Neuropharmacology Intro Flashcards
Cholinergic transmission is important for
cognitive function, sensitization to incoming stimuli, movement control
Describe the difference between nACh receptors and mACh receptors.
nAch receptors are ligand gated cation channels whereas mACh receptors are GPCRs
Where are cholinergic neurons?
concentrated in the basal forebrain and pons, but numerous cholinergic interneurons are found int he cortex and basal ganglia
Dopamine transmission is important for
natural rewards and motor function
Problems in dopamine transmission is implicated in diseases or disorders such as
schizophrenia, parkinsons disease, addiction, depression and ADHD
Two varieties of GPCR dopamine receptors
D1-type (D1 and D5) and D2-type (including D2, D3, and D4)
Where are dopamine neurons?
situated in the midbrain, either the ventral tegmental area or the substantia nigra pars compacta
Norepinephrine activates
adrenergic receptors (GPCRs), ainly alph1 and/or alpha2 in the CNS
NE is involved in
memory, pain transmission, and salience
NE transmission is altered in
depression and addiction
NE neurons are located in
the pons, specifically the locus coeruleus
Serotonin activates
either 5-HT3 ligand gated cation channels, or GPCR-type 5-HT receptors
Serotonin is important in
reward, learning, and mood/affect, and is thought to play a major role in depression and possibly schizophrenia
Where are serotonin neurons located?
in the midbrain/pons, specificially inthe raphe
GABA is produced from
glutamate
Major inhibitory neurotransmitter in the CNS
GABA
GABA activates
GABAA type ligand gated Cl- channels, and GABAB and GABAC receptors which are GPCRs
Where is GABA produced?
produced throughout the brain by numerous cell types, and is altered in many disorders, including epilepsy, muscle spasticity, and addictions such as alcoholism
Main excitatory neurotransmitter in the brain
Glutamate
What does glutamate bind to?
Ion channels (AMPA, NMDA) and GPCRs (mGluRs)
Glutamate may be a useful pharmacologic target in which diseases?
epilepsy and schizophrenia
Two categories of ligand-gated
ion channels and G protein coupled receptors
HCN channels are
cyclic nucleotide-gated channels
Ligand that modifies HCN channels
cAMP or cGMP
Describes what happens when a GIRK channel is activated
activating a GPCR coupled to a GIRK channel results in enhanced outward K+ currents, which serve to hyperpolarize the membrane potential and keep the cell “clamped” near the equilibrium potential for K+, which is around -90mV
Where are NT transporters usually located?
usually located presynaptically where they remove NT molecules from the synaptic cleft and return them back inside the presynaptic terminal
Which ion do most neurotransmitter transporters use?
most are Na+ symporters, making them electrogenic
How is electrical activity altered by drugs
by directly affecting the function of ion channels, or indirectly by changing the overall number or function of important targets in the CNS
Where do drugs act?
NT synthesis, NT storage, NT reuptake, autoreceptors, presynaptic receptors, postsynaptic receptors
What will decreasing the action of NT transporters do?
will decrease re-uptake, and therefore prolong the action of drugs released into the synaptic cleft
Difference between blocking a presynaptic autoreceptor versus a postsynaptic receptor.
Blocking an inhibitory autoreceptor on the presynaptic side will increase activity of the synapse whereas blocking a receptor on the postsynaptic side can decrease the output of a synapse
BBB formed by
tight junctions between endothelial cells, which contributions from astrocytes as well
BBB typically restricts
microscopic objects (bacteria, viruses) and hydrophilic molecules, but allows small hydrophobic molecules (hormones, gases) and glucose
Two ways drug affinity for receptors is measured
saturation assays and competition assays
Describe saturation assays
directly measures drug affinity for receptor, but require the test drug to be radiolabeled, therefore a large amount of prior knowledge about the drug and its candidate receptor must be in hand
What is Kd?
the concentration of the radioligand where 50% of receptors are bound
What is Bmax?
the total number of receptors in a preparation
Describe competition assays
they’re done with a known, labeled drug and unlabeled test drugs which are used to compete off the labeled drug. Provides an indirect assessment of affinity of the drug for the receptor because it is measuring how well it can displace the labeled drug
What is the Ki?
the concentration of drug where 50% of the radioligand is displaced
Functional Assays
Biochemical: enzyme function
Second messenger response assay
Transporter function assay: uptake and/or efflux assay
Patch clamp electrophysiology (ion channel function)
Describe patch clamp electrophysiology
involves placing a glass pipette onto the surface of the cell expressing the channel of interest, followed by forming a high-resistance seal between the glass and the cell membrane
Where do full agonists bind?
binds at the orthosteric binding site where the natural ligand binds, and activates the receptor as well as the natural ligand
Where do partial agonists bind?
binds the receptor and activates it, but can never achieve full activation of the receptor population like a full agonist can - also has antagonist activity
Where do antagonists bind?
bind at the orthosteric binding site, do not have any ability to actiate the receptr on its own, but will prevent the ability of the natural ligand or an agonist to activate the receptor?
What does an inverse agonist do?
reduces the activity of a receptor to levels BELOW what they would be if no ligand is present at all
