Introduction to CNS Pharmacology Flashcards
List the bioelectric properties of nerve cells
- phospholipid membranes are essentially impermeable to ions
- however, several protein families have evolved that function to allow ionic passage across the membrane
What protein families have evolved to allow ionic passage across the membrane
- ion channels: ion movement is allowed, follows concentration gradient
- transporters, ATPase driven pumps
Ion Channels
- integral membrane proteins
- multiple membrane spanning domains
- form a hydrophillic channel in the center
- highly evolved to be selective for ions and to be regulated by changes in the cellular environment
Properties of ion channels
- commonly composed of multiple subunits that are separate gene products
- glycosylated on the extracellular side
- specificity for ions that flow through
- kinase consensus sequences on the intracellular side, thus can be regulated by intracellular signaling
3 functional classifications of ion channels
- passive
- active
- leak
Passive ion channels
non-gated, always open
Active ion channels
- some mechanisms exits for regulation of open/closed states
- Gating mechanisms include
- membrane potential (voltage-gated)
- some extracellular molecules (neurotransmitters)
- other membrane proteins (ex: beta gamma subunits of G proteins
- intracellular molecules (ions ATP)
Leak channels
-A channel that is open at resting membrane potential
-can be active or passive
(All passive channels are leak channels but not all leak channels are passive
Resting Membrane Potential-what is it and why does it exist
- a potential difference (approximately -60 mV relative to the outside of the cell) exists across the membrane of neurons because of the following factors
1. Most intracellular proteins are anions, trapped in the cell
2. there are leak channels in the membrane that allow for movement of potassium and chloride across the membrane
3. conductance (g) of K is about 100x greater than the conductance to Na (bc of many more K leak channels than Na leak channels
What s the result of the resting memebrane potential and conductance of K being 100x greater than Na
there is an unequal distribution of Cl, K and Na across the membrane
-Most Na and Cl are extracellular and most K is intracellular
Electrochemical potential
the chemical difference along with the potential difference in ions means there is an electrochemical potential for these ions
Nernst (equilibrium) potential
- the membrane potential at which an ion is in the electrochemical equilibrium across the membrane
- describes the electrical potential that is required to maintain the E:I ratio
Approximate Nernst potential for the three major ions
K: -90
Na: +50
Cl: -70
how is leak across he membran eopposed
Neurons have a Na/K ATPase pump that moves Na out and K into the cell. This is not enough to se the gradients but opposes leak
Action Potential
- electric impulse transmitted across the plasma membrane
- All or None
- about 100 mV in amplitude and 1-10 msec in duration
- propagated dow the axon through cycles of depolarization and repolarization
Propagation of an action potential primarily involves what 2 channels
- Voltage gated sodium channels
2. Voltage gated potassium channels
How do Voltage-gated sodium channels work?
-depolarization
-voltage gated Na channels open
-increase INA
(this is a cycle)
Equation for I
I=v/R
How do Voltage gated potassium channels work
-more gradual opening and slower inactivation than voltage gated sodium channels
synaptic potential
mechanism by which the initial change in membrane potential occurs t begin an action potential
- These changes in membrane potential are:
- graded, small and shot (only a few mV and few msec in duration)
- local (no propagation)
- able to summate-spatial and temporal summation
What are the two types of synaptic potentials
- excitatory postsynaptic potential (EPSP)
- inhibitory postsynaptic potential (IPSP)
Excitatory postsynaptic potential (EPSP)
- membrane potential moves to more positive values
- spatial and temporal summation
Inhibitory postsynaptic potential
- membrane potential moves to more negative values
- impact on a summating EPSP
What are the two mechanisms by which an EPSP can occur
- Increased conductance
- open a ligand gated channel for sodium or calcium
- examples: nicotinic receptor, several types of glutamate receptor - Decreased conductance:
- close a channel that is open at resting membrane potential (ie a leak channel)
- these are slower onset changes that last longer
Decreased conductance EPSP
- Potassium channels
- Initiated by G protein coupled receptors
- eg: phosphorylation of K channel by protein kinase A, results in its closure
- therefore Gs is involved
