Neuropharmacy 2 Flashcards
What are the divisions of PNS & CNS and ANS?
PNS - Somatic and Autonomic
ANS - sympathetic & parasympathetic
CNS - Brain & Spinal Cord
How do drugs cross the BBB?
By inflammation - blood vessels are more leaky due to damage
Transporters
P- Glycoproteins - cell membrane pumps
How is the cerebrum split?
Into two parts : Creativity - RHS - Contains Grey matter
Logic and learning - LHS
What is the cerebral cortex composed of?
Sensory, motor & association areas
What are the four lobes of the cerebrum?
Parietal - sensorimotor integration - touch
Temporal - Ears - involved with language
Occipital - Visual Processing
Frontal - Memory & Learning
What is the hypothalamus involved in?
Homeostasis, thirst, hunger, emotion & ANS
What abnormalities are associated with the thalamus?
OCD, Bipolar & anxiety
What abnormalities is the hippocampus associated with?
Alzheimer’s, involved with learning & memory
What part of the brain is associated with addiction?
Ventral Tegmental
What regulates coordination of movement, posture & balance?
Cerebellum
What is the brainstem?
Medulla, pons & midbrain - involved with vision, hearing and body movement alongside major control centres
What is the spinal cord involved in?
Conduction pathway to and from the brain.
What are the four functional systems of the brain?
Limbic System - Involved in the reward
responsible for memory, emotion and learning. Connects to hypothalamus & communicates with the cerebrum
Reticular Activating system - Acts as a filter
Network of neurons that heightens alertness and arousal of the brain. Sleepiness and awakeness. Projects from brainstem to thalamus
Basal Ganglia - Connected to the limbic system - reward system. Cluster of neurons regulating initiation and termination of skeletal muscle movement.
Extrapyramidal system - part of motor system involved in the coordination of movement. Reflexes, complex movements & postural control
Define a neuron and explain its four parts
A neuron is an excitable cell that processes and transmits information by electrochemical signalling.
Dendrite - Input of information
Axon - Transports information
Soma/ perikaryon - Processes & maintains information
Nerve Terminal - Output of information
What regulates gene expression?
Neurotrophic factors
Define neuromodulators
Released from astrocytes or neurons and produce slower post or pre synaptic responses
Define neurotransmitters
Released from presynaptic terminals and produce rapid excitatory or inhibitory responses in postsynaptic neurons
What are three types of glial cells
Astrocytes, Oligodendrocytes & microglia
What cells act as macrophages of the brain?
Microglia
How do microglia function?
Proliferate after injury, move to the site of injury and transform in large macrophages to remove cellular debris
What are oligrodendrocytes?
Form the myeline sheath around the axon
What are astrocytes?
Separate neurons and modulate the metabolic and ionic microenvironment
Can glial cells undergo cellular division?
Yes
What are the two forms of neutrotransmitters?
Amino Acid derived and amine-containing
What are types of inhibitory and excitatory neurotransmitters?
GABA & Glycine - inhibitory
Glutamate & Aspartate - Excitatory
What is reuptake required?
Active reuptake of neurotransmitters into the presynaptic nerve or other supporting cells like glia, terminates the function of neurotransmitters. This is dependent on transporter proteins - each specific for particular transmitters
How is glutamate converted to GABA?
By the enzyme glutamic acid decarboxylase. Removes a carboxyl group
What enzyme is used to convert glutamine to glutamate?
Glutaminase
What enzyme is used to convert Glutamate to glutamine?
Glutamine Synthase
Where does glutamate come from?
Derived from glucose in the Krebs cycle by action of GABA transaminase or glutamine - synthesised by glial cells
How is glutamates action terminated?
By carrier-mediated reuptake
What is the role of astrocytes with regards to glutamate
This reaction takes place in astrocytes. Astrocytes take up glutamate and convert to glutamine, enabling it to be transported - back to neurons to be converted back to glutamate.
What are the 4 type of EAA receptors for glutamate?
NMDA
AMPA
Kainate
Metabotropic
Where are NMDA receptors located?
Where are AMPA receptors located?
Expressed on nerve terminals where they can enhance or reduce transmitter release.
Expressed also on astrocytes as well as neurons - play an important communication role
How is glutamate released?
Stored in synaptic vesicles and released by Ca2+ dependent exocytosis - taken up by nerve terminals and neighbouring astrocytes
Describe NMDA transmission
Highly permeable to Ca2+
Blocked by physiological Mg2+, if decreases then becomes unblocked
Requires the presence of glycine - allosteric modulator.
