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Molecular Neuroscience III > 5 - Cannabinoids > Flashcards

5 - Cannabinoids Flashcards

1
Q

What is cannabidiol (CBD)?

A

A weak agonist for CB1 and CB2 cannabinoid receptors

May be a good substitute for THC in medical purposes. Less psychoactive effects.

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2
Q

True or false. The density of CB1 cannabinoid receptors in the brain is really high

A

True

Less CB2, found in peripheral immune system and on glia in the brain

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3
Q

What are the two endogenous cannabinoid? What is the first an agonist of (in addition to cannabinoid receptors)

A

Anandamide
- Also an agonist of TRPV1 (capsaicin) channel

2-arachidonoylglycerol (2-AG)

There are more, such as 2-AG ether and N-arachidonoyl dopamine, but they aren’t as important to know..

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4
Q

What does CB1 cannabinoid receptor activation do?

A
  • Cell transport
  • Synaptic plasticity
  • Modulates ion channels and a variety of G protein-coupled receptors
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5
Q

What does activation of CB1 cannabinoid receptors do?

A

Triggers an anti-inflammatory response through inhibition of microglia and inhibiting their release of inflammatory cytokines.

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6
Q

What is synthesis of endogenous cannabinoids dependent on?

A

Phospholipids and phospholipase C and phospholipase A2

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7
Q

How is human reaction to cannabinoids different from rodents?

A

Rodents don’t show much pleasure, just anxiety. Can’t make a good model for self-administered stimulation.

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8
Q

CB1 receptor increases food intake ‘primarily’ through what type of cell?

A

Melanin concentrating hormone expressing neurons
- Increase excitability by decreasing GABA inhibition

CB1 does this through other pathways as well

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9
Q

What are the two main preparations derived from cannabis?

A
  • Marijuana

- Hashish

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10
Q

Who discovered the analgesic, appetite stimulant, antiemetic, muscle relaxant and anticonvulsant properties of cannabis?

A

William O’Shaughnessy, British Physician

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11
Q

What are the three major psychoactive compounds of cannabis?

A
  • Δ9- tetrahydrocannabinol (THC)
  • Δ8- tetrahydrocannabinol
  • Cannabidiol (CBD)
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12
Q

What type of receptors are cannabinoid receptors?

A

G protein-coupled receptors

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13
Q

Where is the CB1 cannabinoid receptor subtype most commonly found? CB2?

A

The CB1 cannabinoid receptor subtype is found predominantly on neurons in the central nervous system. They are found throughout the brain but are most densely concentrated in the basal ganglia, hippocampus and cerebellum.

The CB2 cannabinoid receptor subtype is present in the immune system in the periphery but also in the brain in the glia.

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14
Q

What is the receptor encoded by GPR55 gene?

A

The receptor encoded by GPR55 gene is also responding to endogenous cannabinoids. The presence of another putative cannabinoid receptor CB3 was suggested in hippocampus.

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15
Q

What is anandamide?

A

The endogenous cannabinoid anandamide is also an agonist of TRPV1 (capsaicin) channel.

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16
Q

Describe cannabinoids and glycine

A

It was recently found that cannabinoids enhance function of glycine receptor. The cannabinoid-induced analgesia is absent in mice lacking α3GlyRs but not in those lacking CB1 and CB2 receptors.

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17
Q

Cannabinoids acting via CB1 inhibit _____ ______ and also inhibit ____, ___ and ___ channels.

A

Cannabinoids acting via CB1 inhibit adenylyl cyclase and also inhibit L, N- and P/ Q-type voltage-sensitive Ca2+ channels.

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18
Q

Describe CB receptor signalling (4)

A
  • Cannabinoids acting via CB1 inhibit adenylyl cyclase and also inhibit L, N- and P/ Q-type voltage-sensitive Ca2+ channels.
  • Reduction of PKA activity is related to a reduction of gene expression through decreasing cAMP response element (CRE) activity.
  • CB1 receptor activation can also stimulate several intracellular kinases, such as focal adhesion kinase (FAK), phosphatidyl inositol-3-kinase (PI3-K) and its downstream effectors protein kinase B (PKB) (also known as AKT) and Raf-1, extracellular signal-
    regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated kinase.
  • CB1 receptor activation can also lead to increased expression levels of calcineurin, also called protein phosphatase 2B. Stimulation of cytoplasmic kinases can also mediate CB1 receptor- induced expression of immediate early genes (IEG).
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19
Q

