week 4 part 2 Flashcards
1
Q
What are cannabinoids?
A
terpenophenolic constituents of the hemp plant (cannabis sativa)
2
Q
What has cannabinoids been used for?
A
over 4000 years as a recreational drug due to its mind-altering effects
3
Q
What is the primary psychoactive constituents of cannabis?
A
Δ8-tetrahydrocannabinol (Δ8-THC)
Δ9-THC
4
Q
What has cannabinoids been shown to produce?
A
a unique syndrome of effects on the behaviour of humans and animas that include:
- disruption of short-term memory
- cognitive impairments
- a sense of time dilation
- mood alterations
- enhanced body awareness
- reduced ability to focus attention
- filter out irrelevant information
- dicoordination
- sleepiness
5
Q
What did Queen Victoria use cannabinoids for?
A
Analgesics effect
6
Q
What was cannbinoids used to treat?
A
seizures
7
Q
How many compounds does cannabis have?
A
30 compounds
8
Q
What are some examples of effects cannabis has on humans?
A
- Euphoria
- Heightened sensory perception
- Distorted sense of time and space
- Hallucinations
- Drowsiness, sleep
- Impairment of memory
- Increased motor activity followed by inertia and ataxia
9
Q
What did animal research show?
A
potential for cannabinoid dependence exists
cannabinoid withdrawal symptoms can be observed
10
Q
What does injection of THC into mice cause
A
- Inhibition of spontaneous locomotor activity
- Antinociception (analgesia)
- Hypothermia
- Immobility
11
Q
Where are endocannabinoids produced?
A
In the body when needed, under stress, or in response to synaptic activity
12
Q
What are the most studied endocannabinoids?
A
- Anandamide (AEA)
2. 2-AG
13
Q
what are endocannabinoid?
A
considered to be dominant
agonist for CB1 and CB2 receptors, with higher affinity to CB1 binding
14
Q
What did Allyn Howlett demonstate?
A
Cannabinoids cause inhibition of adenylyl cyclase in neuroblastoma cells
15
Q
What did this suggest?
A
Cannabinoids may exert their effect by binding to a GPCR
16
Q
What is CP 55,940?
A
Cannabinoid in which mimics the effects of naturally occuring THC
A full agonist at both CB1 and CB2 receptors
17
Q
What was [3H] CP 55,940 used for?
A
It is a radiolabelled synthetic cannabinoid which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol and used to characterise and localise a specific cannabinoid receptor in brain sections
18
Q
What did autoradiography show?
A
in all species very dense binding was found in the
- Globus pallidus
- Substantia nigra
- Pars reticulata
- Molecular layers of the cerebellum and hippocampal dentate gyrus
- stratium
19
Q
For autoradiography where did very low and homogenous binding characterise?
A
- Thalamus
2. most of the brain stem
20
Q
Where are CB1 receptors abundant in?
A
Putamen part of the relay system within basal ganglia that regulates body movement
21
Q
What is the function of cerebellum?
A
Coordinates body movement
22
Q
What is the function of hippocampus?
A
Involved in learning, memory and response to stress
23
Q
What is the function of cerebral cortex?
A
Concerned with the integration of higher cognitive functions
24
Q
Where is CB2 receptors located?
A
cells of the immune system
25
Where are both CB1 and CB2 found?
Alpha clade of the rhodopsin group of GPCRs
26
What can immunocytochemical methods be used to localise?
CB1 proteins in the brain
27
What does immunoctyochemical studies using different antibodies reveal?
Generally consistent pattern of staining that corresponded with the distriubtion of cannabinoid binding sites
28
What did these studies provide?
Important evidence that CB1 is likely to be mediated the effects of cannabinoids in the brain
29
What did determination of the neuroanatomical distribution of CB1 receptor in the brain provide?
A framework for interpreting the behavioural effects of cannabinoids
30
Wjat was CB1 knock out mice been generated independently shown to be?
unresponsiveness to cannabinoids in a standard set of behavioural assays
31
Where is the highest concentration of cannabinoid binding sites?
1. Basal ganglia and cerebrellum
| 2. Regions of the brain that are involved in the inititation and coordination of movement
32
Where is low level or no binding present?
1. Brainstem (medulla and pons)
| consistent with the lack of cannabinoid activity on vital respiratory and cardiovascular function
33
Where is CB1 receptor targeted?
To axons and terminals of neurons, not only in the basal ganglia but probably in all neurons that express the CB1 gene in the brain
34
What is the function of fatty acid amide hydrolase (FAAH)
Catalyse hydrolysis of two putative fatty acid amide signalling molecules, oleamide and anandamide
catalyses hydrolysis of 2-AG
participate in inactivation of both anandamide and 2-AG
35
What did measurement of FAAH enzyme activity in eight regions of rat brain reveal?
highest concentration: Hippocampus and cortex
Lowest concentration: brainstem and hypothalamus
with intermediate concentration in cerebellum, olfactory bulb, stratium and thalamus
36
Comparisons of the distribution of FAAH in rat brain regions based on enzyme assays and western blotting data revealed a significant overlap with expression of CB1
High concentration of FAAH and CB1 are found in both hippocampus and neocortex whilst lower concentration of FAAH and CB1 are found in the brainstem and hypothalamus
37
What 3 brain regions are enriched with both FAAH and CB1?
1. Cerebellum
2. Hippocampus
3. Neocortex
38
in cannabunoid signalling where is CB1 located?
presynaptically
39
in a model of cannabinoid signalling what does anandamide function as?
