturally by the body.
Cannabinoid receptors are concentrated in certain areas of the brain associated with Thinking, Memory, Pleasure, Coordination, and Time Perception. THC attaches to these receptors, activates them, and affects a person’s memory, pleasure, movements, thinking, concentration, coordination, and sensory & time perception.
THC is one of many compounds found in the resin secreted by glands of the marijuana plant. More of these glands are found around the reproductive organs of the plant than on any other area of the plant. Other compounds unique to marijuana, called cannabinoids, are present in this resin. One cannabinoid, CBD is nonpsychoactive, and actually blocks the high associated with THC.
Effects on the body:
THC stimulates cells in the brain to release Dopamine, creating Euphoria.
It also interferes with how info is processed in the hippocampus, which is part of the brain responsible for forming new memories.
THC can induce Hallucinations, change thinking, and cause Delusions. On average, the effects last about 2 hours, and kick in 10-30min after ingestion. Psychomotor impairment may continue after the perceived high has stopped.
In some cases, reported side effects of THC include elation, anxiety, tachycardia, short-term memory recall issues, sedation, relaxation, pain-relief and many more. However, one study found that other types of cannabinoids, as well as terpenes (compounds that produce flavor & fragrance in plants), can modulate and reduce negative effects.
Risks:
The effects of marijuana make it one of the most commonly used illicit drugs in the world. But these effects also concern mental health advocates. THC can trigger a relapse in schizophrenic symptoms.
Another possible risk of consuming THC comes in the form of impaired motor skills. Marijuana may impair driving or similar tasks for approx. 3hrs after consumption and it is the second-most common psychoactive substance found in drivers, after alcohol. People taking medical marijuana are instructed not to drive until it has been established that they can tolerate it and conduct motor tasks successfully.
The use of marijuana may cause problems for younger people and long-term problems.
Some of the side effects of THC include a decrease in IQ, memory & cognition, esp. in young people. However, the jury is still out on long-term effects, as not enough research has been done on it yet. There is some speculation that it could impair fertility in men & women and also compromise a person’s airways, but the studies are still not clear.
Rats exposed to THC before birth, soon after birth, or during adolescence have shown problems with specific learning and memory tasks later in life.
Medicinal Uses:
Marijuana has been used for medicinal purposes for more than 3,000 years.
In many areas of the U.S., the use of medicinal marijuana is legal. In several states, recreational use is also legal.
THC can be extracted from marijuana, or synthesized, as is the case for the drug dronabinol. Dronabinol is used to treat or prevent the nausea & vomiting associated with cancer medicines and to increase the appetites of people with AIDS. It is a light yellow resinous oil.
People tout marijuana as a better drug than prescription pills because it is “all-natural.”
Just because something is considered ‘natural’ doesn’t mean it’s healthy. For example, poison oak can be harmful. Just because it grows in the ground doesn’t mean it’s healthy.
Overdose:
Edibles, foods containing THC, have become a large problem in states that have legalized pot because of overdosing.
Edibles can lead to overdose sometimes because people often ingest more than the diagnosed smaller amount. It’s easier to eat a marijuana cookie, and it’s very attractive to young people or those who don’t want to inhale it in a smoke form. Edibles are extremely potent, and when ingested in the gastrointestinal tract, the drug can last longer and with greater intensity. The effect from inhaling THC will last 45min to a few hours, but edibles can last for 6-8 Hrs and are more likely to lead to an overdose.
Colorado legislators passed a law to limit the amount of THC to only 3.53 ounces (100 milligrams) in edible marijuana products.
Concentrations of THC in cannabis:
When THC is exposed to air, it degrades into cannabinol, a cannabinoid that has its own psychological effects. THC concentration also depends on the cultivation of the marijuana plant, known scientifically as Cannabis sativa L.
A type of cannabis that has a minimal amount of THC, as low as 0.5%, is hemp. Hemp is used for industrial & medical purposes.
Some strains of cannabis can have as little as 0.3% THC by weight. In other strains, THC makes up 20% of the weight in a sample.
The average THC concentration in marijuana is 1-5%; in hashish, it is 5-15%, and in hashish oil, it averages 20%. THC in recreational doses of marijuana is highly variable and the lower the THC content in the marijuana, the more the user must consume to produce the desired effects.
endocannabinoid system (EC)
*from google
The Science of the Endocannabinoid System: How THC Affects the Brain and the Body
The EC system—named after the marijuana plant Cannabis sativa and its active ingredient delta-9-tetrahydrocannabinol (THC)—is a unique communications system in the brain and body that affects many important functions, including how a person feels, moves, and reacts.
The natural chemicals produced by the body that interact within the EC system are called cannabinoids, and like THC, they interact with receptors to regulate these important body functions. So what makes the EC system unique and how does THC’s impact on this system affect a person’s memory, risk for accidents, and even addiction?
How Cannabinoids Work Differently From Other Neurotransmitters: Brain cells (neurons) communicate with each other and with the rest of the body by sending chemical “messages.” These messages help coordinate and regulate everything we feel, think, and do. Typically, neurotransmitters are released from a neuron (a presynaptic cell), travel across a small gap (the synapse), and then attach to specific receptors located on a nearby neuron (postsynaptic cell). This spurs the receiving neuron into action, triggering a set of events that allows the message to be passed along.
But the EC system communicates its messages in a different way because it works “backward.” When the postsynaptic neuron is activated, cannabinoids (chemical messengers of the EC system) are made “on demand” from lipid precursors (fat cells) already present in the neuron. Then they are released from that cell and travel backward to the presynaptic neuron, where they attach to cannabinoid receptors.
Why is this important? Since cannabinoids act on presynaptic cells, they can control what happens next when these cells are activated. In general, cannabinoids function like a “dimmer switch” for presynaptic neurons, limiting the amount of neurotransmitter (e.g., dopamine) that gets released, which in turn affects how messages are sent, received, and processed by the cell.
How Does THC Affect the EC System and Behavior?
When a person smokes marijuana, THC overwhelms the EC system, quickly attaching to cannabinoid receptors throughout the brain & body. This interferes with the ability of natural cannabinoids to do their job of fine-tuning communication between neurons, which can throw the entire system off balance.
Because cannabinoid receptors are in so many parts of the brain and body, the effects of THC are wide-ranging: It can slow down a person’s reaction time (which can impair driving or athletic skills), disrupt the ability to remember things that just happened, cause anxiety, and affect judgment. THC also affects parts of the brain that make a person feel good—this is what gives people the feeling of being “high.” But over time THC can change how the EC system works in these brain areas, which can lead to problems with memory, addiction, and mental health.
G protein coupled receptors
- 7 transmembrane domains
- Heterotrimeric
- Upstream of many signaling cascades
- Modulate synaptic transmission
G-protein-coupled receptors (GPCRs)
*from google
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes.
These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars, and proteins. Such messages inform cells about the presence or absence of life-sustaining light or nutrients in their environment, or they convey info sent by other cells.
GPCRs play a role in an incredible array of functions in the human body, and increased understanding of these receptors has greatly affected modern medicine. Researchers estimate that between 1/3 and 1/2 of all marketed drugs act by binding to GPCRs.
What Do GPCRs Look Like?
GPCRs bind a tremendous variety of signaling molecules, yet they share a common architecture. Many present-day eukaryotes rely on these receptors to receive info from their environment. For example, simple eukaryotes such as yeast have GPCRs that sense glucose and mating factors. GPCRs are involved in considerably more functions in multicellular organisms. Humans alone have nearly 1,000 different GPCRs, and each one is highly specific to a particular signal.
GPCRs consist of a single polypeptide that is folded into a globular shape and embedded in a cell’s plasma membrane. 7 segments of this molecule span the entire width of the membrane (this is why GPCRs are sometimes called 7-transmembrane receptors) and the intervening portions loop both inside and outside the cell. The extracellular loops form part of the pockets at which signaling molecules bind to the GPCR.
What Do GPCRs Do?
As their name implies, GPCRs interact with G proteins in the plasma membrane. When an external signaling molecule binds to a GPCR, it causes a conformational change in the GPCR. This change then triggers the interaction between the GPCR and a nearby G protein.
