Flashcards in CNS neuropharmacology - french Deck (62):
For a neuron to receive information what are the possible axonic connections?
What are hierarchical systems in the brain?
• Clearly delineated pathways that are directly involved in motor control and sensory perception
• Large myelinated neurons with rapid conduction velocity
• Sensory information is processed sequentially and is integrated successively at relay nuclei on the way to the cortex
• Any leasion at any link disrupts the whole pathway
• Relay neurons and local circuit neurons are present in each nuclei
What are local circuit neurons?
• Smaller and branch in immediate vicinity of cell body, synapsing primarily on cell bodies of relay neurons
• Can act as feed-forward and recurrent feedback pathway mechanisms
• Spinal cord - special class forms axoaxonic synapses on terminals of sensory relay neurons
• Most are inhibitory releasing GABA (some glycine)
What are relay neurons?
• Form interconnecting pathways that transmit signals over long distances
• Cell bodies are large and axons project over long distances
• Smaller collaterals that synapse on local interneurons are present as well
• Neurons are excitatory, releasing glutamate and activating ionotropic receptors
What is the main function of the diffuse systems?
• Modulate the functions of the hierarchical systems
• NT in diffuse neuronal systems including ach, dopamine (da), norepinephrine (ne), serotonin (5ht) are produced in neurons whose cell bodies lie in small discrete nuclei, most often in the brainstem
• Despite limited cell number, these nuclei project widely and diffusely throughout brain and spinal cord
• The axons here are divergent enough to innervate functionally distinct parts of the CNS
What is important about the monamine diffuse systems?
• Cannot convey topographically specific information
• CAN affect vast CNS areas simultaneously subserving global functions
• Attention, sleep-wake cycle, appetite, emotions
What are the six key neurotransmitter systems that are targeted by psychopharmacologic agents?
• 5-HT (serotonin)
What should go through your mind as you use symptoms and circuits as a guide to pick a neuro pharm agent?
• Match disease symptoms to hypothetically malfunctioning circuit
• Consider neurotransmitter systems that theoretically regulate each circuit
• Select treatment to target the relevant neurotransmitter system
What are the two broad categories of the rational approach to selecting a neuro-psychopharmacologic agent?
• Using symptoms and circuits
• Specific behaviors hypothetically linked to brain regions
What behaviors are linked to the PFC?
• PFC = pre frontal cortex
• Executive function
• Negative symptoms
What behaviors are linked to the NA?
• NA = nucleus accumbens
What behaviors are linked to the S?
• S = striatum
• Critical relay site from PFC
What behaviors are linked to the thalamus?
• T = Thalamus
• Sensory relay TO cortex
• Sensory relay FROM cortex
What behaviors are linked to the BF?
• BF = basal forebrain
What region of the CNS is pain associated with?
• Spinal cord and brain stem
What part of the brain are memory and reexperiencing linked to?
• H = hippocampus
What behaviors are linked to the C?
• C = cerebellum
• Motor coordination
What behaviors are linked to the Hy?
• Hy = hypothalamus
What does GABA stand for?
• Gamma-aminobutyric acid
How is GABA synthesized?
• Synthesis is intertwined with the synthesis of glutamate (which is major excitatory transmitter)
• Via the GABA shunt
• GAD = glutamic acid decarboxylase, the enzyme that makes GABA from glutamate
What do the receptors for GABA do?
○ Opens ligand-gated Cl channel, decreases neuronal excitability
○ GPCR, inhibits adenylyl cyclase, decrease Ca conductance, open K channel (hyperpolarizes)
What does vigabatrin have to do with GABA?
• Inhibits degradation by GABA-T
• T = transaminase
• Works in the glial cells mostly
How does Tiagabine interact with GABA?
• Inhibits reuptake of GABA by transporter
What do benzodiazepines do in relation to GABA?
• bind to GABA-a receptor to facilitate GABA inhibitory action
How is GABA terminated?
• Action of GABA at synapse terminated by reuptake into the presynaptic nerve terminal and surrounding glial cells
• GABA transporter similar to monoamine reuptake transporters
Where is GABA found in the CNS?
• Found in high concentrations in the brain and spinal cord
• Absent pretty much from the peripheral tissues
• Functions as major inhibitor NT in CNS
• 30-40% of all CNS synapses both postsynaptically and presynaptically
Is GABA-a receptor presynaptic or postsynaptic?
• GABA-a is postsynaptic
• GABA-b is both pre and postsynaptic
In which diseases does GABA play a pathophysiological role?
• Generalized anxiety disorders
• Seizure disorders
• Sleep disorders
• Alcohol abuse and withdrawal
• Huntington disease
How is glutamate synthesized?
• Dependent on interaction between nerve terminals and glial cells
• Glutamate is formed from glutamine by the action of glutaminase in the nerve ending.
• Newly synthesized glutamate is stored in synaptic vesicles for subsequent release
What are the various receptors for glutamate?
• Ionotropic receptors
○ NMDA - increases calcium influx
○ AMPA - increase Na and Ca influx
○ Kainate - increase Na influx
• Metabotropic receptors
○ R1-R5 - Gq - GPCR - increases PLC activity
○ R2-3 - Gi - decreases AC activity and inhibits VSCC, activates K channels
○ R4,6,7,8 - Gi - inhibit VSCC
How is released glutamate terminated?
• Reenters the neuron via a neuronal glutamate transporter (Gt-n)
• or is taken up by the glial cell transporter (Gt-g)
• Converted to glutamine by glutamine synthetase
• Glutaminase will convert glutamine to glutamate for re-use as a NT
What two enzymes are responsible for synthesizing glutamate from alpha-ketoglutarate?
• OAT and AAT
• Both convert alpha-ketoglutarate to glutamate if there is either omithine or aspartate present
Where is glutamate present as a NT in the CNS?
• Virtually all neurons in CNS
• Highest in hippocampus, cortex, lateral septum, striatum, cerebellum
• Functions as the major excitatory NT through AMPA receptors
• Trigger neuroplasticity
• When overactivated can trigger excitotoxicity
In what diseases does glutamate play a pathophysiological role?
• Ischemic brain damage
How is Ach synthesized?
• CAT = choline acetyl transferase
• Choline uptake is the rate limiting step so this enzyme is pretty amazingly fast
How is ach packaged into the vesicles for release?
• VAT - vesicle associated transporter
What is meant by VSSC in french's notes?
• VSSC = voltage senstitive (sodium) channel
• You could have VSCC for calcium channel too
In what diseases does ach play a pathophysiological role?
What is meant by MSN, DB, Ch5-Ch8 in terms of ach?
• These are the regions of the brain where cell bodies make ach as their NT and project into hippocampus and cerebral cortex
• MSN = medial septal nuclei
• DB = diagonal band of Broca
• Ch5-Ch8 = cholinergic brainstem nuclei (numbered)
Where is ach found in the CNS?
• Remember it's used in all NMJs
• In the CNS, specifically produced in cell bodies in the brain stem and basal forebrain of neurons that widely project to cerebral cortex and hippocampus
• MSN, DB, Ch5-Ch8
What are the different receptors for ach?
• Muscarinic receptors
○ M1, M3 - Gq - increases PLC activity
○ M2, M4 - inhibits adenylyl cyclase activity
• Nicotinic receptors
○ N-n - opens receptor gated cation channel (ionotropic)
How is the ach "signal" terminated?
• Ach is terminated in the synapse by enzymatic degradation (ache = acetylcholinesterase)
• Both in the synapse anchored to cells and free in blood (periphery)
What causes ach release?
• Action potential, VSSC opening, VSCC opening, Calcium influx, synaptotagmin binding of calcium and fusion of stored ach vesicles
What NT should come to mind when you hear "monoamines"?
• Catecholamines and indoleamines
• Catecholamines - dopamine and norepinephrine
• Indoleamines - serotonin (5-HT)
How might drug action mess with the storage of the monoamines
• Ultimately by shifting balance between NT being stored in vesicles and being broken down by MAO
• Inhibitors of VMAT - reserpine - block vesicular uptake, increase degradation by MAO, decrease monoamine release and action overall
• Inhibitors of MAO - phenelzine-selegiline) decrease degradation by MAO, allowing greater vesicular storage by VMAT, increases monoamine release and action overall
• All of these affect all 3 monoamine transmission dynamics
How are the monoamines stored?
• Transmitter is taken up into storage vesicle via the vesicular monoamine transporter (VMAT)
• Packaged for release AND protected from degradation by intraneuronal monoamine oxidase (MAO)
How are the monoamines synthesized?
○ NE and DA
○ Rate limiting enzyme in pathway is tyrosine hydroxylase (TH)
○ Tyrosine is the start, dopamine an intermediate of norepinephrine
○ MAO is quite involved in the later stages of the pathway
○ 5-HT (serotonin)
○ Rate limiting enzyme in pathway is tryptophan hydroxylase (TpH)
○ Tryptophan is the start
○ MAO is involved in the later part of the pathway
How is monoamine release different from ach?
• It's not different at all
• Action potential, VSSC, VSCC, vesicle fusion and release
What are the different receptors for norepinephrine?
• NE is a catecholamine, which is a monoamine
• Alpha-1 adrenergic
○ Gq - stimulates PLC activity
• Alpha-2 adrenergic
○ Gi - inhibits adenylyl cyclase, opens K channels
• Beta-1 adrenergic
○ Gs - stimulates AC activity
• Beta-2 adrenergic
○ Gs - stimulates AC activity
What would be the overall effect of blocking specific monoamine transporters?
• Increase duration of synaptic activity and enhance MA neurotransmission
How is the monoamine signal terminated?
• Primarily by presynaptic membrane transporters that suck back up transmitter (reuptake)
• In cytosol, ever-present MAO can destroy it OR it can be re-packaged by VMAT
• Each vesicle will have a specific monoamine transporter to package that vesicle
• Each of these transporters can be inhibited pharmacologically
What are the receptors for dopamine?
• D1 - Gs - stimulates AC
• D2 - Gi - inhibits adenylyl cyclase
What are the receptors for 5-HT?
• 5-HT = serotonin
• 5HT 1a, 1b, 1d - Gi- inhibition of AC, opens K channel
• 5HT 2a, 2b, 2c - Gq - stimulates PLC, closes Ca channel
• 5HT3 - ligand-gated cation channel - excitatory (ionotropic)
• 5HT4 - Gs - stimulates AC
Where can you find Dopamine in the CNS?
• [These are all successive links in a chain]
• Substantia nigra
• Neostriatum pathway (nigrostriatal), ventral tegmental area
• Limbic cortex (mesolimbic), ventral tegmental area
• Frontal cortex pathway (mesocortical), hypothalamus
• Pituitary (tuberoinfindibular pathway)
Where can you find norepinephrine in the CNS?
• Cell bodies in pons and brain stem (lucus ceruleus)
• Projecting to all levels of brain
• A1,2,5,7 = adrenergic brainstem nuclei
• Locus coeruleus projects into cerebellum as well
Where can you find serotonin in the CNS?
• Cell bodies in raphe regions of the pons/upper brain stem
• Project to all levels of brain
• Think Raphe nuclei in brainstem
What is the function of dopamine in the CNS?
• Initiation of voluntary movement
• Necessary for reward-related behaviors
• Cognitive control of behavior including working memory and control of attention
What is the function of norepinephrine in the CNS?
• Regulation of arousal, attention, vigilance, sleep-wake cycle
• Fear response/anxiety
• Descending pathways modulate afferent pain signals
What is the function of serotonin in the CNS?
• Influences sleep, arousal, attention, processing of sensory information in cerebral cortex
• Important aspect of emotion and mood regulation, pain pathways, eating and drinking behaviors
In what diseases does Dopamine play a pathophysiological role?
• Restless leg syndrome
• Obsessive-compulsive anxiety disorder
• Attention deficit/hyperactivity disorder
• Drug abuse
In what diseases does Norepinephrine play a pathophysiological role?
• Anxiety disorders (panic, PTSD)