Lectures 17-24 Flashcards
What are the 3 different types of cannabinoids and what are they?
o Phytocannabinoids- cannabinoids derived from plants
C21 terpenophenolic compounds
• e.g. THC, CBD, CBG, CBDV, THCV, CBC, CBN and THCVA
140 different phytocannabinoids
o Synthetic cannabinoids (from the lab)
Mostly CB1 agonists
• e.g. Nabilone, HU-210, AB-PINACA, JWH-018
Abused in society and potentially quite toxics
• Many synthetic cannabinoids are full agonists of cannabinoid receptors
o Endocannabinoids (in the brain and body)
Neuromodulatory lipids
• E.g. anandamide, 2-AG, noladin ether
How many cannabinoids are there in a plant? How many molecules in cannabis? How many cannabis strains?
• There are more than 100 cannabinoids in the plant- the vast majority are not intoxicating
o Each has its own therapeutic potential
o 500 molecules in cannabis, some of which are bioactive such as the terpenoids and flavonoids, which might also be considered in the actions of new cannabis based medicines
o Different cannabis strains (more than 2000) have different cannabinoid profiles
Describe the composition of street cannabis
o Street cannabis has high amounts of THC (14.9%) and low CBD (<0.1%)
What is the acid precursor to THC? How are they used?
o THC-A is the acid precursor to THC
In the biosynthesis of the plant, you have enzymes like THC-acid synthase and CBD-acid synthase that create acid precursors-> those are then decarboxylated with exposure to light and heat into the neutral forms (THC and CBD)
Why is CBD better than THC?
• CBD might make cannabis more healthy
o Cannatonic- more balanced strain of cannabis (1:1 THC:CBD)
o Industrial hemp: high CBD: low THC
o CBD is not psychoactive
o CBD could be a good anxyolitic compound
What percentage of cannabis is used for pain in Australia?
• Cannabis and its uses in Australia- o Pain (34%)
What percentage of cannabis is used for anxiety disorders in Australia?
o Anxiety disorder (15%)
What percentage of cannabis is used for depression in Australia?
o Depression (11%)
What percentage of cannabis is used for sleep disorders in Australia?
o Sleep disorder (7%)
What percentage of cannabis is used for PTSD in Australia?
o PTSD (6%)
What percentage of cannabis is used for epilepsy/seizure disorders in Australia?
o Epilepsy/seizure disorder (5%)
What percentage of cannnabis is used for cancer in Australia?
o Cancer (4%)
What percentage of cannabis is used for gastro-intestinal disorders in Australia?
o Gastro-intestinal disorder (4%)
What percentage of cannabis is used for attention deficit disorders in Australia?
o Attention deficit disorder (3%)
What percentage of cannabis is used for spinal cord injury in Australia?
o Spinal cord injury (2%)
What is the role of endocannabinoid in homeostasis and how does it do so?
• Endocannabinoid (endCBs) system maintains homeostasis
o EndoCBs comprise a homeostatic regulatory system and subserves normal physiological functions
o EndoCBs synthesised on demand to maintain balance
o EndoCBs activate receptors in a lock and key fashion which regulate cell function in different organs of the body
o Levels of endoCBs are tightly regulated by synthetic and catabolic enzymes
o The optimal function of the endoCB system maintains health
What does THC mimic and activate?
o Δ9-THC mimics endocannabinoids and activates CB1 cannabinoid receptors
Where are CB1 cannabinoid receptors mainly expressed? What are these areas responsible for/ why are they expressed in those areas?
o CB1 cannabinoid receptors are highly expressed in the cortex, amygdala, the hippocampus, throughout the striatum, ventral midbrain and cerebellum, but lowly expressed in the brainstem Motor related regions of the brain • THC can shut down motor functions Memory related (hippocampus) Planning (prefrontal cortex) Anxiety (amygdala) Low expression of brainstem • Hard to overdose on cannabis- has no ability to shut down respiratory/cardiovascular system
Where are CB2 receptors found in the brain?
o CB2 found in the brain and microglia- neuronal expression is controversial
Might help reduce neuroinflammation
What fat molecules activate cannabinoid receptors and what do cannabinoid receptors tend to be coupled with?
o 2-AG (fat molecules) activate cannabinoids receptors
Cannabinoids receptors- tend to be coupled to inhibitory Gi proteins (G-protein coupled)
What are the functions of endocannabinoid signalling in cells?
o Functions:
Activates inwardly rectifying potassium channels: leaks potassium out of cell
• Causes cell hyperpolarisation-less likely that the cell will fire
Inhibit calcium channels
• Inhibits neurotransmitter release and have neuromodulatory function
Affect different enzymatic cascades in cells
• Inhibit adenylate cyclase-> inhibits protein kinase A cascade and changes cellular function
Are endocannabinoids retrograde or anterograde messengers?
o Endocannabinoids are retrograde messengers
CB1 receptors are largely presynaptic
Endocannabinoids are synthesised on-demand from lipids
Travel backwards from post-synaptic to presynaptic
What is the process of endocannabinoid messaging and when does it occur?
