neurotransmitters + hormones involved in psychiatry - lecture

what are the main 2 types of ways that neurotransmitters signal?

- G-protein linked receptors e.g. Gs, Gi, Gq

- ligand gated ion channels

which signalling pathway is most important in psychiatry?

G-protein linked receptors

how do ligand-gated ion channels work?

- flux of ions causes an action potential

- calcium channels open and calcium acts on calcium/calmodulin dependent protein kinase

how do G-protein linked receptors work?

- through secondary intracellular messenger cAMP

- stimulates 'early genes' in nucleus to cause subtle changes activity of the neurone (rather than stimulating an action potential)

what type of receptor are muscarinic receptors?

G-protein coupled

what do G-proteins coupled to?

adenylate cyclase

are G-protein coupled receptors excitatory or inhibitory?

can be both

what happens when G-proteins are bound to adenylate cyclase in an excitatory state?

- increases cAMP

- increase gene expression of the cell

what happens when G-proteins are bound to adenylate cyclase in an inhibitory state?

- decreases CAMP

- decreased gene expression of the cell

what is epigenetics?

the study of how the environment affects which genes are expressed

what are some of the main neurotransmitters in psychiatry?

- amino acids - glutamate + GABA

- ACh

- monoamines

- neuropeptides - opioids

are glutamate receptors excitatory or inhibitory?

excitatory

are GABA receptors excitatory or inhibitory?

inhibitory

what are some examples of monoamines?

- histamine

- dopamine

- noradrenaline

- 5-hydroxytryptamine (serotonin)

- melatonin

what is dopamine activated from?

L-tyrosine

what is L-tyrosine converted to and by what?

converted to L-DOPA by tyrosine hydroxylase (this is the rate-limiting step)

what is L-DOPA converted to and by what?

converted to dopamine by DOPA decarboxylase

what can dopamine also be converted into?

noradrenaline

what can noradrenaline be converted into?

adrenaline

what happens in the pre-synaptic neurone after dopamine has been produced?

packaged into vesicles by vesicular monoamine transporter (VMAT) and released into synaptic cleft

what are the options for what happens to dopamine in the synaptic cleft? (4)

1) bind to D1-D5 receptors (Gs on postsynaptic neurone)

2) bind to D2-D3-D4 receptors (Gi/o on postsynaptic neurone)

3) bind to D2-D3 autoreceptor on presynaptic neurone

4) broken down by monoamine oxidase A or B (MAO-A or B) or COMT

what happens if dopamine binds to D1-D5 (Gs) receptors on the postsynaptic neurone?

EXCITATORY:

- increases adenylate cyclase expression

- increases cAMP expression

- increases gene expression

what happens if dopamine binds to D2-D3-D4 (Gi/o) receptors on postsynaptic neurone?

INHIBITORY:

- decreases adenylate cyclase expression

- decreases cAMP expression

- decreases gene expression

what happens if dopamine binds to D2-D3 autoreceptors on presynaptic neurone?

self-regulating - acts as a negative feedback loop to reduce dopamine vesicle production

what happens if dopamine is broken down by MOA-A or B?

gets transported to presynaptic neurone to be reused

what are the options for noradrenaline when it enters the synaptic cleft? (5)

1) bind to α1-adrenergic receptors on postsynaptic neurone

2) bind to α2-adrenergic receptors on postsynaptic neurone

3) bind to β-adrenergic receptors on postsynaptic neurone

4) bind to α2-adrenergic autoreceptors on presynaptic neurone

5) gets taken up into presynaptic neurone by noradrenaline reuptake transporter (NET)

what happens when noradrenaline binds to α2-adrenergic receptors on postsynaptic neurone?

INHIBITORY:

- decreases adenylate cyclase

- decreases cAMP

- decreases gene expression

what happens when noradrenaline binds to α1 or β-adrenergic receptors on postsynaptic neurone?

EXCITATORY:

- increases adenylate cyclase

- increases cAMP

- increases gene expression

which parts of the presynaptic neurone can neurotransmitters bind to for autoregulation?

