-
Enzyme: Choline + AcetylcoA --> Acetylcholine + coenzyme A
Choline Acetyltransferase
-
The amount of AcetylCholine release is reduced in the presence of (blank) that blocks Vesicular AcetylCholine Transporter.
vesamicol
-
A toxin found in the venom of the black widow spider,(blank) , leads to a massive release of ACh at synapses in the PNS
Latrodectus mactans
-
blocks ACh release at the
neuromuscular junction by preventing fusion of synaptic vesicles with the nerve terminal membrane
Botulinum toxin
-
breaks down the acetylcholine into choline and acetic acid
acetycholinesterase
-
The choline transporter is subject to the blockade by the drug (blank) .
As a result, the rate of ACh production declines
hemicholinium-3 (HC-3)
-
Acetylcholinisterase inhibitor that is able to cross the blood-brain barrier and exerts on the CNS. Poisoning by accidentally taking (it is a compound isolated from Calabar beans, the seeds of a woody plant found in the Calabar region of Nigeria) leads to an over-activity of central cholinergic synapses due to accumulation of ACh. The symptoms include slurred speech, mental confusion, hallucinations, loss of reflexes, convulsions, and even coma and death.
Physostigmine
-
Acetylcholinisterase inhibitors that have therapeutic significance: Since they do NOT cross the BBB, used for treatment of an autoimmune neuromuscular disorder, myasthenia gravis.
Neostigmine and
pyridostigmine (used as an antidote against Sarin or Soman)
-
DISEASE - develop antibodies against their own muscle cholinergic receptors.
the loss of receptor function causes the patient’s muscles to be less sensitive to ACh, which in turn leads to severe weakness and fatigue.
myasthenia gravis
-
AcetylCholinisterase inhibitors are irreversible (therefore it is permanent), which have been developed as “nerve gases” to be used as “chemical weapon”,
ØSymptoms of nerve gas poisoning due to rapid ACh accumulation and overstimulation of cholinergic synapses throughout both the CNS and PNS include slurred speech, mental confusion, hallucinations, loss of reflexes, convulsions, and even coma and death.
Sarin and Soman
-
contains two groups of cholinergic neurons: (1) the medial septal group that project cholinergic axons to the hippocampus and parahippocampal gyrus; and
(2) the nucleus basalis group that project cholinergic axons to all parts of the neocortex, parts of limbic cortex and to the amygdala.
plays an important role in cognitive functioning, and damage to this system may contribute to the dementia observed in Alzheimer's disease.
Basal forebrain cholinergic system
-
cholinergic interneurons in the (blank) play a role of balance with the dopaminergic neurons. A neurotransmitter imbalance happened in Parkinson’s disease (PD) due to
neurodegeration of dopaminergic neurons (anti-cholinergic drugs are used in the early stages of PD).
striatum (basal ganglia)
-
exert a powerful excitatory
influence on dopamine neurons in the nucleus accumbens via mascarinic cholinergic receptor subtype 5 (M5) and nicotinic cholinergic receptors. These cholinergic actions are involved in the reinforcing effects of nicotine by targeting some nuclei, like NA.
The lateraldorsal and pedunculopontine tegmental nuclei
-
two major cholinergic receptor subtypes:
1) nicotinic (ionotropic receptors + fast excitatory)
- 2) muscarinic (metabotropic)
- - Some activate the phosphoinositide second-messenger system (PKC), while others inhibit the formation of cyclic adenosine monophosphate (cAMP)-PKA
- stimulation of K+ channel opening (via G-protein coupled to K+ channels). This leads to a hyperpolarization of the cell membrane and a reduction in cell firing.
-
A chemical relative of Acetylcholine called (blank) is AChE resistant, so it continuously stimulates the nicotinic receptors and induces a depolarization block of the muscle cells.
Nicotinic receptor agonist that causes depolarization block
cause a persistent depolarization of the cell membrane, in which the resting potential of the
membrane is lost and the cell cannot be excited
until the agonist is removed and the membrane re-polarized.
succinylcholine
-
Blocks nicotinic receptors (antagonist)
nicotinic antagonists (2 more)
D-Tubocurarine
Curare and mecamylamine
-
Stimulates muscarinic receptors (agonist) (3 of them)
muscarine
pilocarpine
arecholine
-
blocks muscarinic receptors (antagonist)
atropine scopolamine benztropine
-
partial agonist for nicotinic receptors
Varenicline
-
tacrine inhibits acetylcholinisterase
tacrine inhibits acetylcholinisterase
-
What Enzyme?
