Neurotransmitters Flashcards
What are the 4 main neurotransmitter classes
Amino acids
Biogenic amines
Purines
Neuropeptides
How are neurons classified from a neurotransmitter view point?
The predominant neurotransmitter they synthesize and releases when firing
- all neurons release different types of neurotransmitter sand have various receptors, but the predominant one is how the neuron is labeled
Two main type of neurotransmitter receptors
1) ion channels
- known also as inotropic receptors
- very rapid intracellular changes
2) G-protein coupled receptors (GPCRs)
- known also as metabotropic receptors
- effects lasts tens of seconds -> minutes
- activated G-Protein propagates cAMP/calcium production -> desired cell response
Excitatory vs inhibitory receptor actions
Excitatory
- depolarize membranes of neurons (becomes more positive by influx of Ca+2 and/or NA+)
- excitatory ionotropic receptors generate EPSP which helps simplify action potential depolarization
Inhibitor
- hyperpolarize membranes
- inhibitory ionotropic receptors generate IPSPs which antagonizes action potentials
metabotropic receptors on neurons contribute by setting overall tone of the neuron (prime it to be easy or harder for it to fire. DOES NOT actually generate the action potential or inhibit the action potential
Metabotropic signaling G-protein specifics
G(as) protein activation stimulates cAMP production
G(aio) protein activation inhibits cAMP production
G(aq) protein stimulates Phospholipase C (PLC)
An increase in PLC is directly correlated with increases in DAG and IP3
- resulting signal is intracellular increases in calcium and subsequent downstream signaling
An increase in cAMP is directly correlated with an increase in Protein Kinase A (PKA)
- resulting signal is phosphorylation of a protein target (activates)
What does the protein calmodulin do?
Acts as a protein activator in response to elevated calcium levels
- phosphorylated downstream proteins in a signal
ONLY activated in response to increased calcium
Secondary effects of GPCR kinase activity
Changes in gene transcription
Receptor desensitization
Receptor sensitization
Receptor desensitization mechanism
1st dose
- receptors are internalized and either recycled or degraded via phosphorylation to attempt to prevent OD or ADRs
2nd dose
- Fewer receptors are present on cell surface = less amplitude in response
a refractory period is required for “receptor recovery” (reversal of sensitization), hence if giving two doses with a small time frame, the second has less of an effect
Receptor sensatization mechanisms
usually only occurs in the chronic presence of an antagonist
Neuron responds by upregulating target receptor (survival mechanisms)
Sudden absence of the antagonists after upregulation causes increased apparent does and elevated response to drugs that were being antagonized
applies to both ionotropic and metabotropic receptors
Hierarchical vs diffuse pathways of neurotransmitters
both are movement of action potentials through neurons or series of neurons
Hierarchical
- signal moves down 1 by 1 neuron
Diffuse
- signal moves across an area at once, not 1 by 1
Tracts vs circuits
Tracts
- anatomical structures/bundles of neuronal axons
Circuits
- group of neurons that interact with each other to modulate a specific set of organism functions
Hierarchical neurotransmitter specifics
Glutamate, GABA and glycine all work in this way
Neurotransmitters that use this method of propagation function to control the following
- sensory perception
- motor control
- some cognitive functions
Use myelinated long axons
Possess local circuit neurons (interneurons) that tune and regulate signals (allow it to propagate at the correct speed and stay on the hierarchical pathway)
Diffuse neurotransmitter specifics
Dopamine, NE, serotonin, histamine, Orexin and ACh all work this way
Neuro transmitters that use this pathway function closely for global body functions and changes (ex: sympathetic response throughout the body)
Where are dopamine cell bodies found?
Ventral regimental area and substantia Nigra in the Brain
Where are NE cell bodies found?
Locus coeruleus in the brain
Where are serotonin cell bodies found?
Raphe nuclei in the brain
Where are ACh cell bodies found?
