CHAPTER 4: NEUROTRANSMITTERS AND NEUROMODULATORS Flashcards
What is the excitatory amino acid NT in the brain?
glutamate
What is the inhibitory amino acid neurotransmitter in the brain?
-Gamma-aminobutyric acid or GABA
What is the inhibitory amino acid NT in the spinal cord and lower brain stem?
glycine
What is glutamate?
- amino acid
- most important excitatory neurotransmitter in the brain
What is a vesicle glutamate transporter?
-proteins in the vesicle membrane that pump glutamate into a vesicle
How is glutamate produced, stored and released?
- PRODUCTION: Synthesized from a precursor (glutamine) by an enzyme (glutaminase).
- STORAGE: vesicle glutamate transporters package glutamate into vesicles.
- RELEASE: action potential, glutamate released from presynaptic terminal.
What are the 4 major types of glutamate receptors?
3 ionotropic receptors, 1 metabotropic receptor
- ionotropic: NMDA receptor, AMPA receptor, kainate receptor.
- metabotropic: metabotropic glutamate receptor
What is the main function of metabotropic glutamate receptors?
-presynaptic autoreceptors
What is the main function of AMPA and NMDA receptors?
-important roles in the cellular basis of learning and memory.
How can glutamate open a calcium channel on an NMDA receptor?
- a glycine molecule must be attached.
- a magnesium ion must be removed from the magnesium binding site (this happens if the post synaptic membrane is partially depolarized.
What are the two conditions for an NMDA receptor to open?
- glutamate is present
- postsynaptic membrane is depolarized.
- NMDA receptor= voltage and neurotransmitter dependent ion channel
How does PCP (phencyclidine) act on the calcium ion channel?
- binds to its site which is located deep within the ion channel, next to the magnesium binding site.
- Prevents the calcium ions from passing through the ion channel.
Which other drug has similar effects as PCP?
Ketamine, thought to bind on the same site as PCP.
How is glutamate reuptaken and deactivated?
- Removed from synapse by excitatory amino acid transporters
- Broken down into it’s precursor (glutamine) by the enzyme glutamine synthase
What is PCP?
-Phencyclidine a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist
What are excitatory amino acid transporters?
proteins that remove glutamate from the synapse
What is glutamine synthase?
Enzyme that breaks down glutamate into its precursor glutamine.
What is GABA?
- Amino acid
- Most important inhibitory NT in the brain
Where is GABA distributed?
widespread distribution throughout brain and spinal cord
How is GABA produced?
- from a precursor: glutamic acid
- by the action of enzyme GAD
What is a vesicle GABA transporter?
-Proteins in the vesicle membrane that pump GABA into a vesicle
What is the main function of GABA-secreting neurons?
-exhibit inhibitory influence to keep brain stable
What are seizures are result of?
- lacking or poorly functioning GABA-secreting neurons or receptors
- During a seizure interconnected excitatory neurons all fire uncontrollably
Are GABAa receptors ionotropic or metabotropic?
ionotropic
What channels do GABA a receptors control?
-chloride channels
How do some drugs produce their effects with GABA receptors?
- barbiturates, alcohol, and benzodiazepines
- they bind at various GABAa binding sites
How is GABA reuptaken and deactivated?
- removed from synapse by GABA transporters
- broken down by enzyme GABA aminotransferase.
What is glycine?
-Inhibitory neurotransmitter in spinal cord and lower portions of the brain
What are the effects of tetanus on glycine?
-The bacteria that causes tetanus releases a chemical that prevent the release of glycine (and GABA as well)
What would the removal of the inhibitory effects of glycine synapses cause?
-continuous contraction of muscles
What is a direct antagonist for glycine receptor?
Strychnine
Where does Acetylcholine (ACh) function?
Both in CNS and PNS
What is ACh’s primary role in the PNS?
Primary NT to control muscle contraction
In the CNS, what are the 3 specific location sand pathways where ACh is found?
- Dorsolateral pons
- Basal forebrain or nucleus basalis
- Medial septum
What is the function of ACh in dorsolateral pons?
-role in REM sleep
What is the function of ACh in the basal forebrain or nucleus basalis?
facilitate learning
What is the function of ACh in the medial septum ?
memory formation
How is ACh produced?