Process-
• Calcium influx into excitatory pyramidal neurons causes neurotransmitters (e.g. glutamate) to traverse across the synapse to activate post-synaptic receptors
o Feedforward
• Dysfunction of glutamate release (too much)
o Can lead to epilepsy, brain hyperexcitability and neuronal death
• Dysfunction triggers mechanism to synthesise 2-AG, liberate it from the post-synaptic membrane and then travel backwards to activate pre-synaptically located CB1 receptors
o CB1 blocks calcium channels, stops calcium influx which impedes ability of further neurotransmitter release
What does the endocannabinoid system act on to perform its function?
Endocannabinoid system is involved to act on presynapse and block the release of glutamate
• Has neuroprotective applications
On what types of cells can the endocannabinoid system be expressed on?
Can be expressed on excitatory GABAergic neurons and inhibitory GABAergic interneurons
How does 2-AG and AEA travel across synapses in the endocannabinoid signalling system and where to?
Fatty acid binding protein 5 (FABP5)
• Transports 2-AG from the post-synapse to pre-synapse
• Transports N-arachidonoylethanolamine (AEA) intracellularly to ER, where Fatty acid amide hydrolase (FAAH) lives, for degradation
What are synthetic endocannabinoid enzymes and what do they synthesise?
Synthetic enzymes
• DAGL (synthesises 2-AG)
• NAPE-PLD (synthesises AEA)
What are degradative endocannabinoid enzymes and what do they synthesise?
Degradative enzymes
• MAGL (degrades 2-AG)
• FAAH (degrades AEA)
Describe the process of the synthesis and degradation of 2-AG
o Synthesis and degradation of 2-AG
Phosphatidylinositol 4,5 bisphosphate -> diacylglycerol (DAG) by phospholipase C (PLC) action-> 2-Arachidonoyl glycerol (2-AG) by diacylglycerol lipase (DAGL) action-> arachidonic acid by monoacylglycerol lipase (MAGL) action-> prostaglandin H2 by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) action-> prostacyclin, thromboxanes and prostaglandin E2
Describe the process of the synthesis and degradation of AEA
o Synthesis and degradation of AEA
Phosphatidylethanolamine-> N-arachidonoylphosphatidyl ethanolamine (NAPE) by N-acetyltransferase (NAT) action-> Palmitoyl ethanolamide (PEA), Oleoyl ethanolamide (OEA) and arachidonoyl ethanolamide (AEA) through NAPE-Phospholipase D (NAPE-PLD) action-> arachidonic acid through fatty acid amide hydrolase (FAAH) action-> -> prostaglandin H2 by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) action-> prostacyclin, thromboxanes and prostaglandin E2
What are the system functions of the endocannabinoid?
• Endocannabinoid system functions o Sleep and circadian rhythms o Analgesia (by cannabinoid boost) o Positive mood (by cannabinoid boost) o Energy balance o Stress coping
Where are CB receptors found in the pain pathways
o Endocannabinoids and CB receptors are found at all levels of pain pathways
Spinal cord- CB2
Brainstem and brain-CB1
How do CB1 antagonists have antinociceptive effects (how do they act)
CB1R- inhibition of ascending nociceptive transmission, modification of emotional and cognitive manifestations and activation of descending inhibitory pathways at the level of the brain (which gives analgesic effect)
How do CB2 antagonists have antinociceptive effects (how do they act)
CB2R- inhibition of ascending nociceptive transmission and inhibition of neuronal sensitization at the level of the spinal cord
Describe the psychological effects of lowered AEA
o Lowered AEA (anandamides) lead to: Higher anxiety Higher HPA axis Lower neurogenesis Lower fear extinction and anhedonia Higher memory consolidation
Describe the psychological effects of increased 2-AG
o Increased 2-AG lead to: HPA response termination HPA axis habituation Modulates synaptic plasticity Lower memory retrieval Lower pain
How are endocannabinoids related to PTSD? Describe a relevant stufy
• Endocannabinoid deficiency in PTSD
o Study examined patients who developed PTSD following world trade center attacks of 9/11
Found they had lowered levels of 2-AG
Having less 2-AG being released puts less of a break on the HPA axis
• Less 2-AG means that this stress response is not being terminated
o Suggests plasma endocannabinoids deficiency ii PTSD
What are the current pharmacological strategies for boosting endocannabinoid levels and how do they do so?
