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Neuro > CNS neuropharmacology - french > Flashcards

CNS neuropharmacology - french Flashcards

1
Q

For a neuron to receive information what are the possible axonic connections?

A
  • Axodendritic
    • Axosomatic
    • axoaxonic
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2
Q

What are hierarchical systems in the brain?

A
  • 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
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3
Q

What are local circuit neurons?

A
  • 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)
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4
Q

What are relay neurons?

A
  • 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
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5
Q

What is the main function of the diffuse systems?

A
  • 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
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6
Q

What is important about the monamine diffuse systems?

A
  • Cannot convey topographically specific information
    • CAN affect vast CNS areas simultaneously subserving global functions
    • Attention, sleep-wake cycle, appetite, emotions
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7
Q

What are the six key neurotransmitter systems that are targeted by psychopharmacologic agents?

A
  • GABA
    • Glu
    • Ach
    • Da
    • Ne
    • 5-HT (serotonin)
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8
Q

What should go through your mind as you use symptoms and circuits as a guide to pick a neuro pharm agent?

A
  • Match disease symptoms to hypothetically malfunctioning circuit
    • Consider neurotransmitter systems that theoretically regulate each circuit
    • Select treatment to target the relevant neurotransmitter system
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9
Q

What are the two broad categories of the rational approach to selecting a neuro-psychopharmacologic agent?

A
  • Using symptoms and circuits

* Specific behaviors hypothetically linked to brain regions

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10
Q

What behaviors are linked to the PFC?

A
  • PFC = pre frontal cortex
    • Executive function
    • Attention
    • Concentration
    • Emotions
    • Impulses
    • Obsessions
    • Compulsions
    • Motor
    • Fatigue
    • Ruminations
    • Worry
    • Pain
    • Negative symptoms
    • Guilt
    • Suicidality
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11
Q

What behaviors are linked to the NA?

A
  • NA = nucleus accumbens
    • Delusions
    • Hallucinations
    • Pleasure
    • Interests
    • Libido
    • Fatigue
    • Euphoria
    • Reward
    • Motivation
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12
Q

What behaviors are linked to the S?

A
  • S = striatum
    • Motor
    • Critical relay site from PFC
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13
Q

What behaviors are linked to the thalamus?

A
  • T = Thalamus
    • Pain
    • Sensory relay TO cortex
    • Sensory relay FROM cortex
    • alertness
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14
Q

What behaviors are linked to the BF?

A
  • BF = basal forebrain
    • Memory
    • Alertness
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15
Q

What region of the CNS is pain associated with?

A

• Spinal cord and brain stem

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16
Q

What part of the brain are memory and reexperiencing linked to?

A

• H = hippocampus

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17
Q

What behaviors are linked to the C?

A
  • C = cerebellum

* Motor coordination

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18
Q

What behaviors are linked to the Hy?

A
  • Hy = hypothalamus
    • Sleep
    • Appetite
    • Endocrine
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19
Q

What does GABA stand for?

A

• Gamma-aminobutyric acid

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20
Q

How is GABA synthesized?

A
  • 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
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21
Q

What do the receptors for GABA do?

A

• GABA-a
○ Opens ligand-gated Cl channel, decreases neuronal excitability
• GABA-b
○ GPCR, inhibits adenylyl cyclase, decrease Ca conductance, open K channel (hyperpolarizes)

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22
Q

What does vigabatrin have to do with GABA?

A
  • Inhibits degradation by GABA-T
    • T = transaminase
    • Works in the glial cells mostly
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23
Q

How does Tiagabine interact with GABA?

A

• Inhibits reuptake of GABA by transporter

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24
Q

What do benzodiazepines do in relation to GABA?

A

• bind to GABA-a receptor to facilitate GABA inhibitory action

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25
Q

How is GABA terminated?

A
  • Action of GABA at synapse terminated by reuptake into the presynaptic nerve terminal and surrounding glial cells
    • GABA transporter similar to monoamine reuptake transporters
26
Q

Where is GABA found in the CNS?

A
  • 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
27
Q

Is GABA-a receptor presynaptic or postsynaptic?

A
  • GABA-a is postsynaptic

* GABA-b is both pre and postsynaptic

28
Q

In which diseases does GABA play a pathophysiological role?

A
  • Generalized anxiety disorders
    • Seizure disorders
    • Sleep disorders
    • Alcohol abuse and withdrawal
    • Huntington disease
29
Q

How is glutamate synthesized?

A
  • 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
30
Q

What are the various receptors for glutamate?

A 
• 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
31
Q

How is released glutamate terminated?

