Convulsants, Nicotine & Cannabinoids Flashcards
1
Q
what is pentylenetetatrazol ?
or PTZ or metrazol or pentetrazol
A
a convulsant
- used to induce seizures
2
Q
what does PTZ do ?
A
causes over excitability of neuronal circuits in the brain
3
Q
what is ECT ?
A
electro-convulsive therapy
4
Q
what has PTZ been used for ?
A
- (previously ECT)
- now seizure models in rodents
- ‘testbed’ for new anticonvulsants
5
Q
mechanisms for PTZ
A
GABA-A receptor antagonists
GABA-A important in mediating inhibiton, antagonism of this causes disnihibition causing overexcitability of brain circuits
6
Q
Penicillin activity
A
anti-GABA activity
causes disinhibition
7
Q
what can penicillin be used as
A
can be used as a seizure-inducing agent to test anticonvulsants
(convulsant)
8
Q
how is penicillin applied in rodent models and why ?
A
- directly to cortical surface or intracerebral injection
- as penicillin doesn’t normally cross BBB
9
Q
when does penicillin cross the BBB ?
A
except when BBB compromised e.g. infection, damage, inflammation and substances can cross the BBB
10
Q
what are Bicuculine and Gabazine ?
A
GABA-A antagonists
convulsant
11
Q
what can Bicuculine and Gabazine be used for ?
A
- to block ‘fast’ inhibition in the brain to induce seizures
- to dissect CNS circuits
12
Q
what is Strychnine ?
A
- plant alkaloid
- glycine antagonist
convulsant
13
Q
where does Strychnine act ?
A
in spinal cord
14
Q
what did Strychnine used to be used for ?
A
- a ‘tonic’ which lead to ‘risus sardonicus’ (facial muscle tetany)
- rat poison (1600s)
only take 30-120mg to be lethal, hence goof rat poison
15
Q
where is Strychnine derived from ?
A
Nux vomica tree
16
Q
what are convulsants ?
A
drugs that induce zeizure-like state
17
Q
how does Glycine act ?
A
through pentameric ligand-gated Cl- channels
glycine is inhibitory
similar to GABA-A channe;s
18
Q
what do glycine antagonists do ?
A
decrease synaptic inhibition
(disinhibition)(overall excitation)
similar to bicuculine
19
Q
what other drugs can act to modulate glycine receptors ?
A
- benzodiazepines
- isoflurane
have antispasmodic or muscle relaxant
20
Q
what does Tetanus Toxin do ?
A
prevens release of glycine
21
Q
what can convulsants be used for ?
A
to induce seizures or reduce central inhibition (inc. excitability)
22
Q
what do convulsants do ?
A
block activity of central inhibitory neurotransmitters such as GABA and glycine
23
Q
convulsants as pharmacological tools
A
- help understanding neural circuits in models and for testing efficacy of anti-convulsants but no real medical use
24
Q
Nicotine and where it acts
A
- key product in tabacco
- acts as an agonist on central nAChRs
25
where are nAChRs expressed ?
- widely in CNS
- strongly in cerebral cortex, hippocampus, ventral tegmentum
- located pre- and post- synaptically
26
what are nAChRs ?
ligand gated cation channels
## Footnote
premeability highest for K+ and Na+ ions
27
role of nAChRs
enhance neurotransmitter release pre-synaptically and increase membrane (neuronal) excitability post-synaptically
28
what does nicotine acting on nAChRs do ?
- activates them and increase in excitability/ expression
- induces receptor desensitisation (synaptic block)
## Footnote
overall net action is complex and 'push-pull' system
29
what happens if we have a chronic administration paradoxically of nicotine ?
increase in number of nAChRs
30
one behavioural effect of nicotine and how
- inhibits spinal reflexes (induces muscle relaxation)
- due to stimulation of glycinergic Renshaw cells (inhibitory internuerons) (recurrent inhibition) (stimulation increases inhibition of alpha motor neurons that send signals for reflexes)
31
what can low doses of nicotine cause ?