Glutamine -- > Glutamate
Glutaminase
-
Activation of the muscarinic receptors (blank) subtype in the cardiac muscle cells: a slowing of heart rate and a decrease in the strength of contraction – a decrease in the cardiac output
M2
-
Activation of the muscarinic receptors (blank) subtype in the smooth muscle cells: activation of smooth muscle cells, thus causing contraction of the muscle
M3
-
Activation of the muscarinic receptors (blank) subtype in the secretory glands: produces salivation, sweating, and lacrimation (tearing).
M3
-
ØPancreatic β-cells receive their parasympathetic innervation through the vagus nerve, which exhibits increased activity at the beginning of a meal. The resulting release of ACh acts on β-cell (blank) receptors to stimulate insulin secretion, thus regulating blood glucose levels during and following food consumption.
M3
-
Excitatory amino acid transporter locations:
Excitatory amino acid transporter 3
Excitatory amino acid transporter 4
Excitatory amino acid transporter 1 and 2
Excitatory amino acid transporter 5
- - most types of neurons
- - purkinjie cells
- - astrocytes
- - cells of the retina
-
3 ionotropic fast signaling glutamate receptors
Kainate (KA) receptor: Named for the selective agonist kainic acid. This substance actually comes from a type of seaweed called Digenea simplex (Na+)
AMPA receptor: Named for the selective agonist AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid), a synthetic amino acid analog. Most fast excitatory responses to glutamate are mediated by stimulation of AMPA receptors (Na+)
NMDA receptor: The agonist of which is obvious NMDA (N-methyl-D-aspartate). Like AMPA, NMDA is a synthetic amino acid. The channel conducts not only Na+ but also significant amounts of Ca2+ that functions as a 2nd messenger in the postsynaptic cell to directly activate a 2nd-messenger system.
-
Non-NMDA receptor antagonists:(blank) can block both AMPA and KA receptors, although it is somewhat more effective against the former subtype (AMPA). However, the compound has no effect on NMDA receptors.
NBQX (6-nitro-7-sulfamoyl-benzo(f)-quinoxaline- 2,3-dione)
-
A site within the NMDA receptor channel can bind (blank) ions.
When the cell membrane is at the resting potential (-60/-70 mV), (blank) ions are bound to this site relatively tightly. This causes the receptor channel to be blocked even if glutamate and (blank) or (blank) are present to activate the receptor.
B. However, if the membrane becomes depolarized, then the (blank) ions dissociate from the receptor and permit the channel to open if glutamate and (blank) or (blank) are present.
Thus, Mg2+ ion removal is (blank) dependent!
- -Mg2+
- - Mg2+
- - glycine or D-serine
- - Mg2+
- - glycine or D-serine
- - voltage
-
How many metabotropic glutamate receptors?
fast or slow?
eight
slow
-
(3 of them ) are anesthetic agents, non-competitive NMDA antagonists.
- Results in no excitatory effects of glutamate
Ketamine, MK-801 and PCP
-
blank - refers to a persistent (at least 1 hour) increase in synaptic strength produced by a burst of activity in the presynaptic neuron, this mimics the environment or experience changes
Long term potentiation
-
cell death
- shrinking , programmed
- swelling , lysis
-
The best established example of excitotoxic cell in humans due to food ingestion is the
damage produced by ingesting large amounts of an excitatory amino acid called what?
domoic acid.
-
Enzyme:
Glutamate --> GABA
Glutamic acid decarboxylase
-
GABA --- > Glutamate + Succinate
what enzyme?
