Describe the way neurotransmitters are released from cells (very general overview)
What is Gastrin?
Gastrin is a peptide hormone that stimulates secretion of gastric acid by parietal cells
What are the four 4 dopamine pathways of the brain?
Nigrostriatal - initiation and control of movement
Mesolimbic - reward, reinforcement
Mesocortical - cognition, planning, motivation
Tubero-infundibular (hypothalamus to pituitary) - inhibits the release of prolactin hormone from the pituitary gland
Describe the function of Noradrenaline
- Noradrenaline is released by neurones originating from the locus coeruleus in the brainstem.
- Project widely influencing sleep, wakefulness, attention, feeding behaviour
- Inactivated by reuptake into the pre-synaptic neurone (and oxidation)
Describe the function of serotonin (5-HT)
- Particularly released by neurones originating from the raphe nuclei in the brainstem
- These project to various parts of the brain, influencing mood, emotional behaviour, satiety and sleep
- Inactivated by reuptake into the pre-synaptic neurone (and oxidation)
Explain the function of GABA
- GABA is released by inhibitory neurones throughout the CNS
- Once stimulated, GABA receptors allow a flux of chloride ions across the post-synaptic membrane
- This hyperpolarises (stabilises) the neurone
- Negative chloride ions flood into postsynaptic neurone, hyperpolarising it, making it less likely to fire an action potential
Describe the nature of Schizophrenia
- Relapsing and remitting ilness, typically starting in young adult life.
- Characterised by 'positive' symptoms during episodes - hallucinations, delusions, thought disorder.
- An accumulation of 'negative' symptoms over time - lack of motivation, reduced speech, reduced emotion, social withdrawal
How (broadly speaking) do antipsychotics work?
- They antagonist D2 receptors in the mesolimbic system
- They treat schizophrenia, particularly delusions, hallucinations, thought disorder
- Also treat mania, depression with hallucinations, delusions, delirium etc.
- E.g. olanzapine, risperidone, haloperidol
- May take a few weeks to have full effect
- They also antagonise the 5HT2A receptors (resulting in movement difficulties)
What are the side effects of anti-psychotics on other dopamine pathways?
1. Nigrostriatal - extrapyramidal side effects' - e.g. parkinsonism, akathisia, acute dystonia, tardive dyskinesia
2. Tubuloinfundibular - e.g. excess prolactin, galactorrhoea, amenorrhea, infertility
Tardive dyskinesa = uncontrollable movement of mouth and tongue
Acute dystonia = muscle group suddenly tensing up
What are first generation antipsychotics?
What are second generation anti-psychotics and why do they work better?
Risperidone, Olanzapine = have less extra-pyramidal side effects
Clozapine can work where others don't but may cause agranulocytosis
Clozapine side effects: damages bone marrow and WBC production
What are the side effects of antipsychotics related to receptor function
Antagonises Histamine (H1) receptors resulting in sedation.
Antagonises muscarinic receptors resulting in dry mouth, blurred vision, constipation, urinary retention.
Antagonises Alpha 1 adrenoreceptors - resulting in postural hypotension
Antagonises 5-HT2c receptors resulting in hunger & weight gain
What are the metabolic/cardiac side effects of antipsychotics?
- Weight gain, diabetes, raised cholesterol
(especially second generation)
- Important as people with Schizophrenia may lose 15-20 years of life because of increased cardiovascular risk
- Also, rare idiosyncratic 'neuroleptic malignant syndrome'
What are the cases for the dopamine hypothesis in schizophrenia
Definition: Excess dopamine in mesolimbic tracts causes positive symptoms whereas inadequate dopamine in mesocortical tracts causes negative symptoms
- Antipsychotics block dopamine receptors
- Drugs that increase dopamine cause psychosis (amphetamine, cocaine, L-dopa)
- Reserpine depletes dopamine transmission and has antipsychotic effect (stops MOAs getting into vesicles)
- PET and SPECT scans show increased brain dopamine activity when people have schizophrenia
What are the cases agains the dopamine hypothesis of schizophrenia?
