Block 6 W3 Flashcards
What are the 4 dopamine pathways?
- nigrostriatal - initiation and control of movement
- mesolimbic - reward, reinforcement
- mesocortical - cognition, planning and motivation
- tubero-infundibular - hypothalamus to pituitary, inhibits release of prolactin hormone from pituitary.
Describe noradrenaline.
Released by neurones originating from the locus coeruleus in the brainstem.
Projects widely influencing sleep, wakefulness, attention and feeding.
Inactivated by reuptake and oxidation.
Describe serotonin.
Released by neurones originating from raphe nuclei in the brainstem.
Project to various parts of brain influencing mood, emotional behaviour, satiety and sleep.
Inactivated by reuptake.
Describe GABA.
Released by inhibitory neurones throughout CNS.
Activated GABA receptors allow influx of Cl- -> hyper polarises the neurones.
Describe schizophrenia.
Relapsing and remitting illness, typical starting in young adult life.
Characterised by positive symptoms during episodes - hallucinations, delusions and thought disorder.
An accumulation of negative symptoms over time - lack of motivation, reduced speech, reduced emotion, social withdrawal.
Describe the MoA, e.g. and uses of antipsychotics.
MoA - antagonises D2 receptors in the mesolimbic pathway.
e.g. olanzapine, risperidone, haloperidol
Uses - schizophrenia and mania-depression.
What are the side effects of antipsychotics?
Effects on other dopamine pathways:
- nigrostriatal -> Parkinsonian, acute dystonias, tardive dyskinesia
- tubero-infundibular -> excess prolactin - galactorrhea, infertility
Blocking other receptors:
- antagonises H1 receptors -> sedation
- antagonises muscarinic receptors -> dry mouth, blurred vision, constipation
- antagonists a1 receptors -> postural hypotension
- antagonises 5-HT2c receptors -> hunger and weight gain.
What are the metabolic and cardiac side effects of antipsychotics?
Weight gain, diabetes and raised cholesterol.
People with schizophrenia may loose 15-20 years due to increased CV risk.
Arrhythmias and rare idiosyncratic neuroleptic malignant syndrome.
What is the dopamine hypothesis in schizophrenia?
Schizophrenia is a result of dopamine hyperactivity in certain areas of brain:
- excess dopamine in mesolimbic -> positive symptoms
- inadequate dopamine in mesocortical -> negative symptoms.
What are the arguments for and against the dopamine hypothesis of schizophrenia?
For:
+ antipsychotics block dopamine receptors
+ drugs that increased dopamine cause psychosis e.g. amphetamines, cocaine and L-DOPA
+ reserpine depletes dopamine transmission so had antipsychotic effects
+ PET and SPECT scans show increased brain dopamine activity
Against:
- NT effects are immediate but antipsychotics take 2 weeks for effects
- other transmitters appear to be involved with psychosis e.g. glutamate, 5-HT2 and 1A
- cause of schizophrenia may be upstream
What are the other hypotheses for schizophrenia?
- neurodevelopment -> from twin studies, shown not to be purely genetic, enlarged brain ventricles in twins with disease
- psychological
- damage from auto-antibodies
Define depression.
A collection of several symptoms occurring together:
- persistent low mood, reduced enjoyment/interest and fatigue
- sleep, appetite, weight, concentration changes
- loss of confidence, guilt, hopelessness, suicidal thought and acts
What are the classes of antidepressants?
Tricyclic antidepressants
Selective serotonin reuptake inhibitors, SSRIs
Monoamine oxidase inhibitors, MOAIs
Serotonin noradrenaline reuptake inhibitors, SNRIs
What is the MoA, e.g. and uses of tricyclics?
MoA - blocks noradrenaline and serotonin reuptake transporters at synapses -> increases availability of these monoamines.
e.g. amitriptyline, lofepramine
Uses - depression, anxiety and pain
What are the side effects of tricyclics?
Toxic in overdose
Antagonises H1 receptors -> sedation
Antagonises muscarinic receptors -> dry mouth, blurred vision, urinary retention
Antagonises a adrenoceptors -> postural hypotension.
What is the MoA, e.g. and uses of SSRIs?
MoA - Blocks serotonin reuptake transporters -> increases serotonin availability at synapses.
e.g. fluoxetine, citalopram
Uses - depression and anxiety
What are the side effects of SSRIs?
Stimulates 5-HT receptors:
- nausea and vomiting
- sexual dysfunction
- increased suicidal ideation in children
- withdrawal reaction
- safer in overdose
What is the MoA, e.g. and side effects of MOAIs?
MoA - block action of monoamine oxidase in nerve terminals -> increases availability of NA, serotonin and dopamine.
e.g. phenelzine, moclobemide
Side effects: produces hypertensive crisis if people eat food rich in tyramine e.g. mature cheese since tyramine precipitates NA release from vesicles.
What is the monoamine theory of depression?
Depression is a result of deficiency in brain monoamine Its -> NA, serotonin and dopamine.
What are the arguments for and against for the monoamine theory of depression?
For:
+ antidepressants increase availability of monoamines at synapses.
+ reserpine depletes monoamine transmission -> causes depression as it stops monoamines getting into vesicles.
+ people with depression have lower levels of monoamine precursors/metabolites in their CSF/blood.
Against:
- NT effects of antidepressants are immediate but takes 2 weeks for effects.
- cocaine and amphetamine mimic NA and 5-HT but don’t act as antidepressants.
- inprindole is an antidepressant which doesn’t affect NA or 5-HT reuptake. It is a 5-HT2 antagonist.
What are the other hypotheses for depression?
Behavioural, cognitive and other psychological.
Monoamine
Endocrine
Why do antidepressants take 2 weeks for effect?
Initially, the increased 5-HT in synapses is cancelled out by auto-receptors -> reducing 5-HT release and more reuptake of the extra 5-HT in the synapses.
After 2 weeks, the auto-receptors desensitise and the blocked reuptake transporters become internalised so eventually there really is an increase in 5-HT at synapses.
Define anxiety.
Collection of illness
Common thread - excessive fear and associated physical responses.
Nervousness, foreboding, agitation, palpitations, sweating, bowel upset.
GAD, panic disorder, phobias, OCD, PTSD
What is the MoA, e.g. and uses of benzodiazepines?
MoA - bind to regulatory sites on GABA receptors -> potentiates the inhibitory effects of GABA -> causes more Cl- influx -> hyperpolairses -> inhibition.
e.g. diazepam, lorazepam, temazepam
Uses - anxiety, seizures
What are the side effects of benzodiazepines?
Drowsiness, confusion, forgetfulness, impaired motor control, tolerance and dependence, respiratory depression.
What are other anxiolytic and hypnotic drugs?
Anxiety - SSRI sertraline, SNRI venlafaxine.
Hypnotics - Z-drugs zopiclone, zolpidem and short-acting benzodiazepines temazepam.
What are the physical symptoms of anxiety?
Muscle tension - headaches, pain, fatigue
Hyperventilation - dizziness, tingling fingers + toes (reduced pCO2 -> Ca2+ changes)
SNS over-activity - increased HR, BP, sweating, dry mouth, butterflies.
What are the psychological symptoms of anxiety?
CNS - poor concentration, memory
Mood - fear, worry, on edge, irritable
Thoughts - future danger, fear of dying/losing control, worry about worry.
What are the unhelpful behaviours exhibited in anxiety?
- pacing
- attempts at coping - caffeine, smoking, alcohol, drugs
- avoiding
- safety behaviour
- asking for reassurance - visiting GP
CBT reduces 3, 4 and 5
What are the treatment options for anxiety?
Education/explanation Relaxation - mindfulness Advice on sleep CBT - changes thinking and behaviour SSRI - sertraline Benzodiazepine - diazepam
Define learning.
Relatively permanent change in behaviour that occurs as a result of experience. It enables people to adapt to environment and increases chances of survival.
What is the neuronal basis of learning?
Amgydala - in temporal lobe, involved in learning + expressing fear. More axonal connections between neurones. Increased efficiency of NT release between neurones across synaptic cleft.
What are the types of learning?
- associative - learning that certain events go together e.g. classical and operant conditioning
- vicarious - learning by direct observation
- factual transmission - lectures
- complex - social learning, emotional intelligence.
Define classical conditioning.
A learning process where a previously neutral stimulus becomes associated with another stimulus by repeated pairing. e.g. Pavlov's dogs and taste aversion Explains origin of phobias Respondent learning A reliably predicts B
Define operant conditioning.
The alteration of behaviour by reward or punishment i.e. certain responses are learned because they affect the environment.
e.g. positive reinforcement - praise, negative reinforcement - picking up crying baby, punishment - smacking, extinction - time out.
Explains maintenance of phobias
Instrumental learning
Outcome is controllable
Give clinical examples of classical conditioning.
Visit to dentist/doctors - pain/anxiety linked to white coats, disinfectant smell, equipment.
Chemotherapy - anticipatory nausea entering the room.
Little Albert - scared every time rat was presented.
Music in films - enhances emotions.
Describe positive reinforcement.
Stimulus is given to increase behaviour.
Thorndike’s law of effect - successful behaviour will be repeated.
Reinforcers can be:
- primary -> food, water, escape
- secondary -> money, praise
Reinforcer must be immediate/linked to act if not, harder to change behaviour i.e. stopping smoking.
What are the types of positive reinforcement?
- continuous - every response is reinforced
- partial - occurs but not after every response:
- ratio schedules -> depend on the number of responses e.g. factory worker gets paid for every 3 shirts made.
- interval schedules -> depend on time interval e.g. nurse only gives paracetamol every 4 hours
- fixed (predictable) or variable (unpredictable e.g. slot machines).
What are the rules provided by positive reinforcement?
- people work harder under partial than continuous reinforcement
- effort increases with time or ratio to a point
- extinction of a response much slower with partial vs. continuous reinforcement and unpredictable vs. predictable schedule e.g. Gambling.
Define shaping as a complex action.
Rewarding behaviours which increasingly approximate to the desired more complex behaviour e.g. learning to walk, talk, drive.
Define chaining as a complex action.
Breaking down complex behaviours into series of simple acts - each reinforces next in a chain.
e.g. 1st holding spoon then later add need to put spoon in bowl to get praise.
Describe negative reinforcement.
Stimulus withheld to increase behaviour.
Removal of an aversive stimulus after a desired behaviour has occurred -> increases behaviour.
e.g. baby cries -> mom picks baby up -> stops crying -> mom negatively reinforced (does it next time).
Define phobias.
Marked and persistent fear
Triggered by a specific object/situation
Leads to avoidance of that situation
Interferes significantly with life
What are the 3 types of phobias?
- agoraphobia - public places, crowded
- social - performing in public
- specific - animals, heights
What maintains phobias?
Negative reinforcement
Phobic stimulus -> anxiety -> avoidance/escape -> anxiety reduced.
What are the treatments for phobias?
Graded exposure - deliberate confrontation of a feared object/situation until anxiety reduces (habituation).
Face fear gradually.
Requires SMART targets
Describe punishment.
Stimulus given to reduce behaviour.
Presentation of an unpleasant stimulus after an undesired behaviour occurs.
To be effect:
- link response to consequences, no time delay
- be consistently and sufficiently applied
Give an example of punishment and issues with punishment.
e.g. child scolded for drawing on wall, adult burns hand when touching hot pan, prison.
Issues:
- physical or emotional harm e.g. smacking
- paradoxical attention - any attention is better than none
- teaches aggression as model to solve problems
- no alternate behaviour is taught
- leads to fear/dislike of person and situation = classical conditioning
Describe extinction.
Stimulus withheld to reduce behaviour.
Decrease in behaviour by withholding a previous reward.
e.g. time out for toddler tantrums - reduces attention, depression - lack of pleasure so stop doing things and achieve less, worsening mood -> vicious cycle.
What are the 10 symptoms for recognising depression?
D - depressed mood E - energy loss/fatigue P - pleasure lost/anhedonia R - retardation/agitation E - eating changes S - sleep changes S - suicidal thoughts I - I'm a failure - lack of confidence O - only me to blame - guilt N - no concentration 1-3 = mild depression 4-6 = moderate 7+ = severe 2 weeks duration
How is CBT used for depression?
Cognitive - challenge unhelpful and extreme ways of thinking e.g. thought records
- stop avoiding and ruminating
Behaviour - behavioural activation including activity scheduling + goal setting e.g. activity diary.
- review progress
- rate pleasure and achievement
Therapy - talking and generic skills i.e. empathy, listening, therapeutic relationships.
Describe the somatic nervous system.
Effector - skeletal muscle Single LMN projecting directly to effector muscles NT - ACh Excitatory Interaction with external environment
Describe the autonomic nervous system.
Effector - smooth, cardiac muscles and glands
2 neurone efferents: PreG (cell bodies in CNS, anterior horn cells, cranial nerve nuclei) and PostG (ganglion, PNS).
NT - ACh and NA
Excitatory and inhibitory
Interaction within internal environment
What does ANS control?
Controls and coordinates CVS, respiratory, GIT and reproductive systems -> maintains homeostasis and fine tunes.
Visceral afferents -> visceral reflexes and pain (diffuse).
Involuntary
Define sympathetic nervous system and its function.
Thoracolumbar outflow (T1-L2) Function - fight/flight
Define parasympathetic nervous system and its function.
Craniosacral outflow (CN III, VII, IX & X + S2-S4) Function - rest & digest
Define enteric nervous system and its function.
Myenteric and submucosal plexuses
Function - peristalsis and GIT secretion
Describe the preganglionic and postganglionic neurones of the PNS.
PreG - craniosacral, long.
PostG - short, effects are close to ganglia.
For relaxation, food processing and energy absorption - secretomotor.
PreG axons don’t travel within rami communicantes of spinal nerves.
Describe the NTs of the PNS.
NT - ACh
Ganglion - nicotinic receptors
Effector - muscarinic receptors
Short-lived effects due to cholinesterase and highly localised. Muscarinic stimulation lasts longer.
Describe the effects of PNS stimulation.
Fires when asleep:
- counterbalances SNS
- resting and digesting
- conserves energy
- reduced HR, BP, RR
- eyes adapted for near vision
- increased GIT motility and secretion
- increased smooth muscle activity
- sphincteric relaxation
Describe the preganglionic and postganglionic neurones of the SNS.
PreG - from lateral horn T1-L2, short
- leave cord in spinal cord and enter paravertebral sympathetic chain
- to abdominal organs - splanchnic nerves (greater, less, least) via pre vertebral ganglia
PostG - long
- to body walls and limbs via spinal nerve rami
- to thoracic organs direct to organs
White and grey ramus communicans form connections.
Paravertebral (sympathetic trunk) and pre vertebral (coeliac (midgut), superior and inferior mesenteric (handgun) ganglia and plexuses)
Describe the NTs of the SNS.
PreG - ACh + nicotinic receptors at ganglion
PostG - NE + adrenergic receptors at effector cells
Adrenergic a1 and a2 + b1-b3
Sympathetic stimulation -> NE release locally or NE & E release into circulation.
Effects are wide spread due to nervous and hormonal release and long-lasting -> fight/flight
Few nitroxidergic PostG - release NO promoting vasodilation.
Describe Horner’s syndrome.
Ptosis - lazy upper eyelid
Anhydrosis - absence of sweating
Miosis - unopposed constrictor action of PNS
Describe the effects of SNS activation.
Fight or flight Dilated pupils Increased HR, BP, RR Blood diverted to skeletal muscle Bronchiolar dilation Increased blood glucose Sweating Sphincters closed
Describe the NTs of the ANS.
All PreG ganglion - nicotinic ACh
PNS PostG effector and SNS PostG sweat gland - muscarinic ACh
SNS PostG effector - noradrenergic NE
What are the functions of the SNS and PNS?
Most viscera are innervated by both SNS and PNS e.g. iris.
Most vessels are SNS only.
Reflex activity mediated by spinal cord and brainstem medullary centres.
Cortical centres influence autonomic functioning via limbic system - can modulate ANS by modulating limbic system e.g. bad news makes you cry, limbic system causes glands to secrete.
Describe the ANS reflexes.
Polysynaptic visceral reflexes.
PNS - gastric and intestinal, swallowing, defaecation, urination, pupillary light reflexes, cough, baroreceptor, sexual arousal.
SNS - cardioacceleration, vasomotor, pupillary, male ejaculation.
How is bladder kept under control?
To remain continent, need detrusor muscle to relax and sphincter to close, opposite to wee.
PNS runs to detrusor muscle -> excitatory
SNS PostG has many outputs:
- at PNS ganglion to shut off PNS
- at detrusor muscle to keep bladder full
- at bladder neck to prevent peeing
Turn off SNS control -> incontinence
Describe the effects of complete transection of the spinal cord.
Loss of movement and all sensation below lesioned section.
Initial flaccid paralysis becomes spastic (higher function control) over weeks.
Loss of bladder and rectal sphincter control - no higher level control.
Lesions above T10 -> ineffective cough
Decreased perianal sensation
Describe the effects of hemisection of the spinal cord.
Ipsilateral LMN (anterior horn)
Ipsilateral UMN paralysis (LCST)
Ipsilateral loss of touch, proprioception, vibration (dorsal columns)
Contralateral loss of pain and temp (spinothalamic)
What is the muscarinic cholinergic neurones of the PNS stimulated by?