- synthesized from precursors choline and acetylcoenzyme A,
- by the enzyme choline acetyltransferase (ChAT)
What is choline acetyltransferase (ChAT)?
The enzyme that transfers the acetate ion from acetyl coenzyme A to choline, producing the neurotransmitter acetylcholine.
What is vesicle ACh transporter?
Proteins in the vesicle membrane that pump acetylcholine into a vesicle
What is Botulinum toxin (Botox) and how does it act on ACh?
- produced by the bacteria: clostridium botulinum
- acetylcholine antagonist
- prevents release of ACh by terminal buttons.
What is the ionotropic ACh receptor stimulated by?
nicotine (found in tobacco leaves)
What is the metabotropic ACh receptor stimulated by ?
muscarine (found in the mushroom amanita muscaria)
Which type of ACh receptor is mostly contained in the PNS and why?
- ionotropic nicotinic receptors
- because muscle fiber shave to contract quickly , and nicotinic receptors are rapid-acting
Which type of ACh receptor is mostly contained in the CNS and why?
- metabotropic muscarinic receptors
- they control ion channels and production of second messengers so they are slower
What is ACh deactivated by ?
enzyme acetylcholinesterase (AChE) which is present in the post synaptic membrane.
What are AChe inhibitors used for?
to treat myasthenia gravis.
What are monoamine NT produced by?
Several regions of the brain
What is the general function of monoamine NT?
Modulate functions of widespread regions of the brain either increasing or decreasing brain functions
What are the four types of monoamine? ( also included as indolamines)
- dopamine
- norepinephrine
- epinephrine
- serotonin
What are the 3 that belong to the subclass of monoamines called catecholamines?
- dopamine
- norepinephrine
- epinephrine
What types of post synaptic potentials does dopamine (DA) produce? (excitatory or inhibitory)
both excitatory and inhibitory
What functions of the body does dopamine affect?
- movement
- attention
- learning
- reinforcing effect of drugs
Where do the three most important dopamine pathways originate?
in midbrain structures: subtantia nigra and ventral tegmental area
What is the
-origin
-location of terminal buttons
of the nigrostriatal system?
- ORIGIN: substantia nigra
- TERMINAL BUTTONS: neostriatum (caudate nucleus and putamen)
What is the
-origin
-location of terminal buttons
of the mesolimbic system?
- ORIGIN: ventral tegmental area
- TERMINAL BUTTONS: nucleus accumbens, amygdala and hippocampus
What is the
-origin
-location of terminal buttons
of the mesocortical system?
- ORIGIN: ventral tegmental area
- TERMINAL BUTTONS: prefrontal cortex
What are the behavioural effects of the nigrostriatal system?
control of movement
What are the behavioural effects of the mesolimbic system?
Reinforcement effects of addictive drugs
What are the behavioural effects of the mesocortical system?
short-term memory, planning, strategies for problem solving
What does the degeneration of dopaminergic neurons that connect the substantia nigra with the caudate nucleus cause?
Parkinson’s disease
What is the precursor for the two major catecholamines (dopamine and norepinephrine)?
tyrosine, which is an essential amino acid that we must obtain from our diet.
How is tyrosine modified to become dopamine?
- modified by enzyme tyrosine hydroxylase do become L-DOPA
- L-DOPA modified by enzyme decarboxylase to become dopamine
How does dopamine become norepinephrine?
-converted by enzyme dopamine B-hydroxylase.
What are vesicle monoamine transporters?
Proteins in the vesicle membrane that pump monoamine NT into a vesicle.
What drug are people with Parkinson’s disease often given?
- L-DOPA
- because it can cross the blood-brain barrier for conversion to DA
What are the metabotropic types of dopamine receptors?
-D1, D2, D3, D4, D5.
How is DA reuptaken and deactivated?
diagram
- DA transporters remove DA from synapse
- Deactivation of catecholamines is regulated by an enzyme called monoamine oxidase (MAO)
What drugs serve as agonists for DA?
- amphetamine, methamphetamine (for dopamine and norepinephrine)
- cocaine, methylphenidate (Ritalin). only dopamine
What is cocaine used for?