G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). Some G proteins are small proteins with a single subunit. However, the G proteins that associate with GPCRs are heterotrimeric, meaning they have 3 different subunits: an alpha subunit, a beta subunit, and a gamma subunit. Two of these subunits — alpha & gamma — are attached to the plasma membrane by lipid anchors.
G-protein-coupled receptor (GPCR) and G-proteins in a plasma membrane, which is composed of phospholipids that form a bilayer.
In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a G-protein-coupled receptor (GPCR; loops). Upon receptor stimulation by a ligand called an agonist, the state of the receptor changes. G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell.
A G protein alpha subunit binds either GTP or GDP depending on whether the protein is active (GTP) or inactive (GDP). In the absence of a signal, GDP attaches to the alpha subunit, and the entire G protein-GDP complex binds to a nearby GPCR. This arrangement persists until a signaling molecule joins with the GPCR. At this point, a change in the conformation of the GPCR activates the G protein, and GTP physically replaces the GDP bound to the alpha subunit. As a result, the G protein subunits dissociate into two parts: the GTP-bound alpha subunit and a beta-gamma dimer. Both parts remain anchored to the plasma membrane, but they are no longer bound to the GPCR, so they can now diffuse laterally to interact with other membrane proteins. G proteins remain active as long as their alpha subunits are joined with GTP. However, when this GTP is hydrolyzed back to GDP, the subunits once again assume the form of an inactive heterotrimer, and the entire G protein reassociates with the now-inactive GPCR. In this way, G proteins work like a switch — turned on or off by signal-receptor interactions on the cell’s surface.
Whenever a G protein is active, both its GTP-bound alpha subunit and its beta-gamma dimer can relay messages in the cell by interacting with other membrane proteins involved in signal transduction. Specific targets for activated G proteins include various enzymes that produce second messengers, as well as certain ion channels that allow ions to act as second messengers. Some G proteins stimulate the activity of these targets, whereas others are inhibitory. Vertebrate genomes contain multiple genes that encode the alpha, beta, and gamma subunits of G proteins. The many different subunits encoded by these genes combine in multiple ways to produce a diverse family of G proteins (Figure 2).
A three-part schematic diagram shows a G-protein-coupled receptor (GPCR) and the alpha, beta, and gamma subunits of a G-protein at different stages. The relationships between the molecules change as they transition from inactive to active states.
The relationships of G proteins to the plasma membrane:
In G-protein-coupled receptor activation, the alpha, beta, and gamma subunits have distinct relationships to the plasma membrane. After exchange of GDP with GTP on the alpha subunit, both the alpha subunit and the beta-gamma complex may interact with other molecules to promote signaling cascades. Note that both the alpha subunit and the beta-gamma complex remain tethered to the plasma membrane while they are activated. These activated subunits can act on ion channels in the cell membrane, as well as cellular enzymes and second messenger molecules that travel around the cell.
What Second Messengers Do GPCR Signals Trigger in Cells?
Activation of a single G protein can affect the production of hundreds or even thousands of second messenger molecules. (Recall that second messengers — such as cyclic AMP [cAMP], diacylglycerol [DAG], and inositol 1, 4, 5-triphosphate [IP3] — are small molecules that initiate and coordinate intracellular signaling pathways.) One especially common target of activated G proteins is adenylyl cyclase, a membrane-associated enzyme that, when activated by the GTP-bound alpha subunit, catalyzes synthesis of the second messenger cAMP from molecules of ATP. In humans, cAMP is involved in responses to sensory input, hormones, and nerve transmission, among others.
Phospholipase C is another common target of activated G proteins. This membrane-associated enzyme catalyzes the synthesis of not one, but two second messengers — DAG and IP3 — from the membrane lipid phosphatidyl inositol. This particular pathway is critical to a wide variety of human bodily processes. For instance, thrombin receptors in platelets use this pathway to promote blood clotting.
Many signaling pathways that can be triggered by the activation of a G-protein-coupled receptor (GPCR). Signaling cascades within a cell can interact to affect multiple molecules in the cell, leading to secretion of substances from the cell, ion channel opening, and transcription.