## Footnote
as demonstrated in rodent models
- increased CNS arousal
- impoved reaction times
- enhanced learning
32
what do higher doses of nicotine cause ?
- sedation
- excitation of mesolimbic dopaminergic reward system
## Footnote
evidence from rats chosing to drink nicotine solution over plain water
33
what is the mesolimbic dopaminergic reward system ?
VTA (nAChRs expressed here )
---->
Nucleus accumbens
34
nicotine and dependence
- psychological (i.e. emotional symptoms of withdrawl)
- physical (i.e. somatic withdrawl symptoms)(2-3 weeks)
- tolerance
## Footnote
all due to receptor desensitization
35
what can alleviate nicotine withdrawl ?
- nicotine replacement therapy such as patches
- amfetamines (give additional reward feeling)
36
harmful effects of nicotine
- cough
- cancer(s)
- coronary heart disease
- chronic obstructuve pulmonary disorder (COPD)
- cost
37
what superfamiliy are the family of nicotinic receptors a part of ?
cys-loop receptor superfamily
38
what are the 16 different nAChrR subunit
16
- alpha 1-7, 9, 10
- beta 1-4
- gamma
- delta
- epsilon
39
what are all nAChRs ?
- pentameres (5 subunits)
- 2 binding sites for ACh
- cation permeable
40
neuonal nAChR subunits + nicotine
## Footnote
differ from skeletal AChRs
- contains alpha 4 and beta 2 subunits important in nicotine addication
41
Varenicline
selective partial agonist at a4b2 receptor
- for NRT
- cheaper and can be used long-term
## Footnote
cytisine is similar - may have lower side effects
42
what can prenatal nicotine exposure do ?
- causes low birth weight
## Footnote
animal studies indicate that even low levels of nicotine can effect baby neurodevelopment, even before effects on birth weight
43
what happens with prenatal cocaine exposure ?
- low birth weight
- associated with low IQ scores
- attention problems or poorer language skills (due to direct changes in neurochemicstry or indirect vascoconstriction)
- materal bp raised causing prenatal strokes in the baby
44
what effect does maternal nicotine exposure have on cells of rat embryos at the neural tube stage of development?
- different morphology
- many are dead or dying
## Footnote
effects of prenatal nicotine are underestimated
45
What is a potential risk associated with sustained high doses of cannabinoids?
They can increase the risk of psychotic illnesses.
46
What type of system do we have in our brain and body that is related to cannabinoids?
A 'natural' endocannabinoid system.
47
What do exogenous cannabinoids, like cannabis, bind to?
The same receptors as endocannabinoids.
48
Why have cannabis and related compounds been a topic of intense discussions?
Due to their changing legal status and potential clinical benefit.
49
50
What is the plant from which cannabinoids are derived?
Cannabis sativa
| Hemp plant
## Footnote
traditionally used for making ropes and cloth.
51
Is cannabis considered a central nervous system stimulant?
No, cannabis does not fit the typical definition of a central nervous system stimulant.
52
What are some effects of cannabis on the central nervous system?
* Euphoria
* Calmness
* Relaxation
* Pain reduction
* Increased laughter
* Talkativeness
* Hunger
* Dizziness
53
What impairments can cannabis cause?
* Problem-solving impairments
* Short-term memory impairments
* Psychomotor performance impairments
54
What high doses of cannabis can lead to?
* Severe personality changes
* Hallucinations
55
What is THC?
Delta-9-tetrahydrocannabinol, a main active ingredient in cannabis.
| psychoactive component
## Footnote
low water solubility
56
What is the relationship between high THC content and schizophrenia?
High THC content has been linked to schizophrenia as a risk factor.
57
What are the two other cannabinoids mentioned, and what is their significance?
* Cannabidiol (CBD) - precursor for THC, lacks psychoactivity
* Cannabinol - breakdown product of THC, lacks psychoactivity
58
How have cannabis samples changed over time in terms of THC and CBD content?
Percentage of THC is rising, while the amount of CBD remains stable.
59
What are some central effects of cannabis?