GABA Aminotransferase
-
Glutamate ---> Glutamine
Glutamine synthetase
-
The classic GABAA receptor agonist-like drug is called
muscimol
causes an intoxication characterized by hyperthermia (elevated body temperature), pupil dilation, elevation of mood, difficulties in concentration, anorexia (loss of appetite), ataxia, catalepsy, and hallucinations (similar to other hallucinogenic drugs such as LSD);
-
best-known competitive antagonist for the GABAA receptor. It blocks the binding of GABA to the GABAA receptor, and when taken systemically, it has a potent convulsant effect
GABA-lytic drug
Bicuculline
-
two other convulsant drugs that inhibit GABAA receptor function by acting at sites distinct from the binding site of GABA itself.
non-competitive antagonist
Pentylenetetrazol (Metrazol) (once was used as a convulsant therapy for major depression)
picrotoxin
-
3 GABA agonists that
1) an anxiolytic (anti-anxiety); 2) sedative-hypnotic (sedating and sleep-inducing); and 3) anticonvulsant profile.
- -alcohol
- -benzodiazepines - bind to sites distinct from GABA binding site
- -barbiturates - bind to sites distinct from GABA binding site
- - Neurosteroids
-
GABAa ionotropic mechanism
GABAb metabotropic mechanism
- Open Cl- channels (Cl- influx)
- Open K+ channels (K+ move outside cell) and close Ca2+ channels
both hyperpolarize inhibit
-
the withdrawal symptoms that occur after abstinence from a drug,especially a narcotic, to which one is addicted.
, it promotes drug-taking behavior through a process of negative reinforcement
Drug dependence is the symptom of addiction that becomes evident when repeated drug administration is withdrawn
Abstinence syndrome
-
After dependence has taken place - dominance of negative reinforcement mediated by the anti-reward system, meaning that reward develops an opposing effect.
“Compulsive”
-
Drug reward before dependence (non-addiction) has occurred - dominance of positive reinforcement mediated by the reward system (reward circuit involved).
“Impulsive”
-
Euphoric followed by dysphoric feelings reported by subjects smoking cocaine paste, in that plasma cocaine was still present, but the positive euphoric state was replaced by a negative hedonic state (fatigue, depression, anxiety, and craving
what is this?
– allostatic change.
-
(so called “hot” drug-related) that connects the anterior cingulate cortex (ACC) with the Nucleus accumbens and is involved in emotional drive and motivation
ventromedial circuit
-
dorsolateral circuit (“cold” non-drug related) that projects from the dorsolateral PFC (DLPFC) to the (blank) and is particularly important for executive function
dorsolateral caudate nucleus (striatal region)
-
An orbitofrontal circuit that projects from the orbitofrontal cortex (OFC) to the (blank) and is associated with behavioral inhibition and impulse control - self-constraint.
ventromedial caudate (striatal region)
-
Positron emission tomography (PET) imaging (scan) with radiolabeled (blank) measures regional (blank).
-fluorodeoxyglucose
- glucose uptake and metabolism
-
Fermentation reaction reactants and products
reactants - sugar
products - ethanol and carbonic gas
-
blood alcohol content to produce measurable behavioral effects
0.04%
-
absorbs 10% of alcohol
stomach
-
absorbs 90% of alcohol
small intestine
-
What enzyme?
Alcohol --> Acetaldehyde
alcohol dehydrogenase
-
What enzyme?
Acetaldehyde ---> Acetic acid
acetaldehyde dehydrogenase
-
Acetic acid undergoes oxidation to form
Carbon dioxide , Water, and energy
-
The blood alcohol level is lethal
0.45%
-
blood alcohol content with vomiting
0.15%
-
blood alcohol concentration with unconsciousness
0.35%
-
blood alcohol concentration for legal intoxication
0.08%
-
which involves the accumulation of triglycerides inside liver cells. The liver normally takes up and metabolizes fatty acids as part of the digestive process; however, when alcohol is present, it is metabolized first, leaving the fat for storage.
Fatty liver
-
which is serious and potentially lethal condition developed due to that individuals have abused alcohol for many years. liver cell damage (cell death occurs) is apparently caused by accumulation of high levels of acetaldehyde (a metabolite of alcohol formed in the liver). Symptoms include inflammation of the liver, fever, yellowing of the skin (jaundice), and pain.
Alcoholic hepatitis:
-
The death of liver cells due to hepatitis stimulates the formation of scar tissue.
blood vessels carrying oxygen are cut off leading to further cell death.
permanent irreversible.