increased conductance IPSP
-what is it and three mechanisms of achieving it
- increased conductance of the membrane to either potassium of chloride
- three mechanisms:
1. Ligand gated chloride channel - GAGA receptor
2. Opening of K channels - via changes in phosphorylation state of K channels that are closed
Resting potential
- Channel specificity
- gating mechanism
- properties
- channel specificity:
- non-gated (leak) potassium and chloride channels
- some non-gated (leak) sodium channels
- gating mechanism: none
- Properties: usually steady; from -35 to -70mV
Action potential
- channel specificity
- gating mechanism
- properties
channel specificity: independently gated sodium and potassium channels
gating mechanism: voltage
properties: all or none, 100 mV in amplitude, 1-10msec in duration
EPSP Increased conductance
- channel specificity: non-voltage gated channels, nonselective for univalent cations
- although result is primarily sodium flux
- Gating mechanism: chemical(extracellular binding site)
- properties: graded, fast, several msec in duration, several mV in amplitude
EPSP Decreased conductance
- channel specificity: potassium leak channels
- gating mechanism: chemical(GPCR, then a second messenger)
- properties: graded, fast, several msec in duration, several mv in amplitude
IPSP increased conductance
- channel specificity: non voltage gated channels for potassium or chloride
- gating mechanism: chemical (extracellular binding site)
- Properties: graded, fast, several msec in duration, several mV in amplitude
Major categories of neurotransmitters based on chemical structure
- **Biogenic Amines
- catecholamines: Dopamine, Norepinephrine, Epinephrine
- Indolamines: serotonin
- *Neuropeptides
- eg. beta-endorphin, orexin, neurotensin, etc
- over 100 neuropeptides known
- *Amino Acids
- glutamate, GABA
- *other
- 2-Arachidonylhlycerol (2-AG)- Neuroactive lipid
Role of Norepinephrine in CNS function
- autonomic outflow in brainstem; sympathetic ganglia; arousal
- roles in blood pressure regulation and attention
Role of Dopamine in CNS Fucntion
- regulates reward; extrapyramidal system
- roles in addiction and Parkinson’s disease
Role of Serotonin in CNS function
- regulates sleep/wake cycle; mood
- role in depression
Role of Histamine in CNS function
- regulates sleep/wake; vestibular function
- sleepiness is a side effect f antihistamines
Ionotropic
- binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex
- channel typically opens in less than 10 msec
- eg: AMPA glutamate receptors (Na, K) , GABA receptors (Cl)
Metabotropic
- binding to the receptor engages a G protein which results in the production of second messengers that mediate intracellular signaling cascades
- effects can last tens of seconds to minutes
What two things do metabotropic receptors modulate via
- membrane-delimited pathways: modulation of voltage gated channels
- diffusible second messengers: ex-cAMP production by Gs coupled receptor
Steps in Conventional Synaptic transmission
- Synthesis of neurotransmitter
- Packaging of neurotransmitter in the presynaptic element in preparation for its release
- Release of neurotransmitter from the presynaptic element in the synaptic cleft
- Binding of neurotransmitter to receptors
- Termination of neurortransmitter action
All of these are drugable targets
4 General principles of CNS Pharmacology
- CNS drugs must penetrate the blood brain barrier
- Nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission
- Many CNS disorders involve multiple brain regions and pathways
- A CNS active drug may act at multiple sites with disparate and even opposing effects
How does the blood brain barrier function
-endothelial tight junctions supported by astrocyte foot processes
What are the different steps that drugs can alter neurotransmission at
- Action potential propagation
- synthesis
- storage
- metabolism
- release
- uptake
- degradation
- receptor
- ionic ocnductance
- retrograde signaling
Also:
- presynaptic autoreceptors
- network effects: opioids increase release of mesolimbic dopamine via disinhibition of dopamine neurons
- ion channels
- downstream signaling cascades
Feedback regulation (decreased release) by Alpha2 autoreceptors: Regulation of norepinephrine release
- via beta gamma: inhibit opening of Ca channels
- open K channels (hyperpolarization)
- inhibition of cAMP (decrease synthesis of NE)
Neurons are electrically polarized
enables signal integration and communication via changes in membrane potential
postsynaptic potentials
EPSPs and IPSPs result from increases and decreases in conductances of specific ions
there are many different neurons
-similarities and differences in synthesis, release, and inactivation