• JZL184- MAGL inhibitor
o Boosts levels of endocannabinoids in tissues
• PF-3845- FAAH inhibitor
o Boosts levels of endocannabinoids in tissues
• Paracetamol and NSAIDs increase endocannaboids
o Inhibitors of FAAH which degrade anandamide
May by why there is an analgesic effect
What are examples of current medical cannabis and what are they used to treat?
Medicinal cannabis, Sativex, epidiolex • Sativex: 1:1 THC:CBD formulation o Administered as oral mucosal spray o Approved to treat spasticity (as in MS) o Neuropathic pain (but evidence less convincing) • Epidiolex: purified CBD o Drug in US, EU and Australia o Treating childhood epilepsy
What is synthetic THC used for and how does it act?
THC: CB1 and CB2 orthosteric agonist
• Synthetic THC- treats chemotherapy induced nausea and vomiting
What is CBD and how does it act?
CBD: increases endocannabinoid levels but also a CB1 receptor negative allosteric modulatory effect
• Inhibits fatty acid binding protein 5- activates cannabinoid receptors
What is JNJ-42165279 and what is it used for?
JNJ-42165279: FAAH inhibitor
• Phase II trial social anxiety disorder underway
What is ABX-1431 and what is it used for?
ABX-1431: MAGL inhibitor
• Phase 1b neuropathic pain
What are the positive and negative effects of CB1 and CB2 positive allosteric modulators?
CB1 and CB2 positive allosteric modulators
• CB1 boosts mood but it has problems in that it intoxicates
• Positive allosteric modulation of CB1 (don’t directly activate it but tone up effect of endocannabinoids- may have less sedative effects than through direct CB1 activation)
What is Dravet syndrome, what can it cause and what is it caused by? Is it responsive to current conventional medicines? What medicine improved Dravet syndrome?
o Katelyn Lambert suffers from a rare and catastrophic epilepsy disorder called Dravet syndrome
Has led to developmental delays and autistic-like features
Some children also die without warning
Mutation in Scn1a, which encodes a voltage gated sodium channel
o This syndrome is resistant to conventional medicines
Clear unmet clinical needs
o Many families like Katelyn’s have turned to cannabis to treat their children
o The Lambert family saw a dramatic improvement in Katelyn’s condition and have become fierce advocates for medicinal cannabis
What are the materials used in preclinical cannabis epilepsy program?
o Singlephytocannabinoids o Structural analogues o Phytocannabinoid combinations o Full-spectrum extracts o Screening against conventional epilepsy-relevant targets GABAA 5-HT1A Nav1.4 o Dravet mice- Scn1a+/- mice Heat-induced seizures Spontaneous seizures Reduced lifespan Behavioural abnormalities
What is the procedure fpr using Dravet mice-Scn1a mice and what information can be gotten from them?
and clobazam (benzodiazepine) anticonvulsant potentiation o Inject drug-> heat mice up-> look at threshold by which they have the seizure Increased seizure for threshold=increased anticonvulsant effect
Are CBD and clobazam better when administered independently or together? Why?
o CBD and clobazam combined have a greater magnitude effect (potentially additive)
CBD and clobazam work on their own, but greater anticonvulsant action when they work together
Mechanism for this could involve GABAA receptors
What is the effect of CBD on epilepsy?
o CBD is a novel anticonvulsant
CBD 20mg/kg reduces seizure frequency in phase III clinical trials
o Artisanal cannabis extracts in childhood epilepsy
How is carvone and myrcene made?
o DOXP/MEP pathway-> Geranyl diphosphate (GPP)-> carvone and myrcene
How is OA, PA and OLA made?
o Fatty acid biosynthesis-> olivetolic acid (OA), palmitic acid (PA) and oleic acid (OLA)
How is CBGA made?
o Geranyl diphosphate+ Olivetolic acid-> cannabigerolic acid (CBGA)
Through cannabigerolic acid synthase (CBGAS) action
How is THCA made?
o Cannabigerolic acid (CBGA)-> Δ9-tetrahydrocannabinolic acid (Δ9-THCA)
Through tetrahydrocannabinolic acid synthase (THCAS)
How is CBDA made?
o Cannabigerolic acid (CBGA)-> cannabidiolic acid (CBDA)
Through cannabidiolic acid synthase (CBDAS)
What are examples of phytocannabinoid acids?
carvone and myrcene olivetolic acid (OA), palmitic acid (PA) and oleic acid (OLA) cannabigerolic acid (CBGA) Δ9-tetrahydrocannabinolic acid (Δ9-THCA) cannabidiolic acid (CBDA)
Describe CBGA and its actions
o CBGA works at a lower dose than CBD-most interesting
CBGA has multimodal actions
• CGBA did not affect 1698 GPCRs and 74 orphan GPCRs (eurofins screen)
• Inhibited GPR55, Cav3.1 and TRPV1 but was a positive allosteric modulator of GABA
Are THCA and THC synergistic or antisinergistic in their anti-convulsant effects?
• The case for the entourage effect: an interaction between Δ9-THCA and Δ9-THCA
o 6-Hz mouse model of partial seizures
Mixture of THCA and THC are anticonvulsants
• Suggests cannabinoid synergy between THCA and THC for anticonvulsant effect
o THCA and THC have no anticonvulsant effects independently
Describe the endocannabinoid system deficiency in Dravet syndrome
• Endocannabinoid system deficiency in Dravet syndrome
o Reduced hippocampal CB1 and 2-AG in seizure susceptible mice
o Reduced CB1 and 2-AG in mice can lead to brain hyperexcitability (less of a brake on release on glutamate)
o The CB1 positive allosteric modulator GAT229 is anticonvulsant in Dravet syndrome mice
o The MAGL inhibitor ABX1431 is anticonvulsant
What is epilepsy defined as?
• International league against epilepsy (ILAE) defines epilepsy as;
o A disorder of the brain characterised by an enduring predisposition to generate epileptic seizures
o Occurrence of at least one unprovoked seizure
How many people will have a seizure in their lifetime and how many will go on to develop epilepsy?
• 10% of people will have at least one seizure during their lifetime and about 1/3 will go on to develop epilepsy
Besides epilepsy, why might someone have a seizure?
o An individual may have a seizure due to: head trauma, high fever, alcohol withdrawal, dehydration/low blood pressure/osmolyte imbalances
What are the two main types of seizures? Define them
- Focal (partial)- activation of neurons in a relatively small, discrete region
- Generalised- characterised by involvement of both hemispheres and widespread neuronal activation
What are focal seizures and what are their features?
• Focal (partial)- activation of neurons in a relatively small, discrete region
o Clinical manifestation reflects region of brain in which they occur
o Sensory or motor depending on where epileptic foci is
o Complex partial seizures- impairment of consciousness/weird auras
Familiarity (déjà vu), strangeness (jamais vu), automatisms (physical ticks), hallucinations (auditory and visual), temporal lobe epilepsy
What are generalised seizures and what are their features/stages?
• Generalised- characterised by involvement of both hemispheres and widespread neuronal activation
o Tonic stage- extension of the extremities, rigid stretching
o Atonic stage- sudden loss of muscle tone and people will fall to ground
o Clonic (myoclonic) stage- repetitive muscle twitching
o Tonic-clonic (grand mal)- distinct tonic phase followed by a clonic phase (full body spasms with intermittent relaxation)
o Generalised absence seizures (petit mal)-brief lapse of consciousness
What are the mechanisms behind epilepsy? What are examples of what can happen when these mechanisms are off balance?
• The brain has a fine balance between excitation (glutamate) and inhibition (GABA)
• Too much excitation (or too little inhibition)
o Convulsions, anxiety, high blood pressure, insomnia
• Too much inhibition (or too little excitation)
o Sleep, sedition, depression, coma, low blood pressure
How many of newly diagnosed epilepsy patients are drug resistant?
• 25-40% of newly diagnosed epilepsy patients are drug resistant
o Failure of a patient’s seizures to respond to at least two ASDs used
How is compliance to antiepileptic drug treatments monitored?
• Huge variability in disease management
o Compliance, monitor plasma levels to monitor compliance
Epilepsy is mostly disease of life- a lot of people are born with epilepsy (genetic component) although it can be acquired
What are issues/considerations of general pharmacological considerations to epilepsy?
• Doses need to be individualised
o Drug treatment can change depending on epilepsy development/changes-need to be flexible
• Toxicity issues- long term use
What are non-pharmacological treatments to epilepsy?
