lecture 4 - communication at the synapse 2 Flashcards
biogenic amines neurotransmitters
-dopamine
-serotonin
-histamine
-adrenaline/epinephrine
-noradrenaline/norepinephrine
-all small molecule neurotransmitters
-similar structures
-widespread in the brain (so if prescribed a drug that acts on these, you should be aware side effects can be widespread)
unconventional neurotransmitters
endocannabinoids
serotonin
-structure
-where is most of this
-where is it produced
-its roles
-90% serotonergic signalling is in gut
(works to have an effect on digestion)
-10% serotonergic neurons in the brain
-produced in the pons and upper brainsteam (raphe nuclei) , it has projections to the forebrain
-roles: regulation of mood, appetite and sleep, also involved in memory and learning
serotonin cascade
-serotonin precursor
-single neurotransmitter from its precursors to its final version
-serotonin precursor is tryptophan, mainly taken in by our diet eg oats, fish, cheese
-tryptophan converted to 5htp and then converted to serotonin
-packaged into vesicles, released from the presynaptic neuron to receptors on post synaptic neuron
-action potential which arrives at presynaptic neuron causes cell to release
-
depression and monoamines
key features
-intense feelings of sadness, helplessness and hopelessness
-anhedonia- general lack of interest that you would usually enjoy
-tiredness, lack of energy
-abnormal sleep and eating patterns
-cognitive impairments: concentrations, memory, executive function
the monoamine hypothesis
-how did we come about linking depression to monoamines
-came about from observing side effects of drugs
-reserpine (hypertension medication)
-in 1960s people who took this for blood pressure started to develop depression symptoms (micheals and gibbon 1963)
what is reserpine
-how can it explain monoamines link to depression
-reserpine is antagonist (which reduce normal action of drug) of the monoamines
-so suggests that monoamines are to low in patients who have depression
-reserpine prevents monoamines from being packaged into the vesicles , so nothing to release and so less monoamine action
what category of drug may be used in treatment of depression
agonists - antidepressants
types of antidepressants
-monoamine oxidase inhibitors
-tricyclic antidepressants
-SSRIs
-SNRIs
monamine oxidase inhibitors (MAOIs)
-what does it do
-inhibit the activity of the enzyme called monoamine oxidase that normally breaks down monoamine NTs- dopamine, noradrenaline and serotonin
-so leaves more of the molecule you need
-have to be careful with diet since it can mess with noradrenaline
tricyclic antidepressants
-work on noradrenalin and serotonin
-block reuptake of noradrenaline and serotonin-increasing levels of these two NTs in the synapse
SSRIs
-selective serotonin reuptake inhibitors : first choice for treating depression
eg prozac
SNRIs
selective noradrenaline reuptake inhibitors
serotonin based treatments
-SSRis process
-side effects
-examples
-selective serotonin reuptake inhibitors block the channels that allow serotonin to be removed from the cleft
-side effects :due to high levels of serotonin receptors in the GI tract, side effects of treatments can include weight loss, nausea and diarrhoea
-prozac fluoxetine are examples
agonists _____ serotonin action
enhance
does depression occur only due to low serotonin
moncrieff 2022
-paper found no strong evidence for lowered serotonin actions in depressed patients compared to controls
-royal collge of psychiatrists 2019
saying that ‘anti depressants correct a chemical imbalance is an over simplification’
the timing of effects of ssris
stahl 2000 experiment
-had 316 patients with major depressive disorder
-split into groups
-one group given placebo
-one group had sertraline
-one group citalopram
-two ssri effects measured on Hamilton depression rating scale, and results showed mood getting better
-randomised, double blind and placebo controlled study. so good study
-citalopram took longer to show effect
-when taking these serayonin goes up within hours (if you were to measure) But mood doesnt just change
evidence that anti depressants are effective for some patients
-cipriani et al 2018
-a study of antidepressants found all studied drugs to be more effective than placebo
-3 ssris in particular (escitalopram, paroxetine and sertraline) found to have the highest response/lowest drop out rates
-is it doing more than just increasing seratonin levels?
cognitive mechanisms causing depression
-could have a role in causing depression
-negative automatic thoughts
-negative schema
-negative information processing biases
negative biases in processing
-information recall
-interpreting facial expressions (more likely to interpret it as negative)
-distraction by negative stimuli
-emotional Stroop and negative bias
ssri can influence cognition
-face recognition
-memory
-in depressed participants, following a single dose of ssris we find
-enhanced recognition of facial expressions (tranter et al 2009)
particularly hapiness
-increased recall of positive stimuli in word memory tasks (harmer et al 2009)
no associated increase in self reported mood
acute effects of antidepressants
-how are these findings consistent with cognitive theories of depression
-acute affects of antidepressants are found for processing emotional stimuli
:
-reduced negative bias in attention and memory tasks , enhanced recognition of facial expressions
-findings are consistent with cognitive theories of depression: negative low level biases in perception and attention are related to high level beliefs about self, world and others (becks dysfunctional schemas)
-someone with depression has dysfunctional schemas, caused by negative attention bias
-acute cognitive affects occur with no reported change in mood
-suggested that antidepressants have an effect on cognitive level and gradually over a few weeks they’ll have a noticeable effect in mood
-suggested that combining cbt and antidepressants is effective
dopamine
-produced by ?
-involved in pathways
-produced by tyrosine which is then converted into DOPA and then converted into dopamine
-dopamine is involved in multiple pathways in the brain
dopamine
-key functions
-the four pathways
-key importance in many functions , including reward, movement and the release of hormones
-four pathways
-nigrostriatal
-tuberoinfundibular
-mesocortical
-mesolimbic
dopamine: the tuberoinfundibular pathway
-shortest pathway
-moves from arcuate nucleus of the hypothalamus to the pituitary gland
-has a restraining affect on the gland
-influences release of hormones into the blood stream
-eg growth hormone, adrenocorticoids, prolactin (production of milk)
-pituitary gland further controls hormone release
dopamine: the nigrostriatal pathway
-pathway from substantia nigra to striatum
-involved in the basal ganglia loop and the initiation of movement
-the pathway affected in Parkinson’s disease
dopamine : the mesocortical pathway
-starts ventral tegmentum at the brain stem to frontal lobes
-involved in motivation and emotional responses
-decreased levels of dopamine in this pathway are thought to be associated with the negative symptoms of schizophrenia
-apathy, listlessness, poverty of speech
dopamine : the mesolimbic pathway
- Ventral tegmentum to the limbic system, via nucleus accumbens,amygdala, hippocampus and medial prefrontal cortex
- Associated with feelings of rewardand desire
- Implicated in addiction and depression
- Hyperactivity of dopamine associated with the positive symptoms of schizophrenia (e.g. delusions,hallucinations)
Schizophrenia
a psychotic disorder involving disturbances of thought, emotion and behaviour
literally a ‘split mind’ (but not split personality)
-‘fragmented thinking’
-‘a disconnect between a persons subjective experiences and objective reality’
symptoms of schizophrenia
Positive symptoms = presence of abnormal experiences & behaviour (e.g. hallucinations, delusions,disorganized speech & behaviour)
- Negative symptoms = absence of normalexperiences & behaviour (e.g. lack of emotion, apathy,anhedonia, social withdrawal, poverty of speech)
- Cognitive symptoms = broad impairments in attention,working memory, episodic memory, executive functions
the dopamine hypothesis of schizophrenia
-how does dopamine link to schizphrenia
-the link between dopamine and schizophrenia came about by observing side effects from other drugs
-dopamine agonists (eg amphetamine, cocaine
-producing schizophrenia like symptoms in previously healthy individuals
-worsen symptoms in people who have been diagnosed with a psychotic disorder
what does the dopamine hypothesis of schizophrenia say
-psychosis (positive symptoms) are caused by excessive levels of dopamine
dopamine agonists
-amphetamine and cocaine
-what do they do
-what does chronic abuse of this do
-they increase release and or block reuptake of dopamine
-amphetamine has dual action, it can increase how much dopamine is release in the first place
-chronic abuse of these can cause schizophrenua like symtoms (paranoia, delusions,hallucinations,stereotyped repetitive and complusive behaviours
dopamine agonist
L dopa
-an artificial version of a dopamine precursor
-used to treat parkisons disease
-high dose of this can increase amounts of dopamine made so cause dopamine like symptoms in patients
dopamine antagonists
anti psychotics
-anti psychotics used to treat positive (i.e psychotic) symptoms like hallucinations and delusions
-chlorpromazine/thorazine
-haloperidol
antipsychotic have no effect on negative symptoms, and can actually make these worse
-they block dopamine receptors (specifically type D2) preventing their activation
what about negative symptoms schizophrenia
Original formulation of the dopamine hypothesis didn’t address negatives symptoms
- Current versions regard schizophrenia as a disorder of dopamine regulation –
- Positive symptoms are linked to excessively high levels of dopamine, especially in basal (‘deep’) forebrain areas
- Negative symptoms may reflect abnormally low levels of dopamine (&reduced brain activity) in PFC – this would explain why antipsychotic drugs can worsen negative symptoms
dopamine regulation
One version of this idea (e.g.Davis et al, 1991) sees dopamine under-activity in prefrontal cortex as the primary deficit in schizophrenia
- This then leads to reduced inhibitory control over dopamine producing neurons in basal forebrain areas(‘mesolimbic system’)
- ‘Runaway’ dopamine release in basal forebrain /mesolimbic areas then leads to positive symptom
schizophrenia
complementary therapies
-antipsychotic drugs don’t necessarily prevent hallucinations or delusional thoughts
-but can make them feel less important and less distressing
psychotherapy (eg CBT) may be required to actually change delusional beliefs
but this is more likely to succeed if combined with an antipsychotic to weaken ‘attachment’ to delusional beliefs
-treatment for negative symptoms may involve medication but has also been found to benefit from CBT (eg elis et el 2013)
the side effects of dopamine treatments
agonists
antagonists
Due to the widespread dopaminergic synapses, any treatment involving these dopamine receptors will have the potential for side effects
- Agonists of dopamine: Drugs for Parkinson’s treatment can cause hallucinations, psychosis; impulse control disorders- compulsive gambling, shopping, binge eating (acting on the mesolimbic and mesocortical pathways)
- Antagonists of dopamine: Anti-psychotics can cause Parkinsonism(Parkinson’s like symptoms); tremors and dystonia (acting on the nigrostriatal pathway)Increased secretion of prolactin, leading to galactorrhea (unusual secretion of breast milk) (acting on the tuberoinfundibular pathway)
unconventional neurotransmitter
Must be present in pre-synaptic terminal, stored in synaptic vesicles. NO
* These NTs are not stored in the pre-synaptic terminal
- Must be released into the presynaptic cleft in response to Ca2+increase. NO
- They are not released by exocytosis and may not be released from the terminal at all
- Must have an effect on specific receptors on the post-synaptic neuron. NO
- They may be used in retrograde signalling: the post-synaptic cells ignals back to the pre-synaptic cell
endocannabinoids
Produced ‘on-demand’ from the cell membrane (not stored in vesicles)
- Retrograde signalling: post-synaptic cells signal to pre-synaptic neurons
- Their release reduces the amount of conventional neurotransmitters released for a short period
- Allows post-synaptic cell to control its ‘incoming traffic’
- Role in synaptic plasticity (Vaughan & Christie, 2005)
- Involvement in memory, regulation of appetite, homeostasis