Which kinases can CB1 stimulate? (5)

A
  • Focal adhesion kinase (FAK),
  • Phosphatidyl inositol-3-kinase (PI3-K) and its downstream effectors: protein kinase B (PKB) (also known as AKT) Raf-1,
  • extracellular signal-
    regulated kinases (ERKs),
  • c-Jun N-terminal kinase (JNK)
  • p38 mitogen-activated kinase.
  • It was shown that CB1 cannabinoid receptors also leads to activation or Gs and Gq proteins. In addition the CB1 cannabinoid receptor also signals trough non-G protein partners such as the adaptor protein FAN. Preferential activation of different intracellular effectors by each G protein contributes to diversity and selectivity of responses regulated by cannabinoid receptors
20
Q

List 5 signalling cascades induced by CB1 activation

A
  • cAMP/PKA MAPK
  • Calcium/potassium currents
  • cAMP/PKA calcium currents
  • Intracellular calcium release
  • Transient MAPK

It was shown that CB1 cannabinoid receptors also leads to activation or Gs and Gq proteins. In addition the CB1 cannabinoid receptor also signals trough non-G protein partners such as the adaptor protein FAN. Preferential activation of different intracellular effectors by each G protein contributes to diversity and selectivity of responses regulated by cannabinoid receptors

21
Q

List 6 anti-inflammatory effects of cannabinoids

A
  1. Microglia inhibition
  2. Reduction of pro-inflammatory cytokines released from microglia
  3. CB1/CB2 agonists inhibit glutamate release from synapto- somes
  4. Inhibits glutamatergic transmission
  5. CB1 receptor activation also inhibits cell death by reduction of the NMDA-mediated release of Ca2+ from intracellular
    stores and and ROS release
  6. Cannabinoids also stimulate intracellular Ca2+ uptake into mitochondrial sinks
22
Q

What are endogenous cannabinoids derived from and what class do they belong to?

A

Derived from arachidonic acid

Belong to class of bioactive eicosanoids

23
Q

Describe the two endogenous cannabinoid’s synthesis and degradation

A

Synthetic pathways to endogenous cannabinoids can be regulated by G protein- coupled receptors. - Anandamide and 2-AG are synthesized from membrane phospholipids.

  • Anandamide is degraded by fatty acid amide hydrolase (FAAH)
  • 2-AG is synthesized by monoacylglycerol lipase (MAGL).
24
Q

How do CB1 receptors control cell fate? (6)

A
  • Cannabinoids modulate sphingolipid metabolising pathways by inducing sphingomyelin (SM) breakdown and by increasing the levels of the second messenger ceramide.
  • Ceramide may then induce extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase and p38 mitogen-activated protein kinase.
  • The activation of ERK cascade is known to induce cell proliferation but in
    some situations ERK mediates growth arrest, as well as cell death.
  • Cannabinoids induce generation of ceramide (“tumor suppressor lipid”) by inducing the adaptor protein FAN. There are evidences that cannabinoid- induced ceramide production triggers apoptosis in cancer cells in vitro (C6 glioma and PC-12 pheochromocytoma cells).
  • CB1 receptor modulation of ion channels, inducing inhibition of N- and P/Q- type voltage-sensitive Ca2+ channels and activation of rectifying K+ channels could be responsible for the inhibition of the release of glutamate and other neurotransmitters by affecting membrane depolarization and exocytosis.
  • Not all cannabinoids effects are “beneficial”. THC was shown to have neurotoxic effects. After chronic THC oral administration there were observed, morphological changes in the hippocampus - decreases in the mean volume, synaptic density, and dendritic length of CA3 pyramidal neurons. This effect could result from CB1-mediated apoptosis, and might involve a phospholipase A2-induced release of arachidonic acid, which promotes the activation of cyclooxygenases and lipoxygenases. Both pathways generate free radicals that can lead to lipid peroxidation and cell death.
25
Q

How can endocannabinoids mediate a sustained inhibition of another inhibitory signal?

A
  • Metabotropic glutamate receptor (mGluR) activation is necessary and sufficient
    to induce Long Term Depression (LTD), which is observed in the hippocampus and amygdala. This effect persists as long as 30 min.
  • Hippocampal LTD requires phospholipase C (PLC) and diacylglycerol lipase (DAGL) activity and involves 2-arachidonoyl glycerol (2-AG),
  • Amygdala LTD involves cyclic adenosine monophosphate (cAMP) pathway to generate anandamide (AEA).
  • The released endocannabinoids decrease GABAergic inhibitory tone via presynaptically located CB1 receptors.
  • Upregulation of glutamatergic transmission is also seen for LTD facilitation
26
Q

What is mTOR signalling? (4)

A

THC-mediated CB1 receptor stimulation in vivo triggers the activation of the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (also known as Akt) signaling cascade.

