CAL Flashcards
What are the peptide neurotransmitters of the CNS?
Substance P
Cholecystokinin
Enkephalins
Somatostain
What are the non-peptide neurotransmitters of the CNS?
Noradrenaline Acetylcholine GABA Glutamate Dopamine 5-HT
Give the sequence for the steps involved in neurotransmitter transmission (LONG)
Neurotransmitter synthesis: peptide synthesis occurs in the nucleus and non-peptide synthesis occurs in the pre-cursor terminals - active uptake of the neurotransmitters into the pre-synaptic neurone
The neurotransmitters are then stored within vesicles
Neurotransmitters are released when stimulated by an action potential and they invade the terminal - depolarisation of the neurone occurs
Neurotransmitter presence stimulates the opening of the voltage gated Ca2+ channels and Ca2+ ions enter the terminal
There is an increase in the intracellular concentration of Ca2+ - causes the storage neurotransmitter vesicles to move towards and fuse with the terminal membrane and they are released across the synapse
Neurotransmitters diffuse across the synaptic cleft and bind to receptors on the post synaptic membrane - the action potential is transmitted
Termination occurs via reuptake of the non-peptide neurotransmitters at the pre-synaptic terminal, metabolic degradation and diffusion of neurotransmitters away from the synapse
How long is the typical synaptic delay between the depolarisation of the pre-synaptic terminal to the onset of the post-synaptic response?
0.5 seconds
What are the different post synaptic receptor types?
Ligand gated ion channels is the major one - entrance for amino acids - two neurotransmitters generally must bind for this channel to open
G-protein coupled receptors - single polypeptide chain spanning the membrane seven times - has long lasting effects and works via the displacement of GDP by GTP which then activate the effector protein
What different factors can result in the depolarisation of a membrane?
Excitatory neurotransmitters binding to and activating pre-synaptic fibres
Influx of Ca2+
Closing of K+ channels
Efflux of Cl-
What different factors can result in inhibitory post synaptic potentials (IPSPs)?
Inhibitory neurotransmitter release
Opening of K+ channels
How is dopamine synthesised?
Amino acid tyrosine uptake into nerve terminal
Enzyme tyrosine carboxylase converts tyrosine to DOPA
Enzyme DOPA decarboxylase converts DOPA to dopamine
NB. L-dopa is formed from L-tyrosine
How and where is dopamine stored and what is this dependant on?
Taken up via an active process requiring ATP and is stored in presynaptic vesicles
Storage is dependant on the vesicular monoamine transporter 2 (VMAT2)
Name some neurological conditions in which dopaminergic pathways are involved
Parkinson's disease Schizophrenia Huntington's disease Addiction Chronic pain syndromes
How does dopamine release from the synapse occur?
This is initiated by depolarisation at the presynaptic terminal via an action potential - influx of Na+ carried by the action potential causes the opening of voltage gated N-type calcium channels at the synaptic membrane into the synaptic cleft
Which receptors can dopamine bind to and activate?
Can diffuse across synaptic cleft and bind to and activate post synaptic dopamine receptors D1 or D2
OR can bind to and activate pre-synaptic autoreceptors D2
How is dopamine inactivated once it has bound to its receptors?
Some of the dopamine leaves the synaptic cleft via diffusion
Some is taken up back into the nerve terminal via active transport - this is known as ‘reuptake’ and involves a protein channel
Following reuptake, the dopamine is then either stored into vesicles ready for release again
OR degraded to homovanilic acid (HVA) via COMT and to DOPAC via MAO
What is homovanillic acid (HVA)?
This is a major metabolite of dopamine and its levels are used to determine the dopamine turnover
What type of receptors are dopamine receptors and what are the different types?
They are g-protein coupled receptors and are classified into the D1 and D2 receptor type families
D1 family: D1 and D5
D2 family: D2, D3 and D4
What are the actions of the D1 receptor family and where is each type found?
These receptors are post synaptic and activate adenylate cyclase
D1:
Found mainly in caudate-putamen, nucleus accumbens and olfactory bulbs
Lesser amounts in the cerebral cortex, limbic system and hypothalamus
D5:
Found in much lower concentrations than D1
Found highest in the hippocampus and the hypothalamus (limbic regions)
What are the actions of the D2 receptor family and where is each type found?
These have the following effects: Inhibit adenylate cyclase Activate K+ channels Decrease Ca2+ conduction Potentiate ATP-mediated arachidonic acid release
D2:
Found in the caudate-putamen, nucleus accumbens and olfactory bulb
Mainly post-synaptic but can be presynaptic
D3:
Less abundant
Found mainly in limbic areas
Mediate control of emotional and cognitive functions
D4:
Found in frontal cortex, midbrain, amygdala and medulla
What is the main dopaminergic pathway of the brain?
Nigrostriatal pathway
DOPAMINE DRUGS IN DRUG BANK
DOPAMINE DRUGS IN DRUG BANK
Give the states of serotonin synthesis and include the enzymes that catalyse the reactions
Tryptophan –> 5-HTP
Via tryptophan hydroxylase
5-HTP –> 5-HT
Via Dopa Decarboxylase
5-HT is then stored in vesicles
How is the action of 5-HT inactivated once it has bound to receptors at the post-synaptic membrane?
Taken up into vesicles
Degraded by MAO and product reduced to 5-hydroxytrypophol
Degraded by MAO and product oxidised to 5-HIAA
Where are 5-HT cell bodies located?
Located in the raphe nuclei in the pons and the upper brainstem - split to caudal raphe nuclei and rostral raphe nuclei
Where are the caudal and rostral raphe nuclei located and where to 5-HT neurones project to from here?
Caudal raphe nuclei - located in the lower brain stem - neurones project to medulla and dorsal horn of the spinal cord
Rostral raphe nuclei - located in the upper brainstem - neurones project to the forebrain structures
What is important about the 5-HT pathways?
These are the most extensive of all the monoaminergic pathways of the brain
They have a characteristic pacemaker activity - high during waking arousal and low during sleep
What receptor types are the 5-HT receptors?
There 7 subtypes of 5-HT receptors and they are all G-protein coupled receptors apart from 5-HT3 which is a ligand gated ion channel
What is meant by drug dependence and what are the two types of drug dependence?
The craving or need to take a drug, experienced during periods of abstinence
Psychological
Physical
What are the characteristics of psychological drug dependance?
Give some examples of these drugs
Compulsion, need or craving to take a drug
Produced by all types of drugs of dependence
Long lasting
Produced by the limbic system of the brain
Cocaine
Amphetamine
Nicotine
Caffeine
What are the withdrawal symptoms in psychological dependence?
These symptoms are emotional rather than physical: Mood changes Anxiety Agitation Feeling unable to cope
What different regions of the brain compose the limbic system?
Composed of a number of forebrain structures: Amygdala Nucleus accumbens Striatum (caudate and putamen) Cingulate gyrus
What are the characteristics of physical drug dependance?
Give some examples of drug types which produce symptoms of physical dependence
Characterised by obvious physical symptoms only - there are symptoms of illness upon withdrawal
Relatively short lived - has a duration of about two weeks
Opiates
Barbiturates
Benzodiazepines
Alcohol
What is meant by drug tolerance?
This is when the effects of the drug diminish with repeated, excessive usage
What are the two different types of drug tolerance?
Acute tolerance
Chronic tolerance - cellular tolerance (pharmacodynamic) and pharmacokinetic (metabolic) tolerance
What is acute tolerance?
Short lasting tolerance
Occurs when a drug acts at a receptor which becomes desensitised at the first dose e.g. nicotine
What is cellular tolerance?
Type of chronic tolerance - associated with pharmacodynamic changes
Occurs due to neuroadaptive changes in the brain resulting in diminished responses to the drug
Occurs following chronic exposure to a drug
What is pharmacokinetic tolerance?
How can this be overcome?
Type of chronic tolerance - occurs due to an increase in the metabolism of this drug type via an induction of liver enzymes responsible for the degradation of the drug
This results in a diminished response per a dose of the drug
Can be overcome by an increasing dose of the drug
What are the different types of drugs that can cause dependance?
Give examples of each one
Psychomotor stimulants - these cause excitation and stimulation of brain activity, often accompanied by increased locomotion e.g. nicotine, amphetamine, cocain
CNS depressants - these have an overall effect to depress brain activity and cause sedation
What receptors does nicotine act on and where are these located?
Nicotinic acetylcholine receptors in the brain
In the nucleus accumbens, the ventral tegmentum, hippocampus and the reticular formation
What receptors do benzodiazepines act on and where are these located?
What are benzodiazepines used to treat?
On GABAa receptors in the raphe nuclei and reticular formation
Used to treat anxiety - quickly replaced barbiturates due to adverse effects
What receptors do barbiturates act on and where are these located?
What are barbiturates used to treat?
On GABAa receptors in the raphe nuclei and reticular formation
Used to treat anxiety - quickly replaced by barbiturates due to adverse effects
What receptors does alcohol act on and where are these located?
Acts on voltage gated Ca2+ channels - selectively reduces the activity of this to then reduce neurotransmitter release
Frontal cortex and reticular formation
What receptors do opiates act on and where are these located?
Mu type receptors
Kappa type receptors
Delta type receptors
Nucleus accumbens Periaqueductal grey Ventral tegmentum Reticular formation Area postrema
What receptors does cocaine act on and where are these located?
Dopamine uptake transporter - inhibits the action of this
Nucleus accumbens
Hypothalamus
Reticular formation
What receptors does caffeine act on and where are these located?
Inhibit phosphodiesterase enzyme
Inhibit adenosine type (A1) receptors
These result in an increased level of cyclic AMP
Nucleus accumbens
Reticular formation
What receptors do amphetamines act on and where are these located?
Competes with dopamine for the dopamine uptake transporter and so dopamine uptake is competitively inhibited
Nucleus accumbens
Hypothalamus
Reticular formation
