PBI380-final exam objectives

Describe the mechanisms involved in the synthesis and release of 5-HT, and the processes involved in terminating 5-HT signalling

• Step 1 (making 5-HT): tryptophan (from turkey, egg, bananas) –> tryptophan hydroxylase (enzyme 1) turns tryptophan into 5-HTP –> AADC (enzyme 2) turns 5-HTP into 5-HT (FINAL PRODUCT ASF)

• Step 2 (releasing 5-HT): 5-HT stored in vesicles (little bags in neurons)–> brain says “need 5-HT” & vesicles move to edge of neuron to dump 5-HT into synapse

• Step 3 (doing it’s job): once in synapse, 5-HT floats around & binds to 5-HT receptors on post-synaptic neuron, this sends a message

• Step 4 (stopping signal): 2 ways

  • Reuptake: SERT (like special vacuum cleaner) sucks 5-HT back into neuron so it can be reused

  • Breakdown: some 5-HT gets destroyed by an enzyme called MAO (monoamine oxidase)

Recognize the receptor types that bind 5-HT

Think of them like clubs!

• 5-HT1 (chill clubs): calming and migraine related

  • 5-HT1A: anti-anxiety, helps mood

  • 5-HT1B & 5-HT1D: involved in blood vessels, especially in migraines

• 5-HT2 (hype crew): party drugs, heart risks, & hunger control

  • 5-HT2A: trippy one, involved in hallucinations (LSD, shrooms mess with this one)

  • 5-HT2B: mostly heart, can be bad if overstimulated

  • 5-HT2C: helps control appetite

• 5-HT3 (nausea boss): no subtypes; mostly in gut, controlling nausea

• 5-HT4 (gut crew): no major subtypes, helps digestion and GI movement

• 5-HT5 (mystery receptor): sleep and brain stuff

  • 5-HT5A: only confirmed subtype, seems to help with sleep & learning (we don’t fully understand in yet)

• 5-HT6 (memory booster): almost entirely in brain; seems to help with memory, learning, and maybe mood regulation

• 5-HT7 (mood & body clock regulator): found in brain, blood vessels, and GI tract; seems to help regulate mood, body temp, and sleep-wake cycles; blocking it might help with depression & sleep disorders

Give examples of behaviours that are affected by 5-HT signalling

Give examples of drugs that enhance the activity of 5-HT at the synapse

• Antidepressants: increase serotonin in brain to help with anxiety and depression

  • SSRIs (selective serotonin reuptake inhibitors): block 5-HT from being sucked back up, so it stays in the synapse (e.g. Prozac, Zoloft, Lexapro)

  • SNRIs (serotonin-norepinephrine reuptake inhibitors): like SSRIs but also boost norepinephrine (Effexor, Cymbalta)

  • MAOIs (monoamine oxidase inhibitors): stop serotonin from getting broken down (Nardil, Parnate)

• Psychedelics: over-activate serotonin receptors, especially 5-HT2A, leading to hallucinations:

  • LSD (acid), Psilocybin (shrooms), DMT, Mescaline: all mess with 5-HT2A causing visual & sensory distortions

  • Like serotonin fireworks: too much 5-HT activity = trippy thoughts

• MDMA: dumps a TON of serotonin into the synapse all at once, making you feel euphoric & social

  • Ecstasy, Molly: serotonin on steroids; super happy, super loving – until you crash

Give examples of drugs that interfere with the activity of 5-HT at the synapse

• Antipsychotics: block 5-HT2A receptors to help with schizophrenia & mood disorders

  • 5-HT ‘mute buttons’: less activity = fewer hallucinations (e.g: Risperdal, Seroquel, Clozaril)

• Migraine Meds

  • Target 5-HT to stop headaches; 5-HT ‘on switches’ for pain relief (e.g: Sumatriptan, Rizatriptan)

  • Triptans activate certain receptors to shrink blood vessels & stop migraines

• Anti-nausea drugs: block serotonin to stop vomiting

  • Ondansetron (Zofran) blocks 5-HT3 receptors to prevent nausea (especially from chemo or surgery)

  • 5-HT ‘off switch’ for puking

Summarize the mechanisms of action of first-generation antidepressants

• MAOIs - Serotonin Protectors:

  • MAO breaks down serotonin, dopamine, norepinephrine, but MAOIs stop this from happening (more NTs stay in the brain); more 5-HT = better mood

  • Downside: can interact badly with certain foods (cheese, wine, cured meats)

