Neuro Exam 1

How many drug overdose deaths were there in 2019?

70,630

How many drug overdose deaths were there in the past 12 months? What kind of drug did most involve?

106,584 - most involved opioid

Remember Sheila? She has _____

She has tetanus

What is tetanus?

Tetanospasmin binds irriversibly to membrane at synapse

blocks release of glycine from axon terminals - causes generalized rigidity

What is Opisthotonus?

severe muscle rigidity - dramatic abnormal posture, severe backward arching from toe to heel

• symptom of tetanus

Synapse diagram

What happened to Don?

• Case study:

  • A retired accountant developed tremor and slowing of movements and was diagnosed with Parkinson’s disease at age 67. His neurologist prescribed levodopa to restore dopamine levels. A couple of years later, motor symptoms start to fluctuate and the dopamine receptor agonist ropinirole was added to his treatment.

    A few months later, he developed a strong interest in gambling, first buying lottery tickets and then visiting a casino almost every day. He concealed his gambling activity until he has lost more than $100,000. He came for a consultation 5 weeks ago, and ropinirole was replaced with a monoamine oxidase inhibitor drug. He now reports his interest in gambling has disappeared.

• What’s going on?

  • Levodopa increased dopamine levels, which not only improves substantia nigra, but also increases VTA (ventral tegmental area) activity. The VTA is responsible for reward, motivation, and addiction (among other things). The new monoamine oxidase inhibitor drug does not target the VTA, as shown by the decrease in interest towards gambling after changing medication

What are the two receptor subtypes?

Ionotropic and Metabotropic

How do ionotropic receptors work?

open when bound by a transmitter (ligand-gated ion channel)

direct - NT binds to the channel itself

How do metabotropic receptors work?

transmitter binds to receptor, receptor activates G-protein

indirect - NT binds to receptor which signals for the receptor to open

True or false: most drugs act via ionotropic receptors.

False: 75% of all drugs act via metabotropic receptors

good because: the more steps, the more area to intervene

bad because: hard to find one drug that fits all

What does an agonist do?

drug that initiates normal effects of the receptor

pretends to be the neurotransmitter

all agonistic drugs are partial agonists

True or false: agnoists produce the same level of response as a neurotransmitter

False - all agonists are partial agonists

What does an antagonist do?

prevents a receptor from being activated by other ligands

What are the two types of antagonists?

Competitive and Noncompetitive

what is a competitive antagonist

binds directly on the active site - blocks active site, prevents signal transmission

What is a noncompetitive antagonist?

binds to a different site that causes the protein to denature, causing the shape of the binding site to change, reducing the effectiveness of the receptor (partial signal)

True or false: Drugs only have one shot to affect synaptic transmission

False - drugs can affect synaptic transmitssion at many steps

Ionotropic receptors would be most useful in a body system that

A. Needs slow but adaptable output

B. Needs rapid and reliable output

B. Needs rapid and reliable output

What are the classes of neurotransmitters?

Amino acids, Monoamines, Soluble gases, Acetylcholine, Neuropeptide

What are the amino acids?

Glutamate, aspartate, glycine, GABA

• amino acids make me gagg

What are the two classes of monoamines?

Catecholamines, Indolamines

What are the catecholamines?

Dopamine, Epinephrine, Norepinephrine

What are the Indolamines

Serotonin

What are the soluble gases?

Nitric oxide, carbon monoxide

What are the acetylcholines?

acetylcholine

What are the neuropeptides?

Endorphins

What is glutamate?

• Main excitatory NT of the CNS, responsible for EPSPs

• amino acid NT

• most important NT in the cerebral cortex

What are the ionotropic receptors for glutamate?

AMPA, NMDA (Mg²⁺-blocked), Kainate

How are receptors named?

Named by the first discovered agonist

What are the metabotropic receptors of Glutamate?

mGluRs

How is glutamate removed from the synapse?

reuptake

What is excitotoxicity?

• excessive release of glutamate → kills neurons

• causes:

  • neural injury (stroke, head trauma, etc)

  • abnormalities in glial function

  • failure to remove glutamate from synapse

What kind of protein channels does glutamate activate?

Na⁺, K⁺, Ca²⁺

Summary of glutamate’s actions diagram

What is GABA?