- Neurotransmitter effects are immediate but antipsychotics take 2+ weeks to work on symptoms
- Other transmitters appear to be involved with psychosis - Glutamate, 5HT2, 5HT1A
- The cause of schizophrenia may be upstream
What are the neuro-development hypotheses surrounding schizophrenia?
- Dilated ventricles in brain
- Predictor of onset of schizophrenia
What are the negative symptoms of schizophrenia?
- blunting of affect, poverty of speech, anhedonia etc etc
What is depression?
- Syndrome (collection of several symptoms occuring together)
- Persistent low mood, reduced enjoyment/interest, fatigue
- Changes in sleep pattern, loss of focus, weight change
- Loss of confidence, guilt, hopelessness, suicidal thoughts and acts
What are the four classes of antidepressants?
- Tricyclic antidepressant
- Selective serotonin reuptake inhibitor (SSRIs)
- Monoamine Oxidase Inhibitors (MAOIs)
- Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
How do Tricyclic antidepressants work?
They block Noradrenaline and Serotonin reuptake transporters at synapses, increasing the availablility of these monoamines.
They treat depression (as well as pain & anxiety)
E.g. Amitryptline, Lofepramine
- Can take a couple of weeks to take effect
What are the side effects of tricyclic antidepressants?
- Toxic in overdose
- Antagonises Histamine (H1) receptors resulting in sedation
- Antagonises muscarinic receptors resulting in dry mouth, blurred vision, constipation, urinary retention.
- Antagonises alpha adrenoreceptors resulting in postural hypotension
How do SSRI's work?
- Block only serotonin reuptake transporters, increasing serotonin availability in the synapse.
- Treats depression (also anxiety)
- E.g. fluoxetine, citalopram
- May take a couple of weeks to take effect
What are the side effects of SSRIs?
- Nausea and Vomiting
- Sexual Dysfunction
- increased Suicidal Thoughts
- Withdrawal Reaction
- Safer in Overdose
How do MAOIs work?
- Mono-amine oxidase inhibitors
- They block the action of this enzyme in the nerve terminals, increasing the availability of noradrenaline, serotonin, dopamine
E.g. PHENELZINE, MOCLOBEMIDE
- Can produce a hypertensive crisis - if people eat foods rich in Tyramine e.g. mature cheese, bovril
- Tryamine precipitates Noradrenaline release from vesicles
What are the cases for the monoamine theory of depression?
Theory: Depression is a result of a deficiency in brain monoamine neurotransmitters - noradreanaline, serotonin, dopamine
- Antidepressants increase the availability of monoamines at synapses
- Reserpine which depletes monoamine transmission causes depression (stops monoamines getting into vesicles)
- People with depression can have lower levels of monoamine precursors/metabolites in their CSF or blood
What are the theories against the monoamine theory of depression?
- Neurotransmitter effect of antidepressants are immediate but they take 2+ weeks to work on symptoms
- Cocaine and amphetamine mimic NA and 5-HT but do not act as antidepressants
- Inprindole is an antidepressant which does not effect NA or 5-HT reuptake (5HT2 antagonist)
Why do antidepressants take at least 2 weeks to work?
Neuron knows that there is extra serotonin so it produces less receptors, but eventually this cancels out as the auto-receptors become less sensitive.
After a few weeks the increase in neurotransmitter is more sustained so the anti-depressants eventually have an effect.
What are anxiety disorders?
- Collection of illness
- Common thread is excessive fear and associated physical responses
- Nervousness, foreboding, agitation, palpitations, sweating, bowel uspet
- GAD, Panic disorder (episodic), specific phobias
How do Benzodiazepines work?
- They bind to a site on the GABA receptor potentiating the effects of GABA (i.e. GABA causes more Cl- influx and more inhibition)
- E.g. Diazepam, Lorazepam, Temazepam
- Also used vs seizures and increased muscle tone (spasticity)
- GABA agonist
What are the side effects of benzos?
- Impaired Motor Control
- Tolerance and Dependence
- Respiratory Depression - especially with alcohol