  • e.g: Nardil, Parnate

• TCAs (Tricyclic Antidepressants) - Reuptake Blockers:

  • TCA blocks serotonin & norepinephrine reuptake, more stays in synapse; more NTs = betters mood

  • Downside: side effects (drowsiness, weight gain, heart risks)

  • e.g. Amitriptyline, Imipramine

Summarize the mechanisms of action of second-generation antidepressants

• SSRIs - Serotonin Hoarders 2.0

  • `Only block 5-HT reuptake; more serotonin stays in the synapse = better mood; most commonly perscribed

  • Advantage: fewer side effects than MAOIs or TCAs

  • e.g: Prozac, Zoloft, Lexapro

• SNRIs - SSRIs with extra powers

  • Block reuptake of both serotonin & norepinephrine; boost in mood & energy (good for depression & fatigue)

  • Advantage: more energizing than SSRIs, good for people with both depression & low energy

  • e.g: Effexor, Cymbalta

Describe the synthesis and release of acetylcholine (ACh), and how its signal is terminated at the synapse

• Step 1 (making ACh): Choline (from fish, eggs, peanuts) + Acetyl-CoA (made in neurons) –> Choline Acetyltransferase (ChAT, enzyme 1) sticks them together –> Acetylcholine (ACh, aka FINAL PRODUCT)

• Step 2 (releasing ACh): ACh stored in vesicles (tiny neuron bags) –> brain says “need ACh!“ –> vesicles move to the edge of the neuron & dump ACh into the synapse

• Step 3 (doing its job): ACh floats around in the synapse & binds to ACh receptors on the post-synaptic neuron –> sends message for movement, memory, or whatever ACh is controlling

• Step 4 (stopping signal #nomoreAChdafuq): only 1 way (ACh doesn’t get reuptaken); breakdown – AChE (enzyme) DESTROYS ACh in the synapse –> Chloine gets taken back up into the neuron to make new ACh later

Give examples of where in the brain and body ACh is found

In the brain:

• Basal forebrain (memory & attention HQ)

  • ACh helps you focus, learn, & remember stuff

  • Damage linked to Alzheimer’s disease (memory loss)

• Pons & Midbrain (sleep control)

  • ACh helps you stay awake & controls REM sleep (dreaming)

  • Low ACh = might sturggle with sleep problems

In the body:

• Neuromuscular Junction (tells muscles to move)

  • ACh released onto muscles to make them contract

  • No ACh? PARALYSIS!

• Parasympathetic Nervous System (rest & digest)

  • ACh slows heart rate, increases digestion, chills you out

  • messed up ACh = body goes into overdrive

• Sympathetic Nervous System (fight or flight)

  • ACh helps send signals before adrenaline kicks in

  • messed up ACh = messed-up stress response

Recognize the receptor types that bind ACh

• Nicotinic Receptors (nAChRs) - Fast Ones

  • in muscles, brain, ANS

  • instant activation with ACh binds to nicotinic receptors; found in places where quick reactions are needed (muscle movement, brain signals linked to focus & addiction)

  • e.g: Nictotine (overactivates receptors), Curare (blocks receptors = paralysis)

• Muscarinic Receptors (mAChRs) - Slow & Steady Ones

  • in brain, heart, lungs, digestive system

  • slower, long-lasting effects (more fine-tuned control)

  • heart: ACh binds –> heart rate slows (relax mode AF)

  • lungs: ACh binds –> airways tighten (too much ACh = breathing issues)

  • brain: ACh binds–> memory & attention (damaged in Alzheimer’s)

  • e.g: Atropine (blocks muscarinic receptors–speeds up heart rate, dilates pupils), Poisonous Mushrooms (overactivate muscarinic receptors–sweating, diarrhea, slowed heart rate, death)

Give examples of behaviours that are affected by ACh signalling

Give examples of drugs that enhance the activity of ACh at the synapse

• Cholinesterase Inhibitors: block AChE (enzyme), ACh stays in synapse longer

  • Donepezil, Rivastigmine, Galantamine –> boost memory in Alzheimer’s disease

  • Physostigmine, Neostigmine –> help muscle strength in myasthenia gravi (disorder that causes muscle weakness)

• Nicotinic Receptor Agonists: activate nicotinic ACh receptors –> brain & body stimulation

  • Nicotine (cigs, vapes, patches) –> increases alertness & focus, but also highly addictive

• Muscarinic Receptors Agonists: activate muscarinic ACh receptors –> affect organs like heart eyes, & saliva glands