- axon terminal (presynaptic end)

- somatodendritic end

what happens with autoregulation at the axon terminal?

binding autoreceptors causes decreases release of the neurotransmitter

what happens with autoregulation at the somatodendritic end?

binding to autoreceptors causes a reduced likelihood for the neurone to fire

what is 5-HT derived from?

tryptophan

what are the options for 5-HT when it is released into the synaptic cleft?

1) bind to 5-HT1 receptors on postsynaptic neurone

2) bind to 5-HT2 receptors on postsynaptic neurone

3) bind to 5-HT3 receptors on postsynaptic neurone

4) broken down by monoamine oxidase (MAO)

5) binds to 5HT1 autoreceptors on presynaptic neurone

what happens when 5-HT binds to 5-HT1 receptors on postsynaptic neurone?

INHIBITORY

what happens when 5-HT binds to 5-HT2 receptors?

EXCITATORY (LHD and magic mushrooms)

what happens when 5-HT binds to 5HT1 autoreceptors on presynaptic neurone?

INHIBITORY - autoregulation via a negative feedback loop

what happens when 5-HT binds to 5HT3 receptors on postsynaptic neurone?

EXCITATORY - linked with nausea

what is an example of monoamines regulating each other?

when noradrenaline (na) and 5-HT neurones are laid close to each other, the na neurone can interact with the 5-HT neurone in the raphe nucleus of the brain

where are the α1 and α2-adrenergic receptors found on the 5-HT neurone?

α1 - found on cell bodies in the raphe nucleus

α2 - found on nerve terminals in the cortex

what happens in this interaction between na neurones and 5-HT neurones?

- when there is increased na release at cell body end, they bind to α1 receptors and cause EXCITATION of 5-HT neurones

- when there is increased na release at the nerve terminals in the cortex, they bind to α2 receptors and cause INHIBITION of 5-HT neurones

where do dopamine projections originate from?

ventral tegmentum (midbrain)

where do noradrenaline projections originate from?

locus coeruleus (pons)

where do 5-HT projections originate from?

raphe nucleus (medulla)

what are the general functions of dopamine? (6)

- cognition and memory

- mood

- motivation

- motor control

- reward (addictions)

- sexual function

what are the general functions of noradrenaline? (6)

- cognition and memory

- anxiety

- sympathetic ns

- wakefulness and attention

- hunger

- emotional memory

what are the general functions of 5-HT? (7)

- appetite

- mood

- emotion

- arousal

- body temp regulation

- sensory perception

- sleep

what circuits are useful to view in neuroimaging for depression?

- amygdala - emotions

- nucleus accumbens - rewards

- ventromedial prefrontal cortex - processing emotion

- dorsolateral prefrontal cortex - cognition

what neuroimaging technique can be used to see which circuits are activated?

FMRI - function MRI

what happens to the HPA axis in chronic stress?

excessive glucocorticoid release from zona fasciculata

what does excessive glucocorticoid release cause?

hippocampus atrophy

what does the hippocampus normally do in the HPA axis?

negative feedback loop to the hypothalamus when glucocorticoid release is high

what does hippocampus atrophy cause?

chronic activation of HPA axis - no negative feedback loop

what eventually happens to glucocorticoid receptors?

become desensitised to ACTH

what happens when glucocorticoid receptors become desensitised?

increased serum cortisol - leads to chronic inflammation

why is some stress good?

to develop resilience

why is significant stress e.g. child abuse negative?

can sensitise brain circuits, leaving them more vulnerable rather than resilient

what is a CTSC loop?

corticothalamostriatocortical

what is the CTSC loop running between?

- dorsolateral prefrontal cortex

- striatum

- thalamus

what is the anxiety theory linked with the CTSC loop?

in anxiety this loop is overloaded and it leads to worry

what is the CTSC loop regulated by?

- 5-HT

- GABA

- dopamine

- noradrenaline

- glutamate

- voltage gated ion channels

what is the stress-diathesis model?

- some individuals have a genomic predisposition (risk genes) to psychiatric disorders

- normal life stressors can cause activation of these risk genes leading to over or under reactivity of circuits

what does hyperactivation of these circuits lead to?

anxiety

what does hypoactivation of these circuits lead to?

depression