Alcoholic cirrhosis:
-
close to the genes for the D4 dopamine receptor and tyrosine hydroxylase
chromosome 11p
-
near the gene for the GABAA receptor complex
chromosome 4p
-
what drug inhibits ALDH, the enzyme that converts acetaldehyde to acetic acid in the normal metabolism of alcohol?
disulfiram (antabuse)
-
what drug reduces the positive feelings and
subjective "high" of alcohol by blocking the effects of alcohol-induced endorphin release.
opiate receptor antagonist
reduce reinforcement
Naltrexone
-
what drug acts as a partial antagonist at NMDA receptors and significantly reduces the effect of glutamate increase that occurs during alcohol withdrawal in rats. This may explain its therapeutic effects on withdrawal symptom relief.
also has a chemical structure similar to GABA and returns basal GABA levels
Acamprosate
-
Animal studies suggest that blocking the (blank) for substance P reduces alcohol consumption and relapse behavior after withdrawal by alleviating anxiety symptoms.
neurokinin-1 receptors (NK1R)
-
The principal active ingredient in opium is called
morphine
-
Morphine group
Codeine group
Heroin group
Hydroxy (-OH)
Methoxy (-OCH3 exchanged for one OH)
- codeine less analgesic and less side effects
Heroin (2 acetly groups exchanged for 2 OH)
-
Chemical modifications of the morphine molecule also produce pure competitive antagonists such as
naloxone and nalorphine
-
morphine , codeine , thebaine, papaverine
natural narcotics
-
heroin , oxycodone, hydromorphine, etorphine
semisynthetic narcotics
-
enkephalins, endorphins, dynorphins
endogenous opioids (neuropeptides)
-
pentazocine, meperidine, fetanyl, methadone, LAAM, propoxyphene
totally synthetic narcotics
reduced dependence less respiratory depression and less potent than morphine and less constipation
-
highest potency inhibiting electrically induced contracting intestine guinei pigs for opiods/ opiates
etorphine
-
highest potency inhibiting guinei pig ileum twitch and analgesia in humans
etorphine
-
what opioid receptor ?
With a high affinity for morphine and related opiate drugs and the widest distribution in both the brain and spinal cord
The μ-receptor
-
what opioid receptor?
They are predominantly found in forebrain structures such as the neocortex, striatum, olfactory areas, substantia nigra, and nucleus accumbens
The δ-receptor
-
what opioid receptor?
With a very distinct distribution found in the sub-cortical areas, like striatum and amygdala, but additionally has a unique distribution in the hypothalamus and pituitary
κ-receptors
-
what opioid receptor?
localization in the spinal cord, raphe nuclei, periaqueductal gray (PAG) and limbic areas suggests a significant role in analgesia (anti-nociception), feeding, learning, motor function, and neuroendocrine regulation.
NOP-Rs
-
All four opiate receptors have been successfully cloned having between blank and blank amino acids
370-400
-
pro-opiomelanocortin or POMC (267 amino acids), pro-enkephalin (267 amino acids), pro-dynorphin (254 amino acids), and pro-nociception/orphanin FQ (180 amino acids);
four large propeptides opiods
-
üIn addition, a group of peptides called (blank) , bind quite selectively to the µ-receptor and are as potent as morphine in relieving pain.
endomorphins
-
pituitary gland has high concentrations of which propeptide?
Pro-opiomelanocortin (267 AA)
-
what opioid receptor these bind to?
Enkephalins
Dynorphin
Endorphin
- δ-receptors
- κ-receptor
- µ- and δ-receptors, but bind preferentially to the µ-receptors
-
opioids and N/OFQ work by both of those mechanisms to 1). open K+ channels and close Ca2+ channels (G-protein-coupled to channels); 2). inhibit adenylyl cyclase activity (effector enzyme to trigger 2nd messenger).
The overall effects of opiate-like opioid on nerve cell function include the 1) reduction of membrane excitability; 2) subsequent slowing of cell firing and 3) the inhibition of neurotransmitter release.
The opioid receptor types are linked to G-proteins (metabotropic receptors);
ØOpioid receptor-mediated cellular changes are inhibitory
opioids and N/OFQ work by both of those mechanisms to 1). open K+ channels and close Ca2+ channels (G-protein-coupled to channels); 2). inhibit adenylyl cyclase activity (effector enzyme to trigger 2nd messenger).
