Kapatos - Introduction to Neuropharmacology Flashcards
Glia: neuron ratio
Glia: outnumber neurons by ~10:1
Glia general:
How do they promote signaling between neurons?
Synthesize and release:
Other functions
General:
Promote signaling between neurons by accumulating or metabolizing NTs
Synthesize and release trophic factors that are important for neuronal survival (ie. GDGF)
Physically support the neurons, provide structure to the brain, and separate/insulate neuronal groups and synaptic connections
Microglia:
Scavengers that remove debris after cell death (like macrophages)
Activated microglia secret cytotoxic cytokines that induce cell death.
Macroglia
Oligodendrocytes
Schwann Cells
Astrocytes
Oligodendrocytes:
Produce myelin in CNS that insulates nerve cell axons (saltatory conduction)
Schwann Cells:
Produce:
Regulate:
Produce myelin in PNS that insulates nerve cell axons (saltatory conduction)
Regulate the properties of the presynaptic terminal at the nerve-muscle synapse
Astrocytes
Help form the blood brain barrier
Radial glia:
Guides:
Serves as:
Radial glia: a type of astrocyte
Guides migrating neurons
Serve as neuronal progenitors (constantly made) in some brain regions (ie. hippocampus- involved in memory)
Neurons:
Four defined regions:
Main signaling units of the nervous system
Four Defined Regions:
Cell body (soma)
Dendrites
Axon
Presynaptic Terminals
Cell body (soma):
Metabolic center containing the nucleus (stores genetic info) and endoplasmic reticulum (proteins synthesis)
Dendrites:
Voltage-gated Na channels?
Receptor types:
Dendrites: receive incoming signals
No voltage gated Na channels (do not convey classic APs)
Contain ionotropic NT receptors (glutamatergic) and voltage gated Ca channels (capable of propagating electrical signals to the soma)
Axon:
Contains
Where is AP initiated?
Axon: extends away from the cell body and is the output unit for neurons (conveys electrical signal)
Contains voltage gated Na channels (conduction of AP)
APs initiated in the axon hillock
Presynaptic Terminals:
Site of:
Presynaptic Terminals: form synapses to communicate with other neurons across the synaptic cleft
Site of classical NT biosynthesis (packages into vesicles and secreted by exocytosis)
State of dendritic spines:
Synaptic plasticity definition:
What happens when spines make contact with active nerve terminals?
Dendritic spines are in a constant state of flux.
Synaptic plasticity is defined as morphological alterations in dendritic architecture in response to changes in neuronal activity.
Spines that make contact with active nerve terminals are stabilized while spines that do not retract.
Types of Synapses:
Types of Synapses:
- Axo-dendritic
- Axo-somatic
- Axo-axonic (synapse on a synapse)
Seven steps in synaptic transmission
Synaptic Transmission: each of the steps in transmission can be targeted by neuropharmacological intervention
- Neuron synthesizes NT and stores in vesicle
- Action potential travels down the neuron and depolarizes the presynaptic nerve terminal
- Activation of voltage-dependent Ca++ channels –> Ca++ enters nerve terminal
- Increase in Ca++ causes vesicle fusion with plasma membrane and release of NT into the synaptic cleft
- NT diffuse across cleft and binds to post-synaptic receptors
Ionotropic and Metabotropic: binding activates intracellular signalling cascades - Signal termination accomplished by removal of transmitter from synaptic cleft (degraded by enzymes or recycled by reuptake into presynaptic cell)
- Signal termination may also occur by enzyme degradation (ie. phosphodiesterase) of postsynaptic signaling molecules (ie. cAMP)
Ionotropic vs. Metabotropic
Ionotropic: binding causes channel opening and changes in permeability; may result in change in postsynaptic membrane potential
Metabotropic: binding activates intracellular signalling cascades
Amino acid NTs
primary excitatory and inhibitor NTs in the CNS
o Excitatory: glutamate and aspartate
o Inhibitory: glycine and GABA
Biogenic Amines:
3 types:
Biogenic Amines: primary modulatory NTs in the CNS
o Catecholamines: DA, NE, EPI
o Imidazole Group: histamine
o Indole Group: serotonin
Other small molecule NTs: (3)
ACh: found in diffuse modulatory systems in the CNS
Adenosine
Nitric Oxide (NO): atypical NT (made on demand and released by diffusion- not stored in/released by synaptic vesicles)
Peptide NTs:
Where?
co-localize with what?
synthesized on demand?