Aminata, muscaria and inocybe
What is the nicotinic cholinergic neurones of the PNS stimulated by?
Nicotiana alata
How can the presynaptic terminal be blocked?
Uptake blocker -> hemicholinium - decreases ACh synthesis.
Release blocker -> botulinum - decreases release of ACh into cleft.
Describe synaptic agonists.
Physostigmine (calabar bean) - ANS stimulation and CNS stimulation, muscle fasciculations, death.
e.g. nerve gases, insecticides.
Describe synaptic cholinesterase inhibitors.
Competitive inhibitor at ganglia and PNS
Tissue and plasma (pseudo)
e.g. edrophonium, neostigmine, pyridostigmine (muscarinic).
Sarin - organophosphorus - very potent
What are the antidotes of cholinesterase inhibitors?
Atropine - competitive, reversible antagonist of muscarinic ACh receptors.
Pralidoxime - combats poisoning by organophosphates and acetylcholinesterase inhibitors i.e. sarin.
Describe post-synaptic nicotinic antagonists.
Curare - competitive, reversible inhibitor of nicotinic AChR.
Tubocurarine - competitive antagonist -> causes flaccid paralysis, muscle relaxation, respiration.
Atracurium - intermediate. Pancuronium - long. Mivacurium - labile in plasma.
Describe the MoA of suxamethonium.
Depolarising agonist - mimics ACh at NMJ but hydrolysis is much slower than ACh so depolarisation prolonged, resulting in neuromuscular blockade.
- hydrolysed by psuedo-cholinesterase
Causes: tonic paralysis and respiration.
Describe muscarinic receptor drugs.
Antagonist:
- atropine, scopolamine -> long acting. Motion sickness, depressant.
- tropicamide -> short acting. Ophthalmology to keep eyes dilated.
Agonist:
- pilocarpine -> glaucoma - constricts the eye.
How is NE recycled in the SNS?
- Uptake 1 and 2 -> reuptake of NE into synapses
- Leakage -> NE broken down by monoamine oxidase (MAO and COMT) in liver.
Where do alpha and beta adrenoceptors work?
Alpha - blood vessels
Beta - heart and lungs.
How is adrenaline made?
In adrenal medulla, an extra enzyme adds extra methyl group to NA -> adrenaline - more beta effects.
1 function of adrenaline - starvation (hypoglycaemia) releases adrenaline - goes to liver to stimulate gluconeogenesis.
Describe presynaptic inhibition of synthesis in SNS.
Inhibition of synthesis - methyltyrosine.
Uptake 1 blockers:
- cocaine -> continuos vasoconstriction - blue nose
- tricyclic antidepressant -> desipramine, potentiates endogenous NA.
Describe indirectly acting sympathomimetics.
Tyramine - marmite, cheese - releases NA from vesicles.
Amphetamines - releases NA.
Describe MAO inhibitors.
Increases levels of all monoamines - NA, serotonin and dopamine.
- type A and B
- e.g. phenlzine - antidepressant
- ANS interaction through food and wine.
Describe adrenoceptor agonists.
NA > Adrenaline (more potent on beta than NA) > isoprenaline (beta agonist - treatment of asthma with less SE, metabolised very quickly by COMT, only short-term bronchodilator) > salbutamol (like isoprenaline, COMT doesn’t metabolise this, 6-7 hours action).
Describe the effects of adrenaline.
Works mainly on beta adrenoceptors.
Increases BP but baroreceptors reduces it.
Describe the effects of NA.
Works mainly on alpha adrenoceptors.
Greater increase in BP and diastolic BP as contracting arterioles (baroreceptors have no effect).
Describe the effects of isoprenaline.
Works on beta adrenoceptors.
Has no effect on BP.
Describe alpha adrenoceptor antagonists.
Phenoxybenzamine - non-selective alpha antagonist, used for adrenal tumours, pheochromocytoma -> releases NA and adrenaline.
Prazosin - alpha-1 selective, limited use in hypertension.
Describe beta-antagonists.
Propanolol - beta 1 and 2, variable 1st pass metabolism.
Side effects - asthma -> causes bronchospasm by blocking beta 2 receptors.
Describe the MoA of atenolol.
Beta 1 - mainly heart.
Cardioselective and causes less bronchospasm.
List beta-1 agonists.
Dobutamine, dopamine.
List beta-2 agonists.
Salbutamol, salmeterol (short-acting) and terbutaline (long acting as no metabolism by COMT).