The overall effects of opiate-like opioid on nerve cell function include the 1) reduction of membrane excitability; 2) subsequent slowing of cell firing and 3) the inhibition of neurotransmitter release.
The opioid receptor types are linked to G-proteins (metabotropic receptors);
ØOpioid receptor-mediated cellular changes are inhibitory
-
opioid Postsynaptic inhibition (axodendrtic or axosomatic):
open K+ channels
-
axoaxonic opioid inhibition
activate Gi protein linked to Ca2+ channel to close Ca2+ channels
inhibit adenylyl cyclase then cAMP then PKA
-
which pain fibers carry pain signal fastest Aδ- fibers or C-fibers and why?
Aδ cuz they myelinated while C-fibers are unmyelinated so slow conduction
-
Where do early pain signals go?
Primary and secondary somatosensory cortex
-
Blank and blank are especially activated by late pain information
Anterior cingulate cortex, secondary somatosensory cortex and other limbic areas
-
Endogenous analgesic system. The most important descending pathways begin in the pariaqueductal gray (PAG). The PAG is a brain area rich in endogenous opioid peptides and high concentrations of opioid receptor, particularly (blank) and (blank).
The neurons begin in the PAG and end on cells in the (blank), including the serotonergic cell bodies of the (blank), and noradrenergic cell bodies of the (blank).
µ and κ
medulla
nucleus of the raphe nuclei
locus coeruleus
-
Neurons of the PAG decend to (blank)
then (blank) and (blank) neurons descend to the (blank) to modulate the transmission of the pain signal at that level
brain stem nucleus of the raphe and the locus coeruleus
serotinergic and noradrenergic
spinal cord
-
β-endorphin (endogenously) inhibits the inhibitory effects of GABA in the (blank) , this is called (blank) and this allowing the firing rate of the (blank) cells to increase and the cells to release more (blank) in the (blank).
They can decrease the release of GABA by (blank) or reducing (blank) on GABA terminals (axoaxonic inhibition);
Ventral tegmental area
disinhibition
mesolimbic dopaminergic
dopamine
nucleus accumbens (NA)
opening K+ channels
Ca2+ influx
-
Dynorphins inhibit the release of dopamine from mesolimbic dopaminergic cells by (blank)
no dopamine is release in the (blank)
preventing Ca2+ entry
nucleus accumbens
-
α-adrenergic agonist used for opiate withdrawal that reduce cell hyperexcitability by rebound by activating noradrenergic autoreceptors to reduce norepinephrine release
Clonidine
-
(two of them ) drug used in treatment of heroin addiction
Methadone
buprenorphine (Buprenex)
-
VGLUT1 gene expression occurs primarily in the blank and blank, whereas VGLUT2 gene expression is found mostly in blank.
cortex and hippocampus
subcortical structures
-
activation of NMDA receptor channels needs more sources of excitatory events or stronger stimuli to remove the Mg2+ block. That is, the NMDA receptor usually plays as a kind of biological
.
“coincidence detector”
-
allylglycine, thiosemicarbazide, and 3-mercaptopropionic acid
block GABA synthesis by inhibiting glutamic acid decarboxylase including
-
GABA 1 and 2 transporters are found in
neurons and astrocytes
-
GABA 3 transporters are found in
astrocytes only
-
an irreversible inhibitor of GABA-Transporter and thereby elevates GABA levels in the brain.
licensed for the treatment of certain types of epilepsy.
Vigabatrin
-
2 α, 1 β, 1 γ & 1 δ
what receptor?
acetylcholine ionotropic receptor
-
(1) two α-subunits, two β-subunits, and one γ-subunit or (2) two α-subunits, one β-subunit, and two γ-subunits
what receptor?
GABA ionotropic receptor
-
When a BDZ, such as (blank) binds to the BDZ binding sits, it increases the potency of GABA to open the Cl- channels, good for anxiolytic action. However, BDZs cannot activate the GABAA receptor by themselves; thus, they have no effect in the absence of GABA.
diazepam (trade name Valium)
-
A selective GABAB receptor agonist called (blank) has been used for a number of years as a muscle relaxant and anti-spastic agent
baclofen (Lioresal)
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