A
  • 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
32
Q

What two enzymes are responsible for synthesizing glutamate from alpha-ketoglutarate?

A
  • OAT and AAT

* Both convert alpha-ketoglutarate to glutamate if there is either omithine or aspartate present

33
Q

Where is glutamate present as a NT in the CNS?

A
  • 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
34
Q

In what diseases does glutamate play a pathophysiological role?

A
  • Epilepsy
    • Ischemic brain damage
    • Addiction
    • schizophrenia
35
Q

How is Ach synthesized?

A
  • CAT = choline acetyl transferase

* Choline uptake is the rate limiting step so this enzyme is pretty amazingly fast

36
Q

How is ach packaged into the vesicles for release?

A

• VAT - vesicle associated transporter

37
Q

What is meant by VSSC in french’s notes?

A
  • VSSC = voltage senstitive (sodium) channel

* You could have VSCC for calcium channel too

38
Q

In what diseases does ach play a pathophysiological role?

A
  • Alzheimer’s
    • Parkinson’s
    • schizophrenia
39
Q

What is meant by MSN, DB, Ch5-Ch8 in terms of ach?

A
  • 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)
40
Q

Where is ach found in the CNS?

A
  • 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
41
Q

What are the different receptors for ach?

A

• Muscarinic receptors
○ M1, M3 - Gq - increases PLC activity
○ M2, M4 - inhibits adenylyl cyclase activity
• Nicotinic receptors
○ N-n - opens receptor gated cation channel (ionotropic)

42
Q

How is the ach “signal” terminated?

A
  • Ach is terminated in the synapse by enzymatic degradation (ache = acetylcholinesterase)
    • Both in the synapse anchored to cells and free in blood (periphery)
43
Q

What causes ach release?

A

• Action potential, VSSC opening, VSCC opening, Calcium influx, synaptotagmin binding of calcium and fusion of stored ach vesicles

44
Q

What NT should come to mind when you hear “monoamines”?

A
  • Catecholamines and indoleamines
    • Catecholamines - dopamine and norepinephrine
    • Indoleamines - serotonin (5-HT)
45
Q

How might drug action mess with the storage of the monoamines

A
  • 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
46
Q

How are the monoamines stored?

A
  • 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)
47
Q

How are the monoamines synthesized?

A

• Catecholamines
○ 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
• Indoleamine
○ 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

48
Q

How is monoamine release different from ach?

A
  • It’s not different at all

* Action potential, VSSC, VSCC, vesicle fusion and release

49
Q

What are the different receptors for norepinephrine?

A 
• 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
50
Q

What would be the overall effect of blocking specific monoamine transporters?

A

• Increase duration of synaptic activity and enhance MA neurotransmission

51
Q

How is the monoamine signal terminated?

A
  • 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
52
Q

What are the receptors for dopamine?

A
  • D1 - Gs - stimulates AC

* D2 - Gi - inhibits adenylyl cyclase

53
Q

What are the receptors for 5-HT?

A
  • 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
54
Q

Where can you find Dopamine in the CNS?

A
  • [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)
55
Q

Where can you find norepinephrine in the CNS?

A
  • 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
56
Q

Where can you find serotonin in the CNS?

A
  • Cell bodies in raphe regions of the pons/upper brain stem
    • Project to all levels of brain
    • Think Raphe nuclei in brainstem
57
Q

What is the function of dopamine in the CNS?

A
  • Initiation of voluntary movement
    • Necessary for reward-related behaviors
    • Cognitive control of behavior including working memory and control of attention
58
Q

What is the function of norepinephrine in the CNS?

A
  • Regulation of arousal, attention, vigilance, sleep-wake cycle
    • Fear response/anxiety
    • Mood/emotion
    • Descending pathways modulate afferent pain signals
59
Q

What is the function of serotonin in the CNS?

A
  • Influences sleep, arousal, attention, processing of sensory information in cerebral cortex
    • Important aspect of emotion and mood regulation, pain pathways, eating and drinking behaviors
60
Q

In what diseases does Dopamine play a pathophysiological role?

A
  • Schizophrenia
    • Parkinson’s
    • Restless leg syndrome
    • Obsessive-compulsive anxiety disorder
    • Attention deficit/hyperactivity disorder
    • Drug abuse
61
Q

In what diseases does Norepinephrine play a pathophysiological role?

A
  • Mania
    • Depression
    • Anxiety disorders (panic, PTSD)
    • ADHD
62
Q

In what diseases does Serotonin play a pathophysiological role?

A
  • Depression
    • Anxiety disorders
    • Schizophrenia
    • Eating disorders

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