• Non-pharmacological treatments-
o Surgery
Risky and only used in extreme circumstances
o Vagal nerve stimulation (device)
Device inserted near the brainstem- if someone is feeling they might have a seizure, they can activate a device to give signal/pulse to brain region
o Diet- ketogenic/Atkin’s/low carb diet
o Medicinal cannabis
Describe the history of antiseizure drug development
• History of antiseizure drug development
o 1800s- bromide was used
o 1900s- phenobarbital was discovered and there are first generation/second generation ASDs
o In 1937- started to use animal models for drug screening: meant boom in drug screening/development
o In 1970s- International consortium on epilepsy- lead to another boom for antiseizure drug development- led to third generation drugs
What are the two main mechanisms of anticonvulsants?
• Mechanisms of anticonvulsants-
o Reducing excitation
o Increasing inhibition-elevate GABA in inhibitory synapse
How do anticonvulsants reduce excitation?
• Mechanisms of anticonvulsants-
o Reducing excitation
Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
Block excitatory amino acid action (glutamate)
How do anticonvulsants enhance sodium channel inactivation? Describe an example of such drugs, how they work, and their ability to be tolerated
Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Sodium channel blockers-most commonly used and often first line of defense: drugs are phenytoin, carbamazepine and lamotrigine (lamactil)
o Sodium channels critical for initiation and propagation of action potentials
o Enhance voltage gated sodium channel inactivation
o Use dependent (binding is dependent on the opening of sodium channels which then leads to inactivation)
o Results in a reduction of sustained high-frequency firing of action potentials-specifically act on rapidly firing neurons
o Well tolerated- dizziness, upset stomach, headache, unsteadiness
What are two types of drugs who inhibit excitatory amino acid (glutamate) release for anticonvulsant effects?
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Levetiracetam (Keppra) and brivaracetam
• Ethosuximide (zarontine)
Describe the effects and mechanisms of keppra and brivaracetam, and their tolerance
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Levetiracetam (Keppra) and brivaracetam
o Binds to neuronal synaptic vesicle glycoprotein 2A protein (SV2A, coordinate synaptic vesicle exocytosis)
o Inhibits presynaptic CaV channels
o Reductions in neuronal excitability, reduced glutamate release
o Well tolerated-sleepiness, loss of energy, dizziness, anxiety
Describe the effects and mechanisms of ethosuximide, and their tolerance
• Ethosuximide (zarontine)
o Used in the treatment of generalised absence seizures
o T-type calcium channel block: calcium channels are low voltage and found in thalamic neurons
o Well tolerated- upset stomach, diarrhoea
What are examples of drugs that block excitatory amino acid action for anticonvulsant effects?
• Perampanel (Fycompa)-newer drug
Describe the effects of perampanel, its mechanism and tolerance capability
Block excitatory amino acid action (glutamate)
• Perampanel (Fycompa)-newer drug
o Selective non-competitive AMPA receptor antagonist
o Potent (about 200nM)
o Selective for AMPA over NMDA/kainate
o Small side effect profile
What are ways in which anticonvulsants can increase inhibition for their therapeutic effect?
o Increasing inhibition-elevate GABA in inhibitory synapse
Enhance GABA action
Inhibit GABA breakdown
Inhibit GABA uptake
List two examples of drugs that are an anticonvulsant that enhances GABA action, their mechanisms and their tolerance
- Phenobarbitone (Barbiturate)
* Diazepam (benzodiazepine)
Describe phenobarbitone’s mechanism, effect and tolerability
• Phenobarbitone (Barbiturate)-not used very much now (only used if people are in emergency department for status epilepticus-when person will not come out of the seizure) o May act alone or enhance the actions of GABA o Act on all GABAA receptors Increase affinity for GABA Increase Cl- conductance Prolongs the open time of the chloride channel o Unwanted sedative side effects Tiredness, forgetfulness Confusion and dizziness Anaemia Folic acid deficiency Decrease libido, erection problems
Describe diazepam’s mechanism, effect and tolerability
• Diazepam (benzodiazepine)-more widely used
o Enhances the actions of GABA
o Increases the frequency of channel opening
o Act on GABAA receptors containing alpha1, alpha2, alpha3, alpha5 and gamma subunits
Selective
o Binds at the interface between alpha and gamma subunits
o Patients can develop rapid tolerance
o Sleepiness, fatigue, poor coordination
Describe a drug that inhibits GABA breakdown as its anticonvulsant effect, its mechanism, its effect and tolerability
Inhibit GABA breakdown
• Vigabatrin (gamma-vinyl-GABA)
o Synthetic structural analogue of GABA
o Specific inhibitor of GABA transaminase- hence prevents GABA breakdown
o Fatigue, dizziness
o Loss of peripheral vision (up to 30% of patients that take it)
Describe a drug that inhibits GABA uptake as its anticonvulsant effect, its mechanism and its tolerability
Inhibit GABA uptake
• Tiagabine
o Derivative of nipecotic acid (transportable inhibitor)
o GAT1 inhibitor
o Increase extracellular GABA levels
o Well tolerated- sleepiness, tremor, dizziness and anxiety
List pharmacological anticonvulsants with unknown mechanisms
• Pharmacological anticonvulsants-unknown mechanisms o Sodium valproate (epilum) o Topiramate (topomax) o Felbamate (felbatol) o Gabapentin and pregabalin
Describe the mechanism of sodium valproate, its tolerability and its uses/effects
o Sodium valproate (epilum)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Inhibit GABA breakdown
Contains no nitrogen atoms-hard to overdose on it
Identified when used as a solvent in anticonvulsant screen (1960’s)
Use-dependent sodium channel blocker
• Weaker than phenytoin and carbamazepine
Calcium channel blocker
Increases levels of GABA (unknown mechanism)
• Focused researchers on GABA, lead to newer generation anticonvulsants
Also clinically used to treat bipolar disorder (lamactil)
Fairly well tolerated-dizziness, upset stomach, headache, tremor, weight gain, hair loss
Describe the mechanism of topiramate, its tolerability and its uses/effects
o Topiramate (topomax)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Block excitatory amino acid action (glutamate)
• Enhance GABA action
Inhibit voltage-dependent sodium channels
Antagonist at AMPA/kainate receptors
Augment GABA at some GABAA receptors
Also used in the treatment of migraines, bipolar disorder, obesity/weight loss
Slightly tolerated-dizziness, confusion, problems with word retrieval, tremor, weight loss and hair loss
Describe the mechanism of felbamate (felbatol), its tolerability and its uses/effects
o Felbamate (felbatol)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Block excitatory amino acid action (glutamate)
• Enhance GABA action
Inhibit voltage-dependent sodium channsl
Antagonist at NMDA receptors (NR2B)
Positively modulates GABAA receptors
Fairly well tolerated-headache, weight loss, insomnia, headache
Describe the mechanism of gabapentin and pregabalin, its tolerability and its uses/effects
o Gabapentin and pregabalin
Mechanism unknown
Synthesised as GABA analogues
No proof that they bind to GABA receptors or affect GABA breakdown or reuptake
Do increase total GABA concentrations in cerebrospinal fluid
Bind to the alpha2δ subunit ofvoltage-gated (L-type) calcium channels, thought to be associated with a decrease in neurotransmitter release (mechanism could be Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron)
Fairly well tolerated-sleepiness, weight gain and dizziness
Where are most of the genetic mutations that predispose to epilepsy and where have they been found?
• Brain is predisposed to seizure activity because neurons are so extensively interconnected- a fine balance
• Since the first gene to cause epilepsy was discovered in 1995, more than 30-40 different genes have been found
• Virtually all known mutations that cause epilepsy are found in ion channel subunits
o There are many different mutations in proteins in the brain that have been linked to epilepsy
What are two of the biggest mutations which predispose to epilepsy?
• Mutations-
o GABAA receptor mutation
French family with GEFS+
Lysine 289 to methionine mutation (K289M) in gamma2 subunit of GABAA receptor
Decrease in GABAA receptor amplitude
o Sodium channel mutation
Family with GEFS+
Nav1.1 channel- arginine 1916 to glycine mutation (R1916G)
R1916G renders Nav1.1 non-functional: protein folding
Causes epilepsy because these mutated sodium channels are found in inhibitory GABAergic interneurons
• Affects GABAergic inhibition-less of it
Loss of function mutation
How many females experience depression in life?
• 1 in 4 females
How many males experience depression in life?
1 in 6 males
What percentage of Australians have experienced at least one anxiety disorder, mood disorder or substance mood disorder? Describe
• 45% of Australians aged 16-85 years experienced at least one anxiety disorder, mood disorder or substance use disorder
o Comorbidity between these disorders
How much more common is it to get a mood disorder if a 1st degree relative has it?
• 1.5-3 times more common among 1st degree relatives
o Strong familial components to mood disorders
What is the most common onset for mood disorder?
• Common onset- 16-25
What are the causes of depression?
• Causes- o Spontaneous o Traumatic emotional experience o Chronic stress o Symptom of other disease o Precipitated by drugs
What are the types of depressive disorders?
• Depressive disorders-
o Major depression (episode or disorder)- DSMV
o Persistent depressive disorder (dysthymia)
o Others including atypical depression, premenstrual dysphoria, disruptive mood dysregulation…
What is the DSMV criteria for major depression?
o Major depression (episode or disorder)- DSMV
At least 2 weeks of depressed mood/anhedonia + 3 other symptoms:
• Emotional symptoms
o Depressed mood: sad or empty, hopeless, tearful, irritable
o Inability to experience pleasure (anhedonia)
• Vegetative symptoms
o Significant weight loss or gain/decrease or increase in appetite
o Insomnia or hypersomnia
o Psychomotor agitation or retardation
• Cognitive symptoms
o Feelings of worthlessness/excessive or inappropriate guilt
o Inability to concentrate/indecisive
o Recurrent thoughts of death/suicide
Symptoms must affect social and occupational functioning
• Can be mild or severe
Symptoms must not be due to drugs or another medical condition
What is the DSMV criteria for persistent depression disorder?
o Persistent depressive disorder (dysthymia)
2 years depressed mood for more days than not + additional symptoms that don’t meet criteria for major depression
What is the neural circuitry which regulates mood? Describe
• Neural circuitry which regulates mood
o Frontal cortex (FC) and hippocampus (HP) involved in cognitive symptoms
o Nucleus accumbens (NAc) and amygdala (Amy) involve in emotional symptoms
o Hypothalamus (Hyp) and monoamine brainstem nuclei (Dorsal Raphae, Locus Coeruleus) involved in so-called vegetative symptoms e.g. appetite and energy
Dorsal raphe- serotonin cell body
Locus Coeruleus-noradrenaline cell bodies
What are the major neurotransmitters involved in mood regulation?
• Major neurotransmitters involved : o Noradrenaline o Serotonin (5-HT) o Dopamine o GABA
What is the HPA axis? Describe
• Hypothalamic-Pituitary-Adrenal (HPA) axis-
o Hippocampus, amygdala and monoamine brainstem nuclei input into the hypothalamic paraventricular nucleus, which releases cortico-releasing factor -> acts on the CRF receptors of the anterior pituitary-> anterior pituitary releases adrenocorticotropic hormone -> acts on the ACTH receptors off the adrenal cortex-> releases glucocorticoids which acts on glucocorticoid receptors of the hippocampus and hypothalamic paraventricular nucleus to supress their activity
o Negative feedback loop
What is the monoamine theory of depression? Describe all its versions
• Monoamine theory of depression-
o 1965- depression is caused by a functional deficit of monoamines at certain sites in the brain
But NA and 5-HT are augmented straight away while symptoms take weeks to diminish and delayed therapeutic effect coincides with monoamine receptor downregulation
o 1980s- revised to suggest the hypoNA/hypo5-HT state leads to receptor hyperresponsiveness
So antidepressants increase synaptic levels of NA and 5-HT to normal levels and downregulating the receptors to normal levels accounts for slow action of drugs
• Optimising transmitter and receptor concentrations-> bringing the receptors back to normal responsiveness
What is the neuroplasticity/neurotrophic hypothesis of depression?
• Neuroplasticity/neurotrophic hypothesis
o Neurogenesis- formation of new neurons from stem cell precursors in lateral ventricles and dentate gyrus
o Key players are BDNF (brain derived neurotrophic factor) and TrkB receptors
Major role in birth, survival and maturation of neurons
o 5-HT and noradrenaline promote neurogenesis (likely via 5-HT1A, 5-HT2B and alpha2 and beta receptors), possibly mediated by BDNF
o Stress and depression are associated with:
Neuronal loss in the hippocampus and prefrontal cortex
• Imaging studies of patients show neurodegeneration in these regions
Decreased BDNF and TrKB receptors
Decreased neurogenesis
• Decreased cell proliferation, survival and differentiation
o Depression may be related to a genetic polymorphism in BDNF which predicts chronicity
Describe the neuroendocrine hypothesis of depression
• Neuroendocrine mechanisms-
o Depression arises from a maladaptive response to stress due to HPA axis dysregulation
Chronic stress decreases hippocampal inhibition of the HPA axis (negative feedback response is reduced)
o Plasma cortisol levels are elevated in depressed people
Glucocorticoids interfere with hippocampal neurogenesis and also BDNF
Overactivity of the HPA axis reduces neurogenesis and BDNF levels-> reducing ability to respond to stimuli
o CRF levels are increased in CSF and brain of depressed people
What are the goals/origins/limitations of current therapies for depression?