  • mTOR is a serine threonine kinase that represents an important downstream target of the PI3K/Akt pathway.
  • TOR is the central component of a complex signaling network that regulates cell growth and proliferation as well as animal size.
  • Recently it has been found that long term memory processing is mediated by cannabinoid receptors in hippocampus and involves rapamycin-dependent mTOR activation.
27
Q

List the steps in the mTOR signalling pathway for long term memory formation (5)

A

In hippocampus:

  1. CB1
  2. MAPK/ERK
  3. PI3K/PKB
  4. Rapamycin dependent mTOR activation
  5. L-T memory
28
Q

What is observed with CB1 KO? (5)

A
  • CB1 receptor knockout mice appears healthy and fertile but shows increased mortality rate.
  • They also have reduced locomotor activity and hypoalgesia in hotplate and formalin tests.
  • No hypomobility and hypothermia was observed in CB1 mutant mice given THC but still was present analgesia in the tail-flick test.
  • CB1 knockout shows impairment of learning and memory functions and accelerated age-dependent loss of hippocampal neurons.
  • Alcohol withdrawal symptoms were absent after alcohol cessation in CB1 receptor knockout mice.
29
Q

What is observed in CB2 knockdown mice? (3)

A
  • CB2 deficient mice are hypersensitive to nociceptive stimuli.
  • They show decrease in bone mass.
  • The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating
    that CB2 receptors in the
    brain can modify behavior.
30
Q

How does CB2 knockdown effect alcohol intake?

A

Increases alcohol preference

Agonist JWH015 increased alcohol intake in mice subjected to chronic stress with CB2 KD.

31
Q

True or false? Polymorphism in the CB1 gene in humans is linked to alcoholism

A

False.

Polymorphism in CB2

32
Q

What does prolonged administration of different cannabinoid receptor agonists do to rats?

A

Increased proenkephalin (pre-opioid) gene expression in the caudate- putamen, nucleus accumbens, paraventricular and ventromedial hypothalamic nuclei and medial mammillary nucleus.

33
Q

What is naloxone?

A

An opioid antagonist naloxone blocks THC-induced increase of dopamine release in the nucleus accumbens. It is possible that rewarding properties of cannabinoids are mediated by opioids.

34
Q

How is CB1 receptor involved in addiction to smoking?

A

CB1 receptor activation increases nicotine’s rewarding effects, while decreasing CB1 function reduces the reinforcing effects of nicotine. CB1 receptor antagonist rimonabant in clinical trials increased the quit rate of smokers.

Mice lacking fatty acid amid hydrolase (FAAH-degrades anandamide), exhibit 10- to 15-fold increases in brain anandamide. FAAH mice knockout and FAAH inhibitors enhanced nicotine-induced conditioned place preference. In contrast the effects of FAAH inhibitors in rats were opposite to those observed in mice.q

35
Q

How are CB receptors affected when animals are treated with cocaine or heroin? JWH133?

A
  • Increased CB2 gene transcripts in the brain.
  • Systemic and intra-accumbens administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1 –/–) mice, but not in CB2 KO mice
36
Q

What is 2-arachidonoylglycerol (2-AG) important for in neurogenesis? Describe this in the developing and adult brain.

A
  • Axonal growth
  • Retrograde signalling

During axonal growth, 2-AG synthetic enzyme diacylglycerol lipase (DAGL) and CB1 receptors are expressed in the growth cone, while MAGL expression is restricted to the axon.

In the adult brain, 2-AG is synthesised postsynaptically by DAGLa and released into the synaptic cleft to act on presynaptically located CB1. 2-AG is then degraded by monoacylglycerol lipase (MAGL), which is also located in the presynaptic compartment

In the adult brain, DAGL regulates proliferation of progenitor cells in the subventrcular zone (the second after subgranular zone of hippocampus location of adult
neurogenesis in the brain) and migration of neuroblasts. Adult neurogenesis is reduced in CB1 and CB2 knockout mice whereas FAAH knockout and CB1 and CB2 agonists induce hippocampal progenitor proliferation.

37
Q

What do CB1 knockout show, in terms of food intake? Why?