  • Pilocarpine –> increases saliva & tears (used for dry mouth & glaucoma)

• Toxic Overload: too much ACh = muscle spams, seizures, death

  • Organophosphates (pesticides, berve gas) –> permanently block AChE, leading to uncontrolled ACh buildup –> paralysis & death (used in chemical warfare & insect killers)

Give examples of drugs that interfere with the activity of ACh at the synapse

• Cholinergic Antagonists: block ACh receptors –> less ACh activity

  • Atropine –> blocks muscarinic ACH receptors –> speeds up heart rate, dilates pupils (used for eye exams & treating slow heart rate)

  • Scopolamine –> blocks muscarinic ACh receptors in brain –> reduced nausea & motion sickness (also causes memory issues at high doses)

• Neuromuscular Blockers: stop ACh from activating muscles –> paralysis

  • Curare –> blocks nicotinic ACh receptors at muscles –> paralysis (used poison dart & surgery anesthesia)

  • Botulinum Toxin (Botox) –> prevents ACh release at muscles –> muscles can’t contract = paralysis & wrinkle reduction (used to treat migraines & muscles spasms)

• Acetylcholinesterase Reactivators: reverse too much ACh blockage

  • Pralidoxime (2-PAM) –> reactivates AChE after nerve gas poisoning –> restores normal muscle function

• Toxic Overload: blocking too much ACh = dry, slow, confused

  • Anticholinergic Toxicity (too much ACh blockage) –> dry mouth, blurry vision, confusion, fast heart rate, trouble urinating (can be caused by overdose on antihistamines, antidepressants, or atropine)

Summarize the synthesis pathways of glutamate

• Glutamine Route (Main Way!)

  • Step 1: glutamine (precursor) is floating around in the brian

  • Step 2: glutaminase (enzyme) converts glutamine to glutamate (FINAL PRODUCT ASF)

• Krebs Cycle Route (Backup Plan!)

  • Step 1: cells break down glucose –> a-ketoglutarate (part of Krebs cycle, energy production)

  • Step 2: glutamate dehydrogenase or transaminase (enzymes) convert a-ketoglutarate –> glutamate (FINAL PRODUCT ASF)

Describe how glutamate signals are terminated at the synapse

• Step 1: Reuptake (Vacuum Mode)

  • EAATs (excitatory amino acid transporters) act like tiny vacuum cleaners & suck glutamate out of the synapse so it stops activating neurons

  • important because if glutamate stays in synapse too long –> neurons overfire = bad (toxic, seizures, cell death)

• Step 2: Glutamate –> Glutamine (Safe Mode)

  • glial cells (astrocytes) grab the extra glutamate & convert it into glutamine; glutamine synthetase (enzyme) does that job; glutamine is harmless & gets sent back into neurons to be reused

  • important because glutamine can be stored & safely turned back into glutamate when needed (#recycling)

• Step 3: Breakdown (Destroy Mode)

  • in somes cases, glutamate can also be broken down into other molecules; reuptake & conversion to glutamine is the main way the brain prevents glutamate overload

  • important because it helps fine-tune levels despite being less common

Recognize receptor subtypes for glutamate

• Ionotropic Receptors = FAST & DIRECT

  • act like doors; open when glutamate binds–> ions rush in–> neuron gets excited

  • like light switches (on/off instantly)

  • too much activation = brain overload –> seizures, cell death

  • e.g: NMDA (lets Ca2+ in; memory, learning, brain plasticity), AMPA (lets Na+ in; super-fast signlas, reflexes, movement); Kainate (letsNa+ & K+; less common, still speeds things up)

• Metabotropic Receptors = SLOW & LONG-LASTING

  • wokr through G-proteins & second messengers –> gradual effects on neuron activity

  • like dimmer switches (gradually turn up/down activity)

  • too little activation – brain = slow/sleepy

  • group I (excitatory): activates cells; increases firing; matters for learning, memory, emotions

  • groups II & III (inhibitory): lowers neuron activity; regulates mood, anxiety, motor control

Give examples of behaviours influenced by glutamate release

Summarize the synthesis pathways of GABA

Most GABA comes from glutamine, which gets turned into glutamate first!

