Chapter 11: Introduction to CNS pharmacology Flashcards
the CNS is made of a network of ___ and ___cells that carry signals throughout the brain and through the body
neurons and supporting cells
neurons send signals to each other by release of ___ at synapses
neurotransmitter
the actions of neurons are energy intensive and must be tightly regulated to have efficient ___
signal transduction
support cells include astrocytes, which are glial cells that help remove __, supply___ and make up part of the ___
neurotransmitter form synapses; nutrients; bbb
compared to body BV, vessels entering the CNS are much ___ permeable
less
the BBB is made of ___ and ___
endothelial tight junctions and the end feet of astrocytes (aka astroglia)
the arrangement of the BBB helps prevent ____ of most polar molecules and ____ are required to bring many required substances such as glucose into the CNS
passive diffusions; transporters
what type of molecules are capable of crossing the BBB by passive diffusion?
very small lipophilic
does low penetration mean no penetration in the CNS?
no
L-DOPA and glucose are very polar molecules, but have higher than expected penetrance of the CNS, why?
they are actively transported in as essential nutrients
phenobarbital and phenytoin are very lipophilic drugs, but have lower than expected levels in the CNS, why is this?
they are actively pumped out
molecules can generally cross the BBB if they are one or all of what 3 things?
small, hydrophobic, substrate for carrier
molecules generally can’t cross the BBB if they are one or more of what 2 things?
large, hydrophilic
___ is required to determine if a drug is a substrate for a transporter
experimental data
during ___, the BBB becomes more permeable and allows more molecules to cross
systemic inflammation
the majority of neuronal activity occurs at ___
synapses
NT are made and stored in the ___ nerve terminals
presynaptic
___ causes NT to be released into the synapse where it acts on ___receptors
action potential propagation; post-synaptic
the signal is terminated as the NT ____
diffuses away from the synapse
once the NT difuses away from the synapse, it can be ___ or ___ by ___ or ___ cells
degraded; taken back up by presynaptic or glial cells
some signals between neurons may involve the release of a ___ back into the synapse to retrogradely signal to the presynaptic neuron
signalling molecule
list some CNS NTs
glutamate, GABA, NE, dopamine, serotonin, endocannabinoids, glycine, neuropeptides, Ach, histamines
Glutamate (Glu) is a ___- NT made in ___ and stored in ___
excitatory, presynaptic; vesicles
when glutamate is taken up by glial cells its made into ___
glutamine
after glial cells turn glutamate into glutamine, what happens to it?
taken back into presynaptic neurone terminals so it can be made into glutamate again
what is the primary way a glutamate response is terminated?
glutamate is taken up into glial / astrocyte
what is the role of vesicular glutamate transporter (VGLUT)?
packages glutamate into vesicles for future release
what are the 2 types of glutamate receptors? what type of receptor are they?
metabotropic and inotropic;p bot ligand gates ion channels
metabotropic glutamate receptors on the postsynaptic cell are typically ___ coupled and there activation results in the ___ , giving an overall ___ effect
Gq; closing of K channels; excitatory
metabotropic glutamate receptors on the presynaptic cell has a ___ effect bc these are ___ receptors and are __coupled
inhibitory; autoreceptors;GI
AMPA and NMDA inotropic glutamate receptors are expressed on ___ cells and are permeable to ___ ions
postsynaptic; cations Ca and K
binding of glutamate to inotropic receptors causes ___
membrane depolarization called an EPSP
what happens if only a little bit of glutamate is released to inotropic receptors/
only small membrane depolarization and no AP / signal generated
GABA is a ____ NT
inhibitory
what are the 2 types of GABA receptors?
metabotropic and inotropic
inotropic GABA receptors are aka ____ receptors
GABA a
metabotropic GABA receptors AKA ____ receptors
GABA b
opening of GABA a receptors causes influx of ___ions, resulting in ____
Cl-; hyper polarization and IPSP
activation of GABA b receptors causes postsymptic ___channels to open, resulting in ___
K+; hyperolarzation
what is the effect of hyperpolarizaytion on AP generation?
makes it harder because it requires greater depolarization to threshold
what type of receptors are GABA b receptors?
GPCR
the BY subunits of the GABA b receptors interact with ion channels to further ___
reduce excitability of postsynaptic cells
many cells receive multiple inputs and the overall response is a ____ of those signals
integration
many signals originate in specific brain regions Called __
nuclei
when neurons leave a nuclei in the brain, they go many different places, making _____ difficult and often, drugs used in the CNS can have significant ___
drug targeting one region ; side effects
the same NT can have many different physiologic effects depending on ____ it is in
brain region
most CNS drugs target one of which 5 things?
- presynaptic excitability
- NT synthesis
- NT storage
- NT release
- NT. metabolism / reuptake
- receptor target
- postsynaptic excitability
- retrograde signalling
amphetamine and cocaine influence the storage and reuptake of ___ in presynaptic neurons
NE
amphetamine-like drugs structurally mimic ____ and are good substrates for the transporters to fill up ___ and push NE out casino the NET to allow NE to ___
catecholamines; storage vesicles; release into synapse
is an AP required to release NE when amphetamine is involved?
no
cocaine blocks the NET, preventing NE ____, resulting in ___
reuptake at the presynaptic neuron; longer duration of action for NE
t/f receptors may be more selectively targeted compared to NT
true
t/f similar receptor types exist in many brain regions and may result in adverse effects
t
many ADR of CNS drugs are related to the drug interacting with similar receptors in the ___ and __
CNS and periphery
retrograde signalling pathways can be used influence __
presynaptic neuron excitability
how do retrograde signalling molecules work?
made in post, releases to act on pre after initial signal has been processed
some effects of retrograde signalling can be __ which ___
reduced excitability of pre neuron; reducing NT further NT release
___ are an example of retrograde signalling in CNS
endocannabinoids
what are endocannabinoids?
regulatory molecules made by post in response to excitatory inputs
activation of glutamate simulates ___ which activates Gq and causes downstream activation of ___
mGluR; DAG lipase
DAG lipase is responsible for the production of the endocannabinoid ___, which activates cannabinoid receptors on the presynaptic neuron
2-AG
what is the effect on glutamate release if 2-AG binds to CB1 receptor on the presynaptic neuron?
Gi couples, inhibitory and reduce glutamate (so less excitement)
endogenous stimulation of neurons is typically ___ and ___, this allows neurons to ___
brief and regulated ; be repeatedly active and responsive to AP
neurons like to be active, so if its activity is blocked for a long time, the neuron may ___ to increase ability to regain activity
up regulate their receptor
t/f the long-term remodelling effects of neurons receiving too much or not enough signalling can be intentional or impede the therapeutic effect of a drug
t