Binding of an agonist to the 7-transmembrane G-protein-coupled receptor in the plasma membrane activates a pathway that involves G proteins as well as cAMP-related pathways that modulate cellular signaling. In this example, the activated G alpha (Gαi/0) proteins inhibit (-) adenylyl cyclase (AC, on the right), the enzyme that induces formation of cAMP, which in turn results in the activation of protein kinase A (PKA). This in turn activates a molecule called cAMP-responsive element-binding protein (CREB), which modulates gene transcription. The activated G alpha proteins can also have a variety of other effects, shown at the left. These effects include activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Activation of the enzyme phospholipase A2 (PLA2) may also occur, which induces the release of arachidonic acid (AA), as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Subsequent activation of the MAPK and PI3K pathways results in the phosphorylation of extracellular signal-regulated kinases (ERKs) and protein kinase B (PKB), respectively. Activated PKB will subsequently phosphorylate and thereby inhibit the action of glycogen synthase kinase 3beta (GSK3beta), a major kinase in the brain.
The histamine H3 receptor: from gene cloning to H3 receptor drugs.
Conclusion
GPCRs are a large family of cell surface receptors that respond to a variety of external signals. Binding of a signaling molecule to a GPCR results in G protein activation, which in turn triggers the production of any number of second messengers. Through this sequence of events, GPCRs help regulate an incredible range of bodily functions, from sensation to growth to hormone responses.
Cannabinoid Receptors
CB1:
Expressed by neurons
– Neural stem cells and nearly all neural cell types
– Nerve terminals
– Stimuli or disease state change the level of expression
CB2
Expressed by immune cells
– B lymphocytes, NK cells, monocytes, neutrophils, CD8+ T cells, CD4+ T cells
CB1
Expressed by Neurons
– Neural stem cells and nearly all neural cell types
– Nerve terminals
– Stimuli or disease state change the level of expression
• One of the most common GPCRs in the CNS
• Highly conserved between human and rodent
• Stimulation leads to modulation of neurotransmitter release:
– adenylate cyclase inhibition
– Potassium channel activation
– Calcium channel activation
CB1 KO mice
Radiolabeled high affinity CB1 and CB2 agonist – [3H]CP55,940 in the spleen
• What does this figure suggest about CB2 expression?
- Reduce locomotion
- Hypoalgesia (decreased sensitivity to painful stimuli)
- Hypophagia (reduction in food intake)
- Increased mortality rate, but not inhibiting early development
CB1 KO mice:
Lab Details
Change seen:
Latency Tests. KO mice responded later in hotplate assay and the formalin pain test.
Temperature Tests. KO were worse** in Ring Catalepsy Immobility and worse at Beam Breaks Open Field Activity.
Not much change:
Beam Breaks (hotplate activity; vertical,etc.)
Tail Flick Responce Latency Test
Body Temperature Test
Summary of CB1 ko mice
• CB1 does not play a role in embryonic development
– Why can we make this conclusion?
- Increased risk of seizure development
- Hypoalgesia confirm a role for CB1 receptors in nociceptive behaviors (e.g. pain responses)
CB2
CB2 • Expressed by immune cells • Activation leads to – Adenylate cyclase inhibition – MAP kinase signaling cascade activation
Adenylyl Cyclase
*from google
Adenylyl cyclase (or Adenylate Cyclase) is the enzyme that synthesizes cyclic adenosine monophosphate or cyclic AMP from adenosine triphosphate (ATP). Cyclic AMP functions as a “second messenger” to relay extracellular signals to intracellular effectors, particularly protein kinase A. Regulation of intracellular concentrations of cyclic AMP is largely a result in controlling adenylyl cyclase.
Structure and Function
Adenylyl cyclases are integral membrane proteins that consist of two bundles of 6 transmembrane segments. Two catalytic domains extend as loops into the cytoplasm, as depicted in the figure to the right.
When adenylyl cyclase is activated, it catalyses the conversion of ATP to cyclic AMP, which leads to an increase in intracellular levels of cyclic AMP.
