CNS Pharmacology Flashcards
Blood Brain Barrier
Isolates the CNS
Modified endothelial cells so there are tight junctions instead of fenestrations
Highly lipophilic
Astroglial processes and pericytes surround the endothelial cells
Up-regulation (sensitization)
You have a drug that is blocking the receptor or something, so the postsynaptic cell is making more receptors to try to get any of the NT. When you remove the drug you can have an amplified response because you have way more receptors now
Down-regulation (desensitization)
Also called tolerance
Drug stops working after a while because there is a max response of receptors for a long time so the postsynaptic receptors are internalized and degraded which means less of a response is generated
Membrane delimited metabotropic ion channel
Ligand binds to receptor (7 TM one), activates G protein, and then the G protein subunits go and directly activated an ion channel (usually K)
Diffusible second messenger metabotropic ion channel
GPCR activated by ligand, binds G protein, creates second messengers, then they can go activate and open ion channels
Steps of an action potential
- Excitatory impulse reaches the cell
- Na channels open and Na enters the cell (cell membrane depolarizes
- K channels open, K begins to leave the cell (slowing of depolarization)
- Na channels close when cell gets too positive
- K leaves cell (repolarization)
- K channels close (afterhyperpolarization)
- Excess K outside diffuses away
Cellular Organization
- Long tract
- Local circuit
- Divergent
- Messages over long distances, motor control
- Short, modulating, shape recognition in the optic tract
- Widely projecting neurons, global functioning, sleep-wake cycles
4 Criteria for a NT
- To be present at higher [ ] in the synapse than in other areas (localized)
- To be released by electrical or chemical stimulation via a Ca dependent mechanism
- Produce a postsynaptic response similar to nerve stimulation (synaptic mimicry)
- Mechanism for termination of transmitter action
Amino acid NTs
High concentration in the SNS
Potent modifiers of excitability
Excitatory: Glutamate
Inhibitory: GABA and glycine
GABA synthesis
Glutamine –(glutaminase)–> glutamate –(glutamate decarboxylase)–> GABA
Glutamate
where, types, termination
Major excitatory NT in CNS
Ionotropic subtypes: NMDA receptor, AMPA receptor and KA receptor
Also mGluR 1 (postsynaptic Gq) and 2/3 (presynaptic, Gi)
Termination: Glia Uptake
GABA
Function, receptors
Inhibitory
Ionotropic (GABAa, Cl-) and metabotropic (GABAb; Gq)
Widely expressed
GABAb can be presynaptic
Ligand gated ion channels (it is the orthosteric ligand, barbituates are the allosteric ligand)
Glycine
Function, receptors, location
Inhibitory
Ionotropic (Cl-)
Limited expression (interneurons in spinal chord and brainstem)
Acetylcholine
Receptors, function, disease target
Has ionotropic (nicotinic receptor) and metabotropic (muscarinic receptor)
Excitatory/Inhibitory
Widely expressed
Cognitive functions (sleep, wakefulness)
Target in treatment of Alzheimer’s disease
Ionotropic
Ion channels - not GPCRs
Metabotropic
GPCRs - use G proteins and their receptors to cause downstream signalling
Acetylcholine synthesis
Acetyl CoA + choline –(choline acetyltransferases) –> Acetylcholine (stored in vesicles and then transported)
Acetylcholine receptors
Found in the basal ganglia and cortex.
Excitatory: M1, M3, M5 (all are Gq - cause increase in IP3, DAG and then Ca) or nicotinic (ion channel - increases Ca, K, and Na conductance)
Inhibitory: M2, M4 (both are Gi - cause decrease in cAMP and gK)
Monoamines
Examples, functions
Also called catecholamines Dopamine, NOR, and serotonin Derived from amino acids Small amounts Complex functions (alertness, conciousness, cognition, reward)
Dopamine
Receptors, Function, disease
D1 and D2 receptor families Metabotropic Inhibitory Diffuse Target in treatment of Parkinson's disease
Dopamine Synthesis
L-tyrosine –(Tyrosine hydroxylase)–> DOPA –(L-amino acid decarboxylase)–> Dopamine
TOH is rate limiting
Dopamine Receptors
D1 and D5: Gs (increase cAMP) and Gq (increase IP3/DAG/Ca)
D2, D3, and D4: inhibitory - Gi/o (decrease cAMP, increase K currents, decrease VDCC)
3 Dopaminergic Pathways in the CNS
- Nigrostriatal tract: responsible for movement - Parkinson’s
- Mesolimbic system: reward system - if drugs dont target the mesolimbic system they wont cause addiction
- Mesocortical system: important in cognition and motivation
Norepinephrine
Receptors, function
Adrenergic receptors (alpha and beta - metabotropic)
Excitatory
Diffuse
Attention, arousal
Function in midbrain: anxiety, learning, memory, mood, sensory processing, sleep
NOR synthesis
Dopamine –(Dopamine beta hydroxylase)–> NOR
NOR receptors
Alpha 1: Gq (increase IP3/DAG/Ca
Alpha 2: Gi (decrease cAMP)
Beta 1 and 2: Gs (increase cAMP)
Serotonin
Receptors, function
15 Receptors, all metabotropic except 5-HT3
Tend to be inhibitory (some excitatory)
Diffuse
Sleep, temperature, appetite, and neuroendocrine control
Target in treatment of depression
Serotonin Synthesis
Tryptophan –(tryptophan hydroxylase)–> 5-hydroxytryptophan –(L-amino acid decarboxylase)–> 5-hydroxytryptamine (5HT)
Serotonin Receptors
Excitatory (5-HT2,3,4) or inhibitory (5-HT4)
See slides for more info
Neuropeptides
types, receptors
Many of them: Opioids - pain sensation - target of analgesics - drugs of abuse
Metabotropic
Can be released with other NTs
How are neuropeptides different from non-peptide transmitters?
- They are synthesized in the cell body before transport to nerve ending
- No reuptake or enzyme degradation identified for termination of action
Endocannabinoids
Rapidly synthesized (not stored)
Act at presynaptic receptors (retrograde messengers)
Cannabinoid receptor 1 is one of the most abundant in your brain - metabotropic
Memory, cognition, pain perception
Nitric Oxide
Gas formed from arginine by NO synthase in CNS neurons
May participate in retrograde neurotransmission and LTP
Leptin and Orexin
Hormone neuromodulators formed in hypothalamus
Important in regulating appetite
Purines
Adenosine and ATP
Activate specific receptors
Evidence that ATP is a co-transmitter