A

Reduced body weight and insensitivity to high-fat diet. CB1 antagonist treatment reduces food intake.

CB1 receptors present in the lateral hypothalamus co-localize with melanin concentrating hormone (MCH) and prepro-orexin neurons. MCH neurons (promoting an increase in food intake) are tonically inhibited by GABAergic inputs coming from the limbic system.

  • The interaction of CB1 with feeding can be also mediated by other systems. Presynaptic cannabinoid receptors co-express with CRH neurons and may inhibit CRH release, which acts as anorexigenic mediator.
  • CB1 knockout mice have reduced CART (cocaine- and amphetamine-related transcript), which suppress feeding.
  • Also ghrelin may promote food intake by elevating endocannabinoid level in hypothalamus.
38
Q

How might endocannabinoids enhance the excitability of MCH neurons? What is the consequence of this?

A
  • Endocannabinoids may enhance the excitability of MCH neuron by decreasing GABA release.
  • By inhibiting the voltage-gated calcium currents in the same neurons, leptins may reduce synthesis and release of endocannabinoids.
  • The interaction of CB1 with feeding can be also mediated by other systems. Presynaptic cannabinoid receptors co-express with CRH neurons and may inhibit CRH release, which acts as anorexigenic mediator.
  • CB1 knockout mice have reduced CART (cocaine- and amphetamine-related transcript), which suppress feeding.
  • Also ghrelin may promote food intake by elevating endocannabinoid level in hypothalamus.
39
Q

Describe the acute toxicity of cannabinoids

A

decreased motor coordination, muscle strength, and hand steadiness. Also observed: lethargy, sedation, poor concentration ability, slurred speech, ataxia, hypothermia and an increase in reaction time.

High doses of delta 9-THC can induce frank hallucinations, delusions, and paranoid feelings. Thinking becomes confused and disorganized; depersonalization and altered time sense. Euphoria may be replaced by panic, often as a result of the feeling that the drug-induced state will never end.

Cardiac effects – complex due to action of THC on multiple sites (CB receptors, TRPV1 channel both central and peripheral) - usually observed hypotension.

40
Q

Describe the chronic toxicity of cannabinoids

A

use may be associated with apathy, lack of motivation, and loss of memory. Endocrine effects – infertility observed in laboratory animals but not always in humans.

Chronic and heavy use of cannabis can cause Cannabinoid Hyperemesis Syndrome which is characterized by recurrent episodes of severe nausea and intractable vomiting, and also abdominal pain.

41
Q

Describe cannabinoid withdrawal

A

consists of agitation, apprehension, and aggressiveness, as well
as tremulousness, insomnia, and excessive sweating, and the development of common migraine headaches.

42
Q

True or false? Cannabinoid use can result in tolerance

A

usually not observed but reported in heavy users.

43
Q

How can withdrawal and/or Cannabinoid Hyperemesis syndrome be treated?

A

Benzodiazepines to treat extreme agitation. Haloperidol to treat psychosis. The most important is to put patient in quiet, safe environment.

44
Q

List some things that cannabinoids can be used as therapy for. (15)

A
  • Neuropathic pain in MS and cancer patients
  • Nausea in cancer therapy
  • Anorexia and weight loss in patients with AIDS
  • Reducing growth of glioma tumors
  • Treatment of glaucoma
  • Parkinson’s disease
  • Dystonia
  • Gilles de la Tourette syndrome
  • Improve opiate treatment of pain (increase effect and prevent tolerance)
  • CB2 agonists an prevent osteoporosis
  • CB2 agonists prevent activation of microglia in Alzheimer’s models and reduce volume of infarcts (necrosis) from stroke
  • Allergy, inflammation and MS
  • CB2 agonists also suppress hyperalgesia
  • PTSD
  • CB1 antagonist decreases appetite and food intake
  • JWH015 CB2 agonist protects retinal pigment epithelial cells
  • CB2-selective agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals indicating that agonists of CB2 can be useful in regenerative medicine.
45
Q

What is a growing problem in the world, concerning cannabinoids?

A

Use of synthetic cannabinoids is becoming a growing problem worldwide

• More than 140 synthetic cannabinoids have been identified to date.
• Their abuse can cause severe toxic effects.
• It have been found that many of designer cannabinoids induce apoptosis
in cell culture and animal models.
• Many of these drugs are much more potent
than THC, therefore, the psychoactive dose may be less than 1 mg.

Molecular Neuroscience III (8 decks)

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