• Ionotropic inhibitory NT (Cl^- permable)

• produces fast inhibitory effects

• amino acid NT

• most common inhibitory neurotransmitter in brain

What do the GABA agonists do?

potent tranquilizers (fast inhibitory effects)

What are the GABA agonists?

• Ethanol (alcohol)

• Benzodiazepine (for sleep)

• Barbiturate (ex: Valium)

• Neurosteroids

What channels does GABA open?

Cl^-

Summary of GABA’s actions (diagram, not a knowt)

What is Glycine?

• Major inhibitory neurotransmitter in spinal cord

• amino acid NT

What does Strychnine do?

blocks glycine → opisthotonus

symptoms:

• after 20 minutes

  • neck stiffness

  • twitching muscles

  • feeling of suffocation

  • violent convulsions - body is arched and the head bent backward

• After a minute muscles relax, but a touch or noise causes convulsions to recur, or they recur spontaneously, every few min.

What is strychnine used for?

rat poison - suffocation

catecholamine synthesis

• what is the precursor for dopamine, norepinephrine, and epinephrine?

• what is the rate-limiting step for the precursor → catecholamine reaction?

• precursor: tyrosine

• rate-limiting step: tyrosine hydroxylase (enzyme that breaks down tyrosine)

3-year-old identical twins from London had severely low muscle tone, intellectual disability, and seizures.

What is the cause? What is the treatment, and why does this help?

cause: low activity of tyrosine hydroxylase

treatment: dopamine infusions

• helped because tyrosine hydroxylase indirectly stimulates dopamine production - catacholamine synthesis

What is the catecholamine synthesis pathway?

what is the mesolimbocortical pathway of dopamine and its function?

What is the mesostriatal pathway of dopamine and its function?

mesolimbocortical:

• VTA → nucleus accumbens, cortex, and hippocampus

• function: addiction, learning, schizophrenia

mesostriatal:

• substantia nigra → striatum

• function: motor control

What is the norepinephrine pathway and its function?

locus coeruleus to hippocampus, basal ganglia, and cortex

function: mood, arousal, sexual behavior

(remember: if you see locus coeruleus, always think norepinephrine)

what does ‘locus coeruleus’ mean?

blue spot

Serotonin pathway and function

raphe nuclei - produces serotonin

Mesencephalic serotonergic cells → thalamus, hypothalamus, basal ganglia, and cortex

function: sleep, sexual behavior, anxiety

function of the raphe nuclei

produces serotonin

cholinergic pathway

basal forebrain to fornix

What is the function of the basal forebrain?

Involved in learning and memory

cell death causes Alzheimer’s

True or false: you can easily store gas neurotransmitters

false

Where is nitric oxide produced?

dendrites (produced in the postsynaptic neuron)

NO serves as a(n) ______grade transmitter by diffusing back into the ______________. This _____________ neighboring neurons.

retro, presynaptic neuron, synchronizes

What are the two types of acetylcholine (ACh) receptors?

Nicotinic and Muscarinic

What are the characteristics of a Nicotonic ACh receptor?

• ionotropic

• excitatory

• PNS

• Muscles use nicotinic ACh receptors

______ is an antagonist that causes paralysis when binding to _______ ACh receptors.

curare, nicotinic

What are the characteristics of a Muscarinic ACh receptor?

• Metabotropic

• Excitatory or inhibitory

• CNS

When _________ binds to muscarinic ACh receptors, it ________

scopolamine, alters cognition

main agonists for nicotinic and muscarinic receptors (hint: what were they named after?)

nicotinic: nicotine

muscarinic: muscarine

When are endorphins produced?

During:

• exersise

• excitement

• pain

• eating spicy food

• love

• orgasm

endorphins are the body’s natural ____

painkillers

What are endogenous opiates? Are they addictive?

Peptide NTs that bind to opioid receptors

• naturally made in the body

• relieve pain (analgesics) and produce a feeling of well-being

Yes, they are addictive.

What are the three endogenous opiates?