Mediate slower excitatory responses than AMPA & Kainate
What happens if there are excessive Ca2+ ions?
The entry of excessive amounts of Ca2+ produced by NMDA receptor activation can result in cell death known as excitotoxicity.
How is GABA formed, enzymes?
How is GABA terminated, enzymes?
Formed from glutamate by action of glutamic acid decarboxylase.
Terminated by reuptake and also deamination by GABA transaminase.
Where is GABA located?
Found only in the brain tissue
What effects do GABA receptor agonists have?
What receptors do they act on?
anti-anxiety and anti-convulsive
GABAa & GABAb
What are GABAa receptors?
Located postsynaptically, directly coupled to chloride channels. When these are open they reduce excitability.
Increasing Cl- permeability hyperpolarises the cell
What are examples of GABA channel agonist?
benzodiazepines, barbiturates & ethanol
Benzodiazipine is an allosteric
How does Benzodiazepine work?
Act selectively on GABAa receptors- mediating an inhibitory synaptic transmission.
They act as positive allosteric modulators facilitating the opening of GABA -activated chloride ion channels and act allosterically to enhance the affinity for GABA and the receptor. As the cl- conc increases, this hyperpolarises the cell reducing its ability to be excited.
Example of sedative benzodiazepines
Diazepam
Give examples of GABA reuptake inhibitors
& GABA transaminase inhibitors
Tiagabine
Valproate, Vigabatrine
Where is glycine located and how does it work?
Located in spinal cord & brainstem and works the same as GABA
When glycine receptors are activated - CL- enters and hyperpolarises the cell reducing excitability.
Tetanus Toxins - prevent glycine release - causing hyperexcitability & muscle spasams
Name amine transmitters
Noradrenaline, adrenaline, dopamine, 5-hydroxytryptamine & acetylcholine
What is noradrenaline, where is it located & responsible for?
Neurotransmitter located in small cluster of noradrenergic cells of the pons & medulla. Most prominent cluster is LC (locus coeruleus).
Affect mood, BP & arousal.
LC is connected to spinal cord & involved in descending control of pain.
Some adrenergic cells located in brainstem release adrenaline - due to them containing phenylethanolamine methyl transferase - enzyme responsible for conversion of noradrenaline to adrenaline.
What is dopamine, what are the four pathways?
Neurotransmitter and precursor for noradrenaline.
1 - Nigrostriatal - cell bodies in the substantia nigra whose axon terminate in the corpus striatum, movement & motor control.
2 - Misolimbic - Midbrain to Limbic system. Project into parts of nucleus accumbens and amygdaloid nucelus - reward, learning.
3 - Mesocortical - Midbrain to Cortex. Important for emotional control & motivation
4 - Turbohypophyseal neurons - Hypothalamus to pituitary gland - involved with endocrine system
What are the dopamine receptors?
5
D1 & 5 = stimulate adenylyl cyclase
2,3,4 = inhibit ca2+, stimulate K+ and ultimately inhibit adenylyl cyclase.
D2 - responsible for positives in schizophrenia and parkinsons
D2 - releases prolactin from pituitary gland.
What serotonin receptor is responsible for treatment of nausea and vomitting?
5-HT3
What serotonin receptor is responsible for prophylaxis of migraines?
5-HT2
Alongside being the target for hallucinogenic drugs
What serotonin receptor is responsible for treatment of anxiety and depression and what other treatment?
5-HT1
Agonist drugs act as migraine treatments
What is acetylcholine and its effect on the body/location
ACh is an excitatory neurotransmitter consisting of various subtypes such as nicotinic (ionotropic) or muscarinic (GCPR).
Synthesised, stored and released the same way as in periphery.
Widely distributed - forebrain, midbrain and brainstem
A cluster provides the main cholinergic supply to the hippocampus which is involved in memory and learning - Alzheimers
Important in Parkinson’s
How can neurotransmitter drugs become more specific?
By targeting specific receptors/ identifying receptor subtypes. Drugs targeting neurotransmitters affect the whole system.
What is meant by complexity - HINT COCAINE
Cocaine inhibits reuptake of dopamine into the presynaptic neuron, exposing it for longer in the presynaptic cleft. DA will still bind to the postsynaptic neuron and cause a pleasurable emotional response. Prolonged exposure of DA will cause a downregulation of receptors.