Retrograde signalling
40
What does retrograde signalling molecule do?
modulates (inhibits) the release of 'classical' anterograde transmitters by presynaptic terminals
41
What step 1 of retrograde signalling?
Anandamide is synthesises and released by the postsynaptic cell
42
What is step 2 of retrograde signalling?
Diffuses into the synaptic cleft where it binds to and activates presynaptic CB1-type cannabinoid receptors
43
What is step 3 of retrograde signalling?
Activated CB1 receptors cause inhibition of neurotransmitter release from presynaptoc terminals via G-protein-mediated mechanisms involving activations of K+ channels or inhibitions of Ca2+ channels
44
What is step 4 of retrograde signalling?
Anandamide dissociates from CB1 receptors and then following uptake into the postsynaptic cell
45
What is step 5 of retrograde signalling?
Hydrolysed intracellularly by FAAH
46
Where was CB1-immunoreactivity observed?
somata of GABAergic interneurons in the hippocmapus
47
Where is CB2 (and CB1) receptors expressed?
Perivascular macrophages and microglia
48
Where is CB2 expression enhanced?
Following CNS injury and in neuritic plaques in Alzheimer's disease
49
What does microglia cells use cannabinoids as?
signalling molecule
50
What is anandamide?
''Bliss molecule''
| A substance produced by our body to bind to cannabinoid receptots
51
What is key to making anandamide?
NAPE-PLD
52
What is one way of making anandamide?
from phosphatidylethanolamine FA within membrane and forming PLD
53
How is anandamide synthesised?
upon demand from phospholipid precursors in cell membranes in response to rise in intracellular calcium levels
54
Where are enzymes metabolising 2-AG located?
Both post-synaptically and pre-synaptically
55
How is 2-AG synthesised?
arachidonic acid containing diacylglycerol (DAG) which is derived from the increase of inositol phospholipid metabolism by the action of diacylgylcerol lipase
56
What does CB1 receptor using GPCR reduce?
CAMP
| decrease ca2+ permeability and inhibit neurotransmitter release
57
What does endocannabinoid cause?
depolarisation-induced suppression of excitation
58
What are two related forms of short-term synaptic plasticity of GABAergic and glutamatergic transmission?
Depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE)
59
What are DSI/DSE?
DSI/DSE are two closely related forms of short-term plasticity, which share the same modes of induction, the same type of retrograde messengers (i.e. endocannabinoids) and similar mechanisms of expression.
60
How does DSI work?
classically produced in a brain slice experiment
where a single neuron is "depolarized"
for a period of 1 to 10 secondsAfter the depolarization, inhibitory GABA mediated neurotransmission is reduced.
61
What did experimental evidence suggest?
rather large increases in intracellular [Ca2+] are required for the induction of DSI and DSE via the release of endocannabinoids
62
what does PLCbeta 1 serve as?
coincidence detector through its ca2+ dependency for endocannabinoid release in hippocampal neurons
63
What occurs in the cerebellum?
bursts of parallel fiber (PF) activity evoke endocannabinoid release from Purkinje cell dendrites that results in retrograde synaptic inhibition lasting seconds
64
What do endocannabinoid mediate?
transient associative synaptic plasticity
65
What are endocannabinoids?
key activity-dependent signals regulating synaptic transmission throughout the central nervous system
66
What are endocannabinoids involved in?
Neural functions ranging from feeding homesostasis to cognition
67
What is DSI?
a transient suppression of inhibitory neurotransmitter release onto a neuron following depolarization of that neuron
68
What is the working model for DSI?
Depolarisation of the post-synaptic cell increases dendritic calcium levels which stimulates the production of an endocannabinoid
φ This endocannabinoid is believed to travel retrogradely, from the dendrite, across the synaptic cleft to activate CB1 receptors on the presynaptic terminal and preterminal axon segment. The activated CB1 receptors inhibit calcium channels (and may also stimulate potassium channels or have direct effects on the synaptic vesicle release machinery) thus decreasing neurotransmitter release
69
What is the efficacy of anandamide as a TRPV1 agonist influenced by
succession of factors:
1. Receptor reserve
2. Phosphorylation
3. Metabolism and uptake
4. CB1 receptor activation
5. voltage
6. Temperature
7. PH
8. bovine serum albumin
70
What does this indicate?
endocannabinoid system may play a role in the modulation of TRPV1 receptor activation
71
what does the activation of TRPV1 receptors by anandamide has potential implications in ?
treatment of inflammatory, respiratory and cardiovascular disorders
72
What is Retrograde short term depression mediated by?
dendritic L-type Ca2+ 2-AG synthesis and presynaptic CB1 actions
73
What is LTD mediated by?
mGLUR5 and AEA production - acting on postsynaptic TRPV1
74
Why does the levels of endocannabinoid and/or the expression of cannabinoid receptors in tissue vary?
to increases in intracellular calcium concentration, changes in metabolic enzyme expression and availability of phospholipid precursors
75
What does endocannabinoid directly target?
hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice
76
What is necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)- Induced seizures?
CB1 receptors in glutamatergic hippocampal neurons
77
What does CB1 antagonists given during febrile seizures do?
1. Blocked persistent DSI potentiation
2. Abolished CB1 upregulation
3. Prevented long-term limbic hyperexcitability
78
What are CB1 antagonist?
Acutely proconvulsant