-topical anesthetia
What is methylphenidate used for?
enhance attention and impulse control in ADHD
Where is NE found?
both CNS and PNS
What is epinephrine a synonym of ?
adrenaline
What regions of the brain receive input from noradrenergic neurons?
almost every region
Where are the cell bodies of the most important noradrenergic system located?
in the locus coeruleus (nucleus located in the dorsal pons)
What are the primary effects of an activation of NE neurons?
increase of vigilance and attentiveness.
How is NE produced, stored and released?
- As seen earlier, it is transformed from DA so same thing:
- synthesized from DA by enzyme dopamine B-hydroxylase
- since dopamine is already in vesicle, the storage of NE happens in vesicles themselves.
- Released through axonal varicosities.
What is an axonal varicosity?
An enlarged region along the length of an axon that contains synaptic vesicles and releases a NT and neuromodulator.
How many types of adrenergic receptors are sensitive to both NE and epinephrine and where are they found?
- Four types called alpha a and 2 and beta 1 and 2
- All metabotropic
- Found in neurons in the CNS and various organs of body.
How is NE reuptaken and deactivated?
- NE transporter removes excess NE from the synapse
- Excess NE in the terminal buttons is deactivated by MAO type A.
What are MAO inhibiting drugs (MAOIs) sometimes used for?
- to treat depression, but have side effects
- newer drugs such as selective serotonin, Ne and DA reuptake inhibitors have replaced them.
What does serotonin (5-HT) play a role in?
- regulation of mood
- control of eating
- sleep
- arousal
- pain regulation
- dreaming
Where is 5-HT found?
- found in 9 clusters
- most is located in the raphe nuclei of the midbrain, pons and medulla
- 2 most important clusters: dorsal and median raphe nuclei
What is 5-HT released from
from varicosities, like NE
What is the precursor for serotonin?
-the amino acid tryptophan.
What is the precursor for serotonin?
-the amino acid tryptophan.
What do 5-HT receptors serve as?
- some types of receptors serves as autoreceptors
- other types serve as postsynaptic receptors
How is 5-HT reuptaken ?
serotonin transporter removes it from the synapse
What drugs that inhibit the reuptake of serotonin play an important role in treatment of mental illness?
- Fluoxetine (Prozac): treatment of depression, anxiety, OCD.
- MDMA (ecstasy): excitatory and hallucinogenic effects
Where is histamine found?
In the tuberomammillary nucleus, locate din the posterior hypothalamus
What is the important role of histamine?
wakefulness
What is the effect of drugs that block histamines ?
drowsiness
How is histamine produced?
-Produced from the amino acid precursor histidine by the action of the enzyme histidine decarboxylase
What are the histamine receptors and where are they contained?
- H1, H2, H3, H4
- contained in CNS
What drugs are antagonist to histamine receptors?
-antihistamines like diphenhydramine
What are peptides?
-two or more amino acids linked together by peptide bonds
How are peptides produced?
-from precursor molecules which are large polypeptides broken into smaller neurotransmitter molecules by special enzymes
Where are peptides released from?
- all parts of terminal button
- no reuptake or recycling
What is one of the best known family of peptides?
-endogenous opioid: class of peptides secreted by the brain that act as opiates.
How do opioids reduce pain?
-They mimic some of the effects of endogenous opioid and bind to peptide receptors.
When were the receptors for opiate drugs discovered?
In the 70s
What are the natural ligands for receptors called?
enkephalins
What are the three different types of opioid receptors?
mu, delta, kappa.
What are the three neural systems that are activated when opioid receptors are stimulated?
- analgesia
- inhibition of defensive responses such as fleeing or hiding
- reinforcement (reward): can lead to abuse
What can substances derived from lipids do?
transmit messages within or between cells.
How do lipid NT produce, store and release?
- appear to be synthesized on demand, produced or released as needed.
- they are not stored in synaptic vesicles.
What are the best known lipid NT?
-endocannabinoids: responsible for the effects of THC
What are the two types of cannabinoid receptors?
-CB1 and CB2.
What did scientist Agarwal find about THC?
- THC exerts analgesic effects by stimulating CB1
- acetaminophen also acts on these receptors.
How are lipids reuptaken and deactivated?
- anandamide deactivated by the enzyme FAAH
- anandamide transporters are responsible for the reuptake of anandamide to the presynaptic cell
What are nucleosides?
compound that consists of a sugar molecule bound with a purine or pyrimidine base.
What are examples of nucleosides?
adenosine and caffeine