Nucleus Basalis of Meynert in the brain
Cholinergic brain stem nuclei
Diagonal band of Broca
Medial septal nucleus
Glutamate neurotransmitter specifics
Present in 90% of excitatory synapses
Possess 5 metabotropic glutamine receptors all of which are coupled to either G(aq) of G(aio) proteins
Have three ionotropic receptors as well
- AMPAR
- Kainate
- NMDAR
Difference between AMPA and NMDA receptors for glutamate
AMPA: “solo receptor”
- permeable to (NA+/K+) only
- open super quickly and desensitize quickly
- level of AMPA receptors is directly correlated to sensitivity on a neuron
NMDA: “coincidence detector”
- permeable to (NA+/K+ and Ca2+)
- open slower and desensitize slower
- requires glycine (coagonist) to open
- possess zinc and magnesium bindings sites on Channel pores
- only open after AMPA receptors have been de polarized (since mag. Doesn’t remove until AMPA depolarization)
- very good at fine tuning signals
- always increases intracellular calcium levels, and actually generates more AMPA receptors
Long term depression (LTD)vs Long term potential (LTP)
LTP
- increases in potential of a synapse is present with an increase in AMPA receptors and NMDAR activity
- requires gene transcription (which is only possible if NMDAR activities is high enough to phosphorylate genre transcription proteins
LTD:
- decreases in potential at a synapse is present with not enough NMDA receptors
- low levels of calcium intracellular prevent calmodulin = no/low protein phosphorylation
- also less AMPA receptor expression at synapse
both are required for learnin
Pathologies associated with glutamate signaling
Schizophrenia
- deficiency of glutamine signaling in the cortex
- this is hypothesized since non-competitive NMDA receptor antagonists (phencyclidine and ketamine) produce schizo effects*
Depression
- overexpression of glutamine signaling can cause depression
- treatment is with a ketamine antagonist on NMDARs
Alzheimer’s disease
- overexpression of glutamine signaling
- treatment is with memantine (non-competitive NMDA receptor antagonist)
GABA and glycine neurotransmitter specifics
Note: glycine works almost exactly the same as GABA, just specifically in the spinal cord
Usually released by interneurons and act in an inhibitory fashion, however it is nonspecific
Two GABA receptors
- A: target for sedatives
- B: target for muscle relaxants
Pathologies associated with GABA and glycine
Generalized convulsions
- impaired pathways of GABA causes irregular firing of neurons
Acetylcholine neurotransmitter specifics
Signals through:
1) nicotinic (excitatory/ionotropic/sympathetic)
2) muscarinic (inhibitory/metabotropic/parasympathetic)
- the exception is it sympathetic for sweat glands
Functions in cognitive functions, motor control, and ANS activity
Pathology associated with acetylcholine
Alzheimer’s disease
Cholinergic receptors
Are found on muscarinic and nicotinic receptors
5 subtypes
- M1/3/5 = G(aq) protein coupled
- M2/4 = G(aio) protien coupled
Dopamine neurotransmitter specifics
Can be inhibitory and excitatory
Functions in basal ganglia communication, limbic system communication and regulation and motor circuit activity predominately
Also functions in:
- cognition
- motivation
- mood
- motor coordination
- reward reflex
- salience
Difference between dopamine sup receptor types
5 types
D1/5 = increases cAMP/ excitatory
D2/3/4 = decreases cAMP/ inhibitory
Pathological conditions associated with dopamine
All abuse disorders
- elevated levels of dopamine are found in all abuse-like disorders
Schizophrenia and though disorders
- elevated levels of dopamine activity/receptors are directly associated
Parkinson’s disease
- lowered dopamine levels and signaling/receptors are present specifically in motor tracts
- treat with L-DOPA, which is a precursor to dopamine
Pathological conditions associated with NE defects
PTSD
- disrupted NE signaling
Parkinson’s
- degradation of locus coeruleus neurons decreases NE levels and pathway
Review of NE receptor catagories
A1 = increases PLC levels and calcium levels
A2 = decreases cAMP levels and decreases calcium levels
B1/B2/B3 = increases cAMP and increases calcium levels
Affinity of NE with receptors is as follows
A1=a2 ; B1»_space; B2
Most predominant in CNS
Serotonin neurotransmitter specifics
Pretty much involved in all brain functions
Most important neurotransmitter in depression and bipolar disorders
Also plays a crucial role in peripheral 5-HT symptoms
- nausea, platelet activation, emesis
Serotonin subtypes of receptors
There are 14, however they are best memorized via families
Family 5HT1
- decreases cAMP
Family 5HT2
- increase PLC and PLA2 levels
Family 5HT3
- regulates cations in the brain
- only serotonin receptor that is inotropic excitatory
Family 5HT4
- increases cAMP
Family 5HT5
- decreases cAMP
Family 5HT6/7
- increase cAMP
- all are metabotropic receptors (except 5HT3)*
** 1-3 are most common for pharmacology targets**
Histamine neurotransmitter specifics
Project diffusely through the hypothalamus/Brain and spinal cord
Functions are as follows
- arousal
- attention
- feeding behavior
- memory
- circadian rhythm
3 receptor subtypes, however CNS is H3 subtype only
Endocannabinoids
Not overly important right now
Signal through retrograde signaling and modulate neuronal specific functions (again not overly important right now)
- release form postsynaptic and modulate presynaptic neurons
Peptide neurotransmitters and neuromodulators
Responsible for pain perception/transmission and modulation
- specifically substance P
Responsible for analgesia
- specifically enkephalins
Responsible for neural response to stress/ wakefulness/hunger
- specifically orexin
