CNS neuropharmacology - french Flashcards
For a neuron to receive information what are the possible axonic connections?
- Axodendritic
- Axosomatic
- axoaxonic
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?
- GABA
- Glu
- Ach
- Da
- Ne
- 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
- Attention
- Concentration
- Emotions
- Impulses
- Obsessions
- Compulsions
- Motor
- Fatigue
- Ruminations
- Worry
- Pain
- Negative symptoms
- Guilt
- Suicidality
What behaviors are linked to the NA?
- NA = nucleus accumbens
- Delusions
- Hallucinations
- Pleasure
- Interests
- Libido
- Fatigue
- Euphoria
- Reward
- Motivation
What behaviors are linked to the S?
- S = striatum
- Motor
- Critical relay site from PFC
What behaviors are linked to the thalamus?
- T = Thalamus
- Pain
- Sensory relay TO cortex
- Sensory relay FROM cortex
- alertness
What behaviors are linked to the BF?
- BF = basal forebrain
- Memory
- Alertness
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
- Sleep
- Appetite
- Endocrine
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?
• GABA-a
○ Opens ligand-gated Cl channel, decreases neuronal excitability
• GABA-b
○ 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?
- Epilepsy
- Ischemic brain damage
- Addiction
- schizophrenia
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?
- Alzheimer’s
- Parkinson’s
- schizophrenia
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?
• 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
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
- Mood/emotion
- 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?
- Schizophrenia
- Parkinson’s
- Restless leg syndrome
- Obsessive-compulsive anxiety disorder
- Attention deficit/hyperactivity disorder
- Drug abuse
In what diseases does Norepinephrine play a pathophysiological role?
- Mania
- Depression
- Anxiety disorders (panic, PTSD)
- ADHD
In what diseases does Serotonin play a pathophysiological role?
- Depression
- Anxiety disorders
- Schizophrenia
- Eating disorders