Examples:
Act as NTs in the brain
Typically co-localized with classical NTs (ie. monoamines)
Not synthesized upon demand in nerve terminals (made in cell body and transported intact down the axon)
Examples:
o Opioid peptides
o Tachykinins
Glutamate: type of NT.
Where?
Mechanism:
Channels activated:
Excitatory
Most neurons in the brain use it as a NT to mediate FAST EXCITATORY synaptic transmission
Mechanism: activates ligand gated ion channels (ionotropic receptors), resulting in depolarization of the membrane due to passage of Na+ and Ca++ down their electrochemical gradient
Channels Activated: AMPA, kainite and NMDA
GABA and Glycine
Mechanism
(Inhibitory):
Mechanism: activate another class of ionotropic receptors, resulting in the hyperpolarization of the membrane due to the movement of Cl- down its electrochemical gradient
Output of the neuron:
Output of the neuron is the sum of its inhibitory and excitatory inputs.
Metabotropic G Protein Coupled Receptors:
General:
Speed compared to ionotropic:
G proteins:
- Actions mediated by:
- Where do pharmacological interventions occur?
General: modulate the properties of the neurons themselves and thus how they integrate fast synaptic activity
Slower neurotransmission than ionotropic receptors
G proteins are heterotrimeric proteins that couple receptor activation with various effector mechanisms
- Actions mediated by variety of second messenger systems
- Very biologically complex and therefore a pharmacological intervention can occur at a number of different steps in the signaling pathway.
Beta Adrenergic (NE): types o Gs --> ? --> ?
Beta Adrenergic (NE): B1, B2, B3
o Gs –> Stimulates AC –> Increase in cAMP
Alpha Adrenergic (NE):
Alpha1: Gq –> ? –> ?
Alpha2: Gi –> ? –> ?
Alpha1: Gq –> Stimulates PLC beta –> IP3 and DAG (from PIP2)
Alpha2: Gi –> Inhibits AC –> Decrease in cAMP
Dopamine Receptors (DA): 2 families:
Gs –> ? –> ?
Gi –> ? –> ?
D1 Family (D1, D5): Gs –> Stimulates AC –> Increase in cAMP
D2 Family (D2, D3, D4): Gi –> Inhibits AC –> Decrease in cAMP
Muscarinic Receptors (ACh):
Classes
Gq –> ? –> ?
Gi –> ? –> ?
o M1,M3,M5: Gq –> Stimulates PLC –> IP3 and DAG (from PIP2)
o M2,M4: Gi –> Inhibits AC –> Decrease in cAMP
NTs Acting as Fast and Slow NTs:
Glutamate:
Ionotropic R: AMPA, NMDA, kainite
Metabotropic R: mGluR1-5
ACh:
Ionotropic R: nicotinic (NMJ, GABAergic neurons of hippocampus and cortex)
Metabotropic R: muscarinic (CNS and PNS)
Glutamate:
Ionotropic R:
Metabotropic R:
Ionotropic R: AMPA, NMDA, kainite
Metabotropic R: mGluR1-5
ACh:
Ionotropic R:
Metabotropic R:
Ionotropic R: nicotinic (NMJ, GABAergic neurons of hippocampus and cortex)
Metabotropic R: muscarinic (CNS and PNS)
MONOAMINES:
NTs in this Class: (5)
DA, EPI, NE, 5HT, histamine
Druggable Targets for monoamines
Biosynthesis (DOPA decarboxylase)
Vesicular Storage: VMAT (vesicular monoamine transporter)
Reuptake and Metabolism: DA/NE/5HT transporters or MAO/COMT enzymes
Monoamine neurotransmitters:
Derived from:
They are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-).
All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes.
AUTONOMIC NERVOUS SYSTEM INNERVATION:
Sympathetic:
Preganglionic Neurons: arise in:
Synapse: )
Sympathetic:
Preganglionic Neurons: arise in THORACIC and LUMBAR segments of the spinal cord (SHORT)
Synapse:
in ganglia that lie CLOSE TO THE SPINAL CORD (ie. paravertrbral and prevertebral ganglia
Parasympathetic:
Preganglionic Neurons:
Synapse:
- Postganglionic Neurons:
Parasympathetic:
Preganglionic Neurons: arise in nuclei in the BRAINSTEM and the SACRAL segments of the spinal cord (LONG)
Synapse: in ganglia that lie close to the organs they innervate
- Postganglionic Neurons: short
Neurochemical anatomy:
Primary NTs of 5 types of neurons
Primary NTs:
- Dorsal Root Ganglia: glutamate, substance P, other peptides
- Somatic Motor Neuron: ACh
- Preganglionic Neuron: ACh
- Postganglionic Neuron (SNS): NE
- Postganglionic Neuron (PNS): ACh
CNS Organizational Motifs (3):
- Long Tract Neurons
- Local Circuit Neurons
- Single Source Divergent Neurons
Long Tract Neurons:
o Receive signals from:
o Synapse with:
Long Tract Neurons: act as relays between periphery and higher sites in CNS
o Receive signals from many different neurons (convergent signaling)
o Synapse with many downstream neurons (divergent signaling)
Local Circuit Neurons:
Includes:
Used to:
Local Circuit Neurons: complicated and arranged in layers
Includes both excitatory and inhibitory neurons
Used to process information
Single Source Divergent Neurons:
Originate in a nucleus in the brainstem and have axonal terminals that innervate thousands of neurons, usually in the cerebral cortex.
Dopaminergic pathways:
Arise in:
Project to:
Involved in:
Arise in substantia nigra and ventral tegmental area
Project to striatum (SN) and cerebral cortex (VTA)
Involved in the initiation of movement the brain reward pathway
Cholinergic pathways:
Arise in:
Project to:
Involved in:
Arise in the nucleus basalis, pedunculopontine nucleus, and medial septal nuclei
Project widely throughout the brain
Involved in maintaining sleep-wake cycles and regulating sensory transmission
Cholinergic pathways:
Arise in:
Project to:
Involved in:
Arise in locus ceruleus
Project to the entire brain
Maintain alertness
Serotonergic Pathways:
Arise in:
Project to:
Involved in:
Arise in raphe nuclei
Project to diecephalon, basal ganglia, and via the basal forebrain, to the cerebral hemispheres, cerebellum and spinal cord
Play a role in modulating affect and pain
Retrograde Signaling by Cannabinoids and NO:
Cannabinoids endogenous (in post synaptic membrane)/NO or exogenous (ie. marijuana)
Bind cannabinoid receptor on presynaptic membrane to alter Ca++ influx and alter NT release
Where is there a high density of Na channels?
Trigger zone of the dendrite
How does glutamate activation of ionotropic receptors serve to depolarize the membrane?
Glutamate activation of ionotropic receptors serves to depolarize the membrane via the passage of Na+ and Ca2+ down their electrochemical gradients.
How do GABA and glycine hyperpolarize the membrane?
GABA and glycine serve to hyperpolarize the membrane via the movement of Cl- down its electrochemical gradient.
What inhibits axonal transport?
colchicine
What converts excitatory glutamate into inhibitory GABA?
GAD (Glutamic acid decarboxylase)
What is retrograde transport?
Where are small molecules recycled?
What inhibits programmed cell death?
Following exocytosis large dense core vesicles are returned to the cell body for reuse or degradation. This process is referred to as retrograde transport.
Small molecule synaptic vesicles are recycled in the nerve terminal.
Retrograde transport also transports trophic factors from the target cell to the cell body, where they inhibit programmed cell death.
G Protein Coupled Receptor: targeted by many psychoactive drugs directly (4)
o Opiod analgesics o Antipsychotics (DA R) o Halluncinogens (5HT R) o Antihistamines (histamine R)
What are the binding targets for cholera toxin and pertussis toxin?
G-proteins
What released by the autonomic nerve produces both a fast excitatory postsynaptic potential (EPSP) and a slow EPSP?
ACh
The fast EPSP is produced by:.
The fast EPSP is produced by activation of ionotropic nicotinic ACh receptors.
The slow EPSP is produced by:
The slow EPSP is produced by
activation of metabotropic muscarinic
Ach receptors.
Muscarinic activation stimulates PLC to:
Muscarinic activation stimulates PLC
to hydrolyze PIP2, yielding PIP3 and
DAG.
What does the decrease in PIP2 cause?
The decrease in PIP2 causes the closure of the M-type delayed-rectifier K+ channel, which depolarizes the neuron.