Regulation of Activity
There are at least 9 isoforms of adenylyl cyclase, discovered by cloning of full-length cDNAs. These enzymes differ considerably in regulatory properties and are differentially expressed among tissues, adding support to observations that support a very complex model of interactions that regulate cyclic AMP production.
Studies indicated that cyclase activity was regulated primarily by interactions with alpha subunits of heterotrimeric G proteins, which are activated through G protein-coupled receptors. Binding of a stimulatory G alpha (Gs) enhanced activity while binding of an inhibitory G alpha (Gi) inhibited cyclase activity. This is certainly the case in some situations. For example, the beta-adrenergic receptor is coupled to adenylyl cyclase via Gs and binding of epinephrine to this receptor leads to increased cyclic AMP synthesis. Also, when epinephrine binds to alpha-2 adrenergic receptors, adenylyl cyclase activity is inhibited, because that receptor is coupled to via Gi, an inhibitory G protein.
More recently, it has become clear that cyclase activity is regulated by multiple effectors, which include not the alpha subunits of Gs and Gi proteins, but also the beta-gamma subunits of G proteins and protein kinase C.
Of potentially great significance, 5 of the adenylyl cyclases known are regulated by calcium. 3 of these are stimulated by calcium and 2 are inhibited. Also, ultrastructural labelling has demonstrated a close spatial association of adenylyl cyclases with sites of calcium entry in cells. It thus appears that there is tight integration between cAMP and calcium, the cell’s 2 major internal signallers.
All known adenylyl cyclases are stimulated by exposure of cells to the diterpene forskolin. This drug is widely used in studies aimed at dissecting intracellular signalling pathways.
Some G-Proteins Activate Adenylate Cyclase
*from youtube
- A hormone binds a receptor, activating a G-Protien.
- The G-Protien’s Alpha subunit binds GTP and dissociates from the G-Ptotien body.
- The Dissociated Alpha subunit and GTP complex binds to Adenylate Cyclase, activating it.
- Active Adenylate Cyclase catalyses the conversion of ATP —> cAMP + Pyrophosphate (PPi)
- cAMP activates other molecules, such as Protein Kinase A (PKA), by binding their regulatory subunits.
MAP kinase
*from google
MAP kinases - a kinase family.
MAP kinase family members have been found to regulate diverse biological functions by phosphorylation of specific target molecules (such as transcription factors, other kinases, etc.) found in cell membrane, cytoplasm and nucleus, and thereby participate in the regulation of a variety of cellular processes including cell proliferation, differentiation, apoptosis and imuno responses.
CB2 knockout mice
- Loss of [3H]CP 55940 binding in the spleen
- Spleen morphology was normal
- Cell counts from the spleen & thymus were normal
• THC induces hypothermia and catalepsy in CB2 KO mice
- Catalepsy = Catalepsy (from Greek “catch”) is a nerve condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain.
CB2 receptor is expressed in the rat, mouse, and ferret CNS. (A) RNA was isolated from the spleen (SPL), cerebem (CER), cortex (COR), and brainstem (BS) of rats.
RNA was isolated from the spleen (SPL), cerebellum (CER), cortex (COR), and brainstem (BS) of rats.
Dorsal motor nucleus of the vagus
(DMN of V)
Western blots: protein
Mice can’t throw up
Ferrets can
What are the most common risks with marijuana use?
- altered senses (example: seeing brighter colors)
- altered sense of time
- changes in mood
- impaired body movement
- difficulty with thinking and problem-solving
- impaired memory
- Persistent users lost an average of eight IQ points between 13 to 38
What are the most common risks
with marijuana use?
• Physical Effects
– Breathing problems
– Increased heart rate
• Mental Effects – Use during pregnancy – Temporary hallucinations – Temporary paranoia – Worsens schizophrenia – Linked with • Depression • Anxiety • Suicidal thoughts among teens
What are the most common risks with marijuana use?
Heavy marijuana users self report…
– lower life satisfaction – poorer mental health – poorer physical health – more relationship problems – Less academic and career success
medical marijuana
The term medical marijuana refers to using the whole unprocessed marijuana plant or its basic extracts to treat a disease or symptom