## Footnote
CNS
* Relaxation
* Well-being
* Sharpened awareness
* Analgesic effect
* Anti-emetic activity (reducing sickness)
60
What peripheral effects does cannabis have on the cardiovascular system?
* Tachycardia (fast HR)
* Vasodilation (blood shot eyes)
* Reduced intraocular pressure
* Bronchodilation
61
What are some adverse effects of cannabis?
In cases of overdose:
* Mild respiratory depression
* Confusion
* Dizziness
* Impaired memory
* Fatigue
* Paranoia
* Psychosis
## Footnote
teratogenic effect (cancer causing) in rodents (no evidence for humans)
62
Abstinence of Cannabis
- symptoms similar to alochol withdrawl
## Footnote
physical dependence in heavy users
63
what does the high lipid solubility of THC suggest ?
- actions similar to general anaesthetics
## Footnote
cause changes in membrane excitability
64
What is the endogenous cannabinoid system composed of?
* Endocannabinoid receptors (CB1 and CB2)
* Endocannabinoids (anandamide and 2-AG)
## Footnote
endocannabinoids activate the endocannabinoid receptors
65
What type of receptors are CB1 and CB2?
G-protein coupled receptors of endogenous cannabinoid system
66
what is the exogenous cannabinoid system activated by and what does it affect ?
- activated by exogenous cannabinoids (THC) through CB1 and CB2 receptors
- THC affects the DA synapse
67
what happens in the exogenus cannabinoid system ?
- THC binds to CB1 receptor on inhibitory interneuron (GABAergic) in VTA
- increases cAMP, which dephosphorylates calcium channels - decreasing calcium moving into cell
- causes decreased GABA release
- results in decreased inhibition of DA neurone in VTA (due to decreased influx of chloride ions, more depolarised)
- decreased inhibition (disinhibition) enhances DA release onto post-synaptic neurone in striatum (excitation)
- overactivation of reward pathway
68
What neurotransmitter is primarily affected by THC in the reward pathway?
Dopamine.
69
What is the role of calcium in neurotransmission?
Calcium influx facilitates neurotransmitter release.
70
what happens in the endogenous cannabinoid system ?
- in normal signalling we get a rise in Ca 2+ ions post-synaptically via NMDARs
- this activates Ca2+-sensitive enzymes to produce anandamide and 2AG
- Anandamide and 2AG then move back into the pre-synaptic neuron to act on the CB1 receptor: retrograde transmission
- cause CB1 effects
71
what is retrograde transmission ?
signalling mollecules move from post synaptic back to pre synaptic
72
What are the two major endogenous cannabinoids discussed?
* Anandamide
* 2-Arachidonylglycerol (2-AG)
73
Fill in the blank: Cannabis does not have the potential for _______ and recklessness like ethanol.
aggression
74
True or False: Cannabidiol (CBD) has psychoactive effects.
False
75
What are NMDA receptors associated with?
Glutamatergic receptors
76
What activates calcium-sensitive enzymes in the post-synaptic neuron in the endogenous cannabinoid system?
Calcium influx
77
What are two endogenous cannabinoids produced in the post-synaptic neuron?
* Anandamide
* 2AG
78
What is the process called when cannabinoids move from the post-synaptic neuron back to the pre-synaptic neuron?
Retrograde neurotransmission
79
What receptor do anandamide and 2AG bind to in the pre-synaptic neuron during endogenous cannabinoid system?
CB1 receptor
80
What are the precursors for anandamide and 2AG derived from?
Membrane lipids
81
How is the production of anandamide and 2AG characterized?
'on demand' - more analogue production depending on calcium sensitive enzymes
## Footnote
range of amounts of them produced
82
What is the difference between vesicular release of neurotransmitters and the release of anandamide and 2AG?
Vesicular release is all-or-nothing (activation/inhibition or nothing); anandamide and 2AG release is variable (could be small or large/ infinitly variable amount of levels)
83
What type of degradation and removal mechanisms do endogenous cannabinoids undergo?