• Enkephalins

• Endorphins

• Dynorphins

What are neuromodulators?

indirectly affect transmitter release or receptor response

ex: adenosine

What is adenosine? How does caffeine relate to adenosine?

neuromodulator - inhibits catecholamine release via presynaptic autoreceptors

• during wakefulness, adenosine builds up, making you sleepy

• caffeine blocks adenosine → catacholamine release → arousal

notes about coffee

FYI: Mayo Clinic Proceed Aug. 2013: A study of 40,000 individuals found greater than 50% increased mortality in young men and women who drank more than 4 cups a day

But moderate coffee intake LOWERS all-cause mortality

What are antipsychotic (neuroleptic) drugs? What are the typical neuroleptics?

used for schizophrenia and aggressive behavior

typical neuroleptics - dopamine antagonists

• schizophrenia could be caused by increase in dopamine

What do monoamine oxidase inhibitors do?

prevent breakdown of monoamines at synapse

What is the main antidepressant?

Monoamine oxidase inhibitors (MAOIs)

What is the major action of antidepressants?

accumulation of monoamines

What are the two classes of antidepressants?

Tricyclics

• block reputake of norepinephrine and serotonin

• high BP + adrenaline = higher BP → death

  • older, not used as often because of the risks

SSRIs

• serotonin acccumulates in synapses

• fewer side effects

• prozac, zoloft

Anxiolytics (tranquilizers)

reduce nervous system activity

Types of anxiolytics

Benzodiazepine

• GABA agonists

• endogenous agonists:

  • Allopregnanolone

  • Diazepam-binding inhibitor (released by astrocytes)

Barbiturates are ___________

depressing

What do Barbiturates do? What are their clinical uses?

block sodium channels

increase flow of chloride ions (GABA agonist)

it was used to execute people…main medical use now is for anesthesia and epilepsy

In _____ doses, alcohol is a stimulant, turning off ________, and reducing _________ and ________.

low

cortical inhibition

social constraints

anxiety

At ______ doses, alcohol is a sedative

high

What does alcohol markedly do?

reduces brain metabolism

alcohol’s effects are ____

biphasic (initial stimulant phase followed by a depressant phase)

What neurotransmitter systems does alcohol affect

glutamate, GABA

• inhibits glutamate at low doses

• acts as GABA receptor to increase binding of GABA

• effects:

  • sedation

  • anxiety reduction

  • muscle relaxation

  • inhibitired cognitive and motor skills

What are the pleasurable effects of alcohol

stimulation of dopamine, serotonin, opiates, and cannabinoid

Cause of alcohol-related seizures

compensatory increase in glutamate receptors over time

OJ is a 45 yo man who presents to the ED after a seizure during his first day at a local alcohol/drug rehab center. He was ordered by the court to attend this center after his second drunk driving violation in one year.

It has been about 60 hours since his last drink. What is happening to him?

tonic-clonic seizures

What does alcohol do to your brain?

drink shrinks your brain - damages cerebellum and frontal lobe

note: neurons and glia can recover!!

A child has a small head with a flat face, short nose with a low nasal bridge, and thin upper lip. What is the diagnosis?

Fetal alcohol syndrome

What do opiates do?

What is the treatment for an opoid overdose?

narcan (naloxone)

What is morphine, where is it found, and what does it do?

potent analgesic

found in opium

binds to opoid receptors in the brainstem (locus coeruleus, periaqueductal gray)

What is the origin of the name of heroin?

named for “heroic” - initially marketed as a cure for codeine addiction

• metabolizes into morphine, addictive - not a great cure!

What company made heroin in the beginning?

Bayer company

53 y/o man is found down in the driveway of a house. EMS arrives and on exam he is comatose, and his pupils are tiny (2mm) and barely react to light. An IV is inserted and he is given naloxone. Within a minute he arouses and opens his eyes.

What is the diagnosis?

opiate/fentanyl overdose

What is the active ligand in marijuana?

THC (tetrahydrocannabinoid)

What do cannabinoid receptors bind? (marijuana)

anandamide

2-AG

(endocannabinoids)

What are endocannabinoids

hydrophobic (lipophilic) molecules - can’t store in vesicles, thus exist as part of the membrane

• synthesized on demand

retrograde signaling - activate cannabinoid receptors on nearby neurons

True or false: in 3000 BC, Indian medical practice used marijuana to treat appetite loss

True

What are the effects of marijuana?

• impairs short-term memory

• slow reaction time

• altered judgement/decision making

• alters mood - calmness; in high doses, paranoia

What does nicotine do?

primary psychoactive and addictive drug in tobacco

activates ACh receptors in VTA

• periphery - muscle twitching

• centrally - increased alertness