• Glutamine Route (Main Way ASF):

  • Step 1: glutamine floating around in the brain

  • Step 2: glutaminase (enzyme) converts glutamine → glutamate

  • Step 3: glutamate decarboxylase (GAD) (MVP enzyme) chops off a piece of glutamate → BOOM GABA (FINAL PRODUCT ASF)

• Krebs Cycle Route (Backup Plan):

  • Step 1: cells break down glucose → a-ketoglutarate (a molecule from the Krebs cycle)

  • Step 2: glutamate dehydrogenase or transaminase (enzymes) convert a-ketoglutarate → glutamate

  • Step 3: GAD enzyme (again, MVP) converts glutamate → GABA (FINAL PRODUCT ASF)

Describe how GABA signals are terminated at the synapse

• Reuptake (sucking GABA back up):

  • GAT-1, GAT-2, GAT-3 (special proteins) suck GABA back into neurones & glial cells for neuron to reuse or get rid of

  • e.g: tiagabine blocks GAT-1 → more GABA stays in synapse = extra chill, anti-seizure vibes

• Breakdown (destroying GABA):

  • GABA-T breaks GABA down into inactive metabolites (succinic semialdehyde); metabolites go into Krebs cycle to make energy; no more GABA = no more chill → brain can wake back up

  • e.g: vigabatrin blocks GABA-T → GABA doesn’t get destroyed = extra inhibition, anti-seizure effects

Recognize receptor subtypes for GABA

• GABA-A (Fast & Strong - the knockout switch)

  • ligand-gated ion channel (door that opens when GABA binds)

  • lets Cl- in → neuron gets super negative → no firing = CALM

  • GABA-A boosters: benzos (xanax, valium) – make GABA work better = anti-anxiety, muscle relaxant; barbiturates (phenobarbital) → super strong sedation; alcohol (ethanol) → enhances GABA-A = tipsy, drowsy; neurosteroids → body’s natural chill enhancers

• GABA-B (Slow & Steady - the gentle brake)

  • metabotropic receptor (g-protein-coupled, slower effects)

  • tells neuron to stop firing by blocking Ca2+ entry & opening K+ channels → neuron chills out

  • effects = long-term calm, muscle relaxation

  • GABA-B boosters: baclofen (muscle relaxer) → used for spams, alcohol withdrawal; GHB (club drug, aka liquid ecstasy) → sedative effects, but also abuse potential

Give examples of behaviours influenced by GABA release

Recognize the families of endogenous opioid neurotransmitters in the human nervous system and the ‘preferred’ receptor types

• Endorphins (Runner’s High Crew)

  • most famous opioids; released during exercise, laughter, sex, etc

  • preferred receptor: Mu (μ) receptors

  • effects: pain relief, pleasure, euphoria, sedation

  • “feel amazing” chemicals

• Enkaphalins (Chill Under Pressure Squad)

  • found in brain & spinal cord; released during mild/moderate stress

  • preferred receptor: Delta (δ) receptors

  • effects: mild pain relief, emotional regulation, antidepressant-like effects

  • mood balance & mental resilience

• Dynorphins (Too Much Stress Gang)

  • released during intense stress or trauma

  • preferred receptor: Kappa (κ) receptors

  • effects: pain relief, BUT ALSO dysphoria, stress, anxiety

  • “I feel weird/bad but I don’t hurt” chemicals

Compare and contrast various opiate drugs in terms of their affinity and efficacy at opioid receptors

Best tip to remember:

• Full Agonists = Full Effect!

  • Morphine, Heroin, Fentanyl, Methadone

• Partial Agonists = Stick hard, weak effect

  • Buprenorphine (used in Suboxone)

• Antagonists = Stick super hard, block everything

  • Nalaxone (Narcan), Naltrexone

Describe some processes involved in the development of tolerance to opiate drugs

• Receptor Downregulation - “Too Much = Shut It Down”

  • opioids activate mu receptors to block pain and make you feel good

  • if they’re activated too often → fewer receptors = less effect = you need more drug to get the same high

• Receptor Desensitization - “Still There, But Not Listening”

  • even if receptors don’t disappear, they stop responding as strongly (like brain hitting mute on opioid signal)

  • same amount of drug = weaker effect

• Increased Metabolism - “Get Rid of It Faster”

  • liver gets better at breaking down the drug; doesn’t last as long or hit as hard

  • need more and more, more often

• Opponent Processes - “Brain Tries to Balance”

  • brain doesn’t like being overly relaxed & euphoric all the time

  • starts ramping up opposite systems (pain, stress, alertness)

  • when opioids wear off, you feel worse than before = withdrawal, cravings

  • you don’t even take drug to feel good anymore, you take it to feel normal