Local enzymatic degradation and uptake through transporter proteins
84
Where are CB1 receptors primarily located?
CNS - mainly brain/ 'higher' CNS areas (not brainstem)
## Footnote
not homogenously distributed
85
Where are CB2 receptors primarily found?
Mainly in the periphery
86
what are the most abundant CNS receptors ?
CB1, GABA, Glu
## Footnote
CB1 amongst most abundant
87
what does CB1 being one of the most abundant receptors in our brain mean ?
must be important in modulating CNS function
88
What does upregulation of receptors mean?
Increased likelihood of response to a signal/ligand if more receptors present
## Footnote
CB1 can be upregulated
89
What effect do CB1 receptors have on neurotransmitter release?
Reduction in transmitter release; overall complex effects
90
what kind of synapses do we find CB1 receptors in ?
act within excitatory and inhibitory synapses
91
What is the significance of the CB1 receptor's abundance in the central nervous system?
Indicates importance in modulating CNS function
92
What happens during anterograde transmission in synapses?
Neurotransmitter is released from pre-synaptic to post-synaptic neuron
93
endocannabinoid mechanism
1. vesicular release of neurotransmitter (PRE)(can be excitatory or inhibitory)
2. Depolarisation of membrane (POST) (as neurotransmitter binds)
3. Ca 2+ influx (POST)(activation of Ca membrane channels)
4. (activation of Ca sensitive enzymes) Enzymatic production of endocannabinoids (via metabolisation of membrane lipids)
5. Endocannabinoids diffuse back to bind to CB via retrograde transmission (POST->PRE)
6. CB1 activation decreases activation of Ca 2+ channels
7. less calcium influx upon depolarisation (PRE)
8. Less neurotransmitter release (PRE)
in GABAergic (inhibitory) - disinhibition
excitatory synapse - reduced activation
94
What is rimonabant used for?
Reduces appetite
## Footnote
disorders such as obesity and Prader-Willi syndrome
95
what is rimonabant ?
- first CB1 antagonist
96
What condition can remonabant help manage?
Obesity and Prader-Willi syndrome
97
True or False: Anandamide and 2AG are produced in the pre-synaptic neuron.
False
98
Fill in the blank: The process of anandamide and 2AG moving back to the pre-synaptic neuron is known as _______.
retrograde neurotransmission
99
What type of pharmacological effects do CB1 receptors have?
Complex effects across central nervous system
100
In which types of synapses can CB1 receptors act?
* Excitatory
* Inhibitory
101
What are some clinical uses of THC and CB receptor agonists?
* Reduce motor tics in Tourette syndrome
* Pain management
* Treating glaucoma
* Epilepsy
102
what are some clinical uses of CB receptor antagonists ?
- tobacco dependence
- drug addication
- alcoholism
- obesity
103
where do motor tics relating to Tourette's syndrome stem from ?
likely produced by dopaminergic activation in basal ganglia
104
What can cause upregulation of CB1 receptors?
Various environmental factors and disease states
105
what is the THC pre-cursor
CBD
## Footnote
no psycho-active effects
106
THC chemical name
tetrahydrocannabinol
107
why does long term nicotine use increase the number of nicotine acetylcholine receptors ?
nicotine causes receptor desensitisation
108
what can overdose of THC likely do ?
- confusion and dizziness
## Footnote
heavy long term use = psychosis like symptoms
109
what is one antagonist at inhibitory glycine receptors ?
Strychnine
110
what is Bicuculline ?
GABA-A antagonist
111
what is muscimol ?
agonist at GABA-A
112
hisotrical use of pentylenetetrazol (Metrazol) ?
depression - in convulsive therapy (ECT)
## Footnote
now to model seizures in animals
113
what is the sight of action for pentylenetetrazol (Metrazol) ?
GABA-A as non-competitive or open channel block
114
what is the subtype of nicotinic receptor thought to be involved in nicotine addiction ?
- 2α43β2
## Footnote
upregulated in people addicted to nicotine
115
what is varenicline ?
selective partial agonist at
2α43β2 nAChR subtype for addiction
