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CNS drug effect act on?
specific receptors that modulate synaptic transmission
What are the two types of nerve membrane channels?
voltage gated and ligand gated.
Transmitters in voltage channels
Ligand gated receptors AKA
Binding of what activates ligand gated channels
- Non sensitive to membrane voltage
- 1-Receptor binds a neurotransmitter, activates a G protein(beta gamma subunit) which in turn open an ion channel. Microdomain
- 2- modulate voltage gated channels indirectly by release of a diffusible second messenger. Over significant distance.
Two types of voltage gated channels G protein activate
- 1- calcium: inhibit channel function, presynaptic inhibition
- 2- potassium: Activate post synaptic channels allowing K to enter the neuron. This causes slow inhibition.
Diffusible second messengers activation?
G proteins released by binding of neurotransmitter activate an inter-membrane enzyme (ex: adenylyl cyclase) that produces the second messenger (ex: cAMP)
Length of activation of ionotropic receptors to metabotropic receptors?
- Ionotropic: brief effect
- metabotropic: tens of seconds to minutes
Promotes the fusion of synaptic vesicles with the presynaptic membrane?
Intraterminal calcium concentration.
Time delay from the arrival of the presynaptic action potential to the onset of post synaptic response?
0.5 ms, due to the release process and opening of Ca channels
Two types of synaptic pathways?
inhibitory and excitatory of the post synaptic membrane by ionotropic receptors.
When an excitatory neurotrasmitter is bound?
The cell is depolarized
Action of anoaxonic synapses?
- act on pre synaptic terminal to reduce the amount of transmitter released.
- Found mostly in the spinal cord but receptors are on pre synaptic terminals in the brain, though that neighboring neurotransmitters spill out of the synaptic terminal and bind to these receptors. This will inhibit release of neurotransmitter limiting the activation of multiple pathways at one in the brain.
Presynaptic category target?
synthesis, storage, metabolism, and release of neurotransmitter
Amphetamines effect on presynaptic terminal
causes the release of catecholamines from adrenergic synapses.
blocks the release of neurotransmitters
causes the release of the peptide substance P from sensory neurons
Nuroglia can uptake neurotransmitter
Removal process of neurotransmitters from the synapse
- taken up by presynaptic terminal and neuroglial cells
- enzimatically destroyed
Drugs can work on any step of metatropic receptors
Ex. block the formation of cAMP to inhibit or block the metabolism of cAMP to prolong AP
Identification of neurotransmitter in the CNS?
- Localization - if the neurotransmitter is in the presynaptic terminal
- Release - is the neurotransmitter in the extracelluar fluid of the area.
- Synaptic mimicry - does the application of the suspected neurotransmitter produce the same response as nerve stimulation.
Two neuronal systems of the CNS?
- 1- Hierarchical system
- 2 - non specific or diffuse.
Hierarchial system involvement
pathways of sensory and motor control
Two types of cells in the nucleus of hierarchal systems
- 1 - relay or projection. Transmit signals over long distances. excitatory, glutamate
- 2 - local circuit neurons, short distance, inhibitory, GABA or glycine. synapse on cell bodies of projection neurons. Feed back and feed forward pathways.
In the retina and olfactory bulb local circuit neurons lack?
axon, neurotransmitter is released from the dendrite. they release in a graded fashion without AP stimulus.
Inhibits GABAa receptors ans causes convulsions.
The brain has many pathways but only a few neurotransmitters so manipulating one can cause multiple effects.
Examples of non specific neurotransmitters
- monoamines - epinaphrine, norepinephrine, serotonin, dopamine
- effects are determined by the location of receptors and not by the release site.
- Act on metatrohic receiptors so have a long lasting effect.
Glutimate clearance from the synaptic terminal?
Glutimate is taken up by glial cells and converted to glutamine by glutamine synthetase, glutamine is then released and taken up by presynaptic terminals and converted back to glutamate by glutaminase.
- ionotrophic - 4 subtypes - AMPA, KA, NMDA
- metabotrophic - inhibatory
increases the Ca permeability, excitatory
- heterotetromers made of GluR1-R4
- mostly GluR2
- excitatory, permiable to Na and K
KA receptor location
hippocampus, cerebellum, spinal cord
Glutamine receptors are G-protein coupled, 3 groups
- I- located post synaptically, excitability by activating non specific cation channels.
- II and III are presynaptic and are inhibitory blocking Ca channels and lowering the amount of neurotransmitter released. Only activated when the amount of glutamate rises during repetitive stimulation (self down regulation)
Thickening of post synaptic membrane
post synaptic density, NMDA in the middle and Ampa at the periphery.
Location of glycine releasing interneurons?
- spinal cord and brain stem
Two subsets of GABA receptors
- GABAa - inotropic, fast receptors, selectivly permiable to Cl
- GABAb - metatropic, slow receptors, coupled to G proteins, mostly located on presynaptic and activated by the spill over of GABA self inhibiting GABA neurotransmitter release. Inhibit adenyly cyclase.
CNS response to Ach?
- mediated by a large family of G protein coupled muscarinic receptors
- M1- slow excitation, works opposite of most by decreasing the membrane permeability to K.
- large function in memory by creating long term potentials
- M2 are inhibitory, open K channels.
PNS response to Ach?
Nicotinic receptors, opening of fast sodium channels
- dopamine, morepinephrine, seratonin
- cocaine blocks the reuptake of dopamine and norepinethrine
- five subunits or receptors D1-D5
- two classed D1 like D1 and D5
- D2 like D2 D3 D4
- exerts a slow inhibitory action on the CNS, opens K channels
- noradronergic neurons
- hyperpolorizes neurons by increasing K conductance, mediated by Alpha 2
- can indirectly excite neurons by inhibiting the inhibitory neuron of it.
- pathways originate in the pons and upper brainstem
- inhibitory through K conductance
excitatory post synaptic potention
- NO is made by nitric oxide synthase NOS.
- NOS is activated by calcium-calmodulin, NMDA receptors increase the amount of Ca in a neuron and increase the amount of NO
- THC effects the brain by activating cannabinoid receptor CB1.
- CB1 endogenous ligands are not stored but synthesized in response to depolarization and Ca influx
- can act retrograde, post synaptic will release and they will bind and inhibit presynaptic. Effect memory, cognitive function, and pain in this mannor.