- Current anti-depressants mainly target noradrenaline and serotonin/5-hydroxytryptamine (5-HT)
- Drugs developed from TCAs, discovered serendipitously 50 years ago
- Effectiveness (about 70%) of medication gave rise to monoamine hypothesis of depression (1965)
- Lack of effectiveness (about 30%) and delay in onset of therapeutic effect indicates that our understanding of the aetiology of depression is incomplete
What are antidepressants used for?
• Primary indication is major depressive disorder o Treatment o Prevention of relapse o Maintenance • Post-partum depression • Anxiety disorders • Bulimia nervosa • Pain • Depression with medical illness • Depression associated with schizophrenia
How do antidepressants work as according to the monoamine hypothesis?
• Antidepressants and the monoamine hypothesis
o Over a period of a few weeks-
Down-regulate postsynaptic NA (beta-adrenoceptors) and/or 5-HT2 receptors
• Reduction in binding sites
• Reduction in agonist response
Increase activity/sensitivity of post-synaptic 5-HT1 receptors in the hippocampus (except MAO-l’s)
Desensitisation of presynaptic alpha2 adrenoceptors and/or 5-HT1 receptors (inhibitory receptors which control NA and 5-HT release)
• Facilitate monoamine release and increased monoamine concentration
o Net effect of chronic treatment is an enhancement of monoaminergic function
Optimise monoamine levels and restore optimal receptor sensitivity
o Slow adaptive changes correspond to the timecourse of therapeutic effect
Beta 2 adrenoceptors downregulated
5-HT2 receptors downregulated
alpha2 adrenoceptors downregulated
o Monoamine hypothesis- monoamines are regulators of gradual adaptive responses, the time course of which is parallel by changes in mood
How do antidepressants work as according to the neuroplasticity/neurotrophic hypothesis?
• Antidepressants and the neuroplasticity/neurotrophic hypothesis
o Antidepressants enhance BDNF signalling, TrKB receptors and neurogenesis
BDNF stimulates gene transcription of SERT and tryptophan hydroxylase in raphe nuclei
5-HT receptor activation stimulates BDNF expression
Thus by increasing 5-HT synthesis, release and cell function, antidepressants may work to restore network function, hence mood
o 5-HT and noradrenaline promote neurogenesis
5-HT1A and 5-HT2B stimulation
beta-adrenoceptor stimulation
alpha2-adrenoceptor blockade
How do antidepressants work as according to neuroendochrine hypothesis?
• Antidepressants and the neuroendocrine mechanisms
o Antidepressants are associated with phosphorylation of Glucocorticoid receptors (GR) via PKA, increasing expression of GR inhibitors to promote neurogenesis in the hippocampus
o Antidepressants promote hippocampal neurogenesis which is necessary for restoration of HPA axis function (that is to inhibit stress response)
What are the antidepressant drug classes?
- Monoamine reuptake inhibitors
- Monoamine oxidase inhibitors (MAOIs)
- Tetracyclic antidepressants
What are examples of TCAs used for depression and what is their structure and danger?
o Tricyclic antidepressants (TCAs)
Examples-
• Amitriptyline
• Clomipramine
• Doxepin
• Imipramine
o What the other tricyclic antidepressants modelled off-> in turn, it is modelled off clopromazine (first anti-psychotic developed)
o Originally developed as a antipsychotic
o Binds to serotonin-noradrenaline receptors
Named after their 3 rings
Overdose with TCAs
• Narrow therapeutic index- toxicity at 2-6x therapeutic dose
• Overdose often deliberate, sometimes accidental
• TCAs strongly potentiate alcohol effects
o Combination can cause death from respiratory depression
What are the types of monoamine reuptake inhibitors used for depression?
• Monoamine reuptake inhibitors-
o Tricyclic antidepressants (TCAs)
o Selective serotonin reuptake inhibitors (SSRIs)
o Serotonin and noradrenaline reuptake inhibitors (SNRIs)
o Noradrenaline reuptake inhibitors (NRIs)
What are examples of SSRIs?
Examples- • Citalopram • Fluoxetine o First one-> revolutionised prescription of antidepressants • Paroxetine • Sertraline
What are examples of SNRIs?
o Serotonin and noradrenaline reuptake inhibitors (SNRIs)
Examples-
• Venlafaxine
• Desvenlafaxine
• Duloxetine
Tend not to bind to other receptors that TCAs bind to
