524 exam 2.6

• allows communication between cells at a synapse
• typically occurs in 1 direction - from presynaptic to postsynaptic membrane
• synthesized in presynaptic terminals, vesicles are recycled
• released in response to action potential and influx of CALCIUM
• released through EXOCYTOSIS
• can initiate an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP)

• depolarizes next neuron
• excites next neuron

• hyperpolarizes next neuron
• prevents NT release

• RECEPTOR determines effect on postsynaptic membrane
• some neurotransmitteres, depends on which receptor they bind to, can have an EPSP or IPSP.... therefore, can have different effects on the postsynaptic cell

• EXCITATORY
• 1. glutamate
• - mechanism of action: indirect - G proteins and 2nd messengers; direct - opens calcium channels on pre and post synaptic membranes
• - important in memory and learning, most impt excitatory neurotransmitter in the brain
• 2. aspartate
• - mechanism of action: direct or indirect (G proteins, depending on type of receptor)
• - used by pyramidal cells that provide voluntary motor control over skeletal muscles

• INHIBITORY
• 1. GABA - gamma aminobutyric acid
• - mechanism of action: direct or indirect (G proteins, depending on type of receptor)
• - dirrect effects: open chloride channels; indirect effects: open potassium channels and block entry of calcium
• 2. glycine
• - mechanism of action: direct - opens chloride channels
• - produces postsynaptic inhibition; the poison strychnine produces fatal convulsions by blocking glycine receptors

• common neutrotransmitters are small molecules and work fast
• they're approximately the size of 1 amino acid
• less common neurotransmitters or neuromodulators vary in size and timing of effect, they modulate the activity of common NT (regulate the NT release)

• the 4 AA NTs discussed in this lecture have about 10-19 atoms, and are the size of about 1 AA
• glutamate, aspartate and glycine are AA themselves, act in CNS
• GABA is an AA derivative, that also acts in the CNS
• note!!! all 4 discussed in todays lecture only act in the CNS!!!!

• 1. NTs from afferent neurons released into CNS
• 2. NTs from interneurons released into CNS
• 3. NTs from efferent neurons released into PNS (onto effector organ)

• SPECIFIC PATHWAYS
• - some NTs only produced in specific areas of the CNS
• - they're released in specific tracts in the CNS
• - these are: seratonin, histamine, epi, norepi, dopa and ACh (biologic amines and ACh! beginning part of 12-6 graph)

• NON SPECIFIC PATHWAYS
• - some NTs are widespread, not restricted to specific tracts
• - the 4 AA discussed today have non specific pathways: glutamate, aspartate, GABA and glycine!!!
• - glutamate is responsible for ~75% of excitatory transmission in the brain = GREEN LIGHT = major excitatory transmitter in the CNS!!!
• - GABA os the NT at 20% of CNS synapses = RED LIGHT = major inhibitory transmitter in the CNS

• so... just a reminder:
• excitatory = glutamate + aspartate
• inhibitory = GABA + glycine

note for GABA and glycine: K+ channel opened, K+ goes out of cell, cause hyperpolarization and not lead to an action potential... Cl- will go IN and cause hyperpolarization and cause IPSP

• IONOTROPIC RECEPTORS
• - ligand gated ion channels
• - associated with ion channels
• - ligant (NT) receptor = ligand gated ion channel, opens and things move down gradient

• METABOTROPIC RECEPTORS
• - G protein coupled receptors (GPCRs)
• - receptor associates with G protein which activates an ezyme which causes 2nd messenger... etc etc.

ionotropic is faster, see an immediate response

all stimulates EPSPs!!!

• 1. NMDA receptor (N-Methyl-D-Aspartate)
• - when open, Na+ and Ca2+ enters the cell
• - glycine is co-agonist (has to be around and bind as well as glutamate for this to work)
• - also binds aspartate
• - increase sodium and calcium influx, K+

• 2. AMPA receptor
• - mainly increases sodium, K+

• 3. kainate receptor (seaweed)
• - mainly increases sodium, K+

• 1. GPCRs
• - many subtypes identified
• - most increase IP3 and intracellular calcium OR decrease cAMP
• - stimulates EPSPs!!!
• - remember Gs, Gi, and Gq... Gs and Gi leads to decrease cAMP, and Gq is for calcium increase

• - sustained by stimulation of AMPA Receptors leads to depolarization
• - change in membrane potential activates NMDA receptor

• - at resting membrane potentia, Mg2+ blocks the NMDA receptor from being permeable to ions... but depolarization allows Mg2+ to leave so ions can pass through
• - soooo... need activated AMPA receptor first to cause a little bit of depolarization and take Mg2+ off NMDA receptor... then NMDA receptor to act
• - glutamate around --> binds to AMPA --> Na+ enters the cell --> leads to a change in membrane potential --> depolarization --> Mg2+ can leave NMDA --> NMDA receptor can now bind to glutamate
• - so basically a 2 step process just for NMDA to be activated

• 1. synaptic plasticity: altering strength of the synapse
• - can be altered by alterations in 2nd messenger pathways, kinases, phosphatases, receptor number, gene transcription

2. LTP (long term potentiation): involved in memory and learning, so the more you repeat the pathway, the longer you retain the info, if you keep stimulating it, remember more

• glutamate is normally store in synaptic vesicles
• they are released via calcium influx
• reuptake of glutamate is done by NEURONS and ASTROCYTES to get recycled
• 1. astrocytes convert glutamate --> glutamine
• 2. glutamine is then transported to the neuron
• 3. the neuron then converts glutamine to glutamate
• 4. reuptake then stops the signal

• when too much glutamate, actually toxic to neurons
• when neuronal cell death occurs (due to stroke, exogenous exposure to ionotropic glutamate antagonist), glutamate doesn't undergo reuptae
• this leads to excess glutamate available and excitotoxicity
• neuronal death = glutamate released when cell dies (since its stored in the cell's vesicles) and can't be reabsorbed.. bec cell died!!!

• NMDA receptor (left): the NMDA receptor is usually blocked by the Mg2+ ion... positive ions are unable to rush in even if glutamate binds to NMDA unless the Mg2+ ion is removed by an increase in the cell voltage (depolarization through AMPA receptor discussed earlier)
• NON-NMDA receptor (right): the non-NMDA receptor opens as soon as glutamate binds to it... opening of the non-NMDA receptor allows the entry of positive ions into the cell

• as glutamate continually binds to non-NMDA receptors and allows the entry of positive ions, the cell's voltage rises
• ultimately, the voltage reaches a certain value that causes the Mg2+ ion to be removed from the opening of the NMDA receptor
• calcium flows through the open NMDA receptor and causes various activities to occur that lead to cell death
• causes: (1) increase in free radicals, (2) degrade cell membranes, (3) degrade proteins
• so too much glