lecture 4- neurotransmitters 2 Flashcards
1
Q
neurotransmitters- biogenic amines
A
- dopamine
- serotonin
- histamine
- adrenaline/ epinephrine
- noradrenaline/norepinephrine
- small molecule NTs
- similar structures
- widespread in the brain
2
Q
serotonin in the CNS
A
- 90% serotonergic signalling in the gut
- 10% serotonergic neurons in the brain
- produced in the pons and upper brainstem (raphe nuclei), it has projections to the forebrain
- roles: regulation of mood, appetite and sleep, also involved in memory and learning
3
Q
depression and monoamines
A
- depressions key clinical features:
- intense feelings of persistent sadness, helplessness and hopelessness
- anhedonia (general lack of interest)
- tiredness, lack of energy
- abnormal sleep and eating patterns
- cognitive impairments: concentration, memory, executive functions
4
Q
the monoamine hypothesis
A
- reserpine (hypertension medication)
- reported side effect: symptoms of major depression (Michaels & Gibbon, 1963)
- antagonist of monoamines
5
Q
antidepressants
A
- monoamine oxidase inhibitors (MAOIs)- inhibit the activity of the enzyme MAO that normally breaks down monoamine NTs- dopamine, noradrenaline and serotonin
- tricyclic antidepressants (TCAs) block reuptake of noradrenaline and serotonin- increasing the levels if these two NTs in the synapse
- SSRIs- selective serotonin reuptake inhibitors: first choice for treating depression
- SNRIs- selective noradrenaline reuptake inhibitors
6
Q
serotonin based treatments
A
- selective serotonin reuptake inhibitors (SSRIs) block the channels that allow serotonin to be removed from the cleft
- side effects are still seen:
- due to the high levels of serotonin receptors in the GI tract, side effects of treatments can include weight less, nausea and diarrhoea
- example of SSRIs, prozac, fluoxetine
7
Q
depression = low serotonin?
A
- agonists enhance serotonin action
- thus depression = low serotonin? yes
- moncrieff, 2022: meta-analysis
- no strong evidence for lowered serotonin actions in depressed patients compared to controls
- royal college of psychiatrists (2019)
- stated that saying anti-depressants correct a chemical imbalance is an “over-simplification”
8
Q
anti-depressants are effective for some patients:
A
-Cipriani et al (2018) review/meta-analysis of antidepressants found all studied drugs to be more effective than placebo
- three SSRIs (escitalopram, paroxetine & sertraline) found to have the highest response/lowest drop out rates
9
Q
what other effects might SSRIs have?
A
- beck (1967): cognitive mechanisms causing depression
- negative automatic thoughts
- negative schema
- negative information processing biases
- negative biases in processing
- information recall
- interpretating facial expressions
- distraction by negative stimuli
10
Q
SSRIs can influence cognitions
A
- in depressed participants, following a single dose of SSRIs, we find:
- enhanced recognition of facial expressions (Tranter et al., 2009)
- particularly happiness
- increased recall of positive stimuli in word memory tasks (Harmer et al., 2009)
- no associated increase in self reported mood
11
Q
acute effects
A
- acute effects 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’ (perceptual & attentional) biases are related to ‘high level’ beliefs about self, world & others (Becks dysfunctional schemas)
- importantly, acute cognitive effects occur with no reported change in mood
12
Q
dopamine
A
- produced from tyrosine -> DOPA -> dopamine
- dopamine is involved in multiple pathways in the brain
- it is a key importance in many functions, including reward, movement and the release of hormones
- four pathways:
-nigrostriatal- tuberoinfundibular
- mesocortical
- mesolimbic
13
Q
dopamine: the tuberoinfundibular pathway
A
- arcuate nucleus of the hypothalamus to the pituitary gland
- influences the release of hormones into the blood stream
- eg growth hormone, adrenocorticoids, prolactin (production of milk)
- pituitary gland further controls hormone release
14
Q
dopamine: the nigrostriatal pathway
A
- substantia nigra to striatum
- involved in the basal ganglia loop and the initiation of movement
- the pathway affected in Parkinson’s
15
Q
dopamine: the mesocortical pathway
A
- ventral tegmentum 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 skits
- apathy, listlessness, poverty of speech
16
Q
dopamine: the mesolimbic pathway
A
- ventral tegmentum to the limbic system, via, nucleus accumbens, amygdala, hippocampus and medial prefrontal cortex
- associated with feelings of reward and desire
- implicated in addition and depression
- hyperactivity of dopamine associated with the positive symptoms of schizophrenia (eg delusions, hallucinations)
17
Q
schizophrenia
A
- a psychotic disorder involving disturbances of thought, emotion and behaviour
- literally ‘split mind’-
- ‘fragmented thinking’
- a disconnect between a persons subjective experiences and objective reality
18
Q
symptoms of skits
A
- positive symptoms = presence of abnormal experiences and behaviour (eg hallucinations, delusions, disorganized speech and behaviour)
- negative symptoms= absence of normal experiences and behaviour (eg lack of emotion, apathy, anhedonia, social withdrawal, poverty of speech)
- cognitive symptoms= broad impairments in attention, working memory, episodic memory, executive functions
19
Q
the dopamine hypothesis of skits
A
- link between dopamine and skits?
- dopamine agonists (eg amphetamine, cocaine)
- produce skits like symptoms in previously healthy individuals
- worsen symptoms in people who have been diagnosed with a psychotic disorder
- the dopamine hypothesis of skits: psychosis (positive symptoms) are caused by excessive levels of dopamine)
20
Q
dopamine agonists
A
- amphetamine & cocaine: increase release and/or block reuptake of dopamine
- chronic abuse can cause skits-like symptoms (paranoia, delusions, hallucinations, stereotyped repetitive & compulsive behaviours) in non-schizophrenics
- amphetamine psychosis first described in 1950s
- L-dopa: dopamine precursor
- used to treat Parkinson’s disease since early 1960s
- high doses can cause skits like symptoms in patients
21
Q
dopamine antagonists
A
- anti-psychotics used to treat positive (ie psychotic) symptoms like hallucinations and delusions
- chlorpromazine/thorazine
- haloperidol
- but little or no effect on negative on negative symptoms, and can actually make these worse
- block dopamine receptors (specifically type D2) preventing their activation
22
Q
what about negative symptoms
A
- original formulation of the dopamine hypothesis didnt address negative symptoms
- current versions regard skits 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
23
Q
dopamine regulation
A
- one version of this idea (eg Davis et al, 1991) sees dopamine under-activity in prefrontal cortex as the primary deficit in skits
- 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 symptoms
24
Q
complementary therapies
A
- antipsychotic drugs dont 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
25
Q
the side effects of dopamine treatments
A
- due to widespread dopaminergic synapses, any treatment involving these receptors will have the potential for side effects
- agonists of dopamine: drugs for parkinsons 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 (parkinsons 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)
26
Q
definition of a neurotransmitter
A
-needs to be present in the presynaptic terminal
- needs to be released when an action potential arrives and calcium moves into the synapse
- needs to be something on the post synaptic membrane that it can bind to, a specific receptor that it fits with
27
Q
unconventional neurotransmitters
A
- these NTs are not stored in the pre-synaptic terminal
- they are not released by exocytosis and may not be released from the terminal at all
- they may be used in retrograde signalling: the post-synaptic cell signals back to the pre-synaptic cell
28
Q
endocannabinoids
A
- 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
29
Q
endocannabinoids cont
A
- anandamide (ANA)
- endocannabinoid synthesised in the body
- binds to cannabiniod receptors CB1 and CB2 in the CNS and PNS
- effects on hunger, sleep, memory, identification of novelty
30
Q
agonists of cannabinoid receptors
A
- cannabinoid receptors are the molecular target of the tetrahydrocannabinol (THC), the psychoactive component of marijuana
- CB1 receptors in the neocortex: effects on perception
- CB1 receptors in the basal ganglia: effects on motor behaviour
- CB1 receptors in the hippocampus: effects on short-term memory
- CB1 receptors in the hypothalamus: effects on appetite
31
Q
uses of THC
A
- anti-emetic properties (inhibits vomiting) are useful in the treatment of cancer patients on chemotherapy (Fride et al., 2006; Mechoulam et al., 2006)
- eases symptoms (eg muscle stiffness) in multiple sclerosis (Zajicek et al., 2012)
- recent review into possibility of using THC to treat mental health conditions suggests that this aspect is not well supported (black et al., 2019)
- risks of developing schizophrenia with adolescent use, slowing in cognitive functions (Borgelt et al., 2013) (causality debated here)
32
Q
antagonists of cannabinoid receptors
A
- rimonabant
- blocks CB1 receptor
- affects appetite, reducing food intake
- initially used as a weightloss drug
- withdrawn worldwide in 2008 due to a psychiatric side effects
increases in depression, anxiety
33
Q
antagonists of cannabinoid receptors cont
A
- CBD aka cannabidiol
- as an antagonist at CB1 receptors, there is interest in using CBD to treat psychosis (Bhattacharyya et al., 2015, 2018)
- some evidence that CBD might interact with certain medications (Levinsohn and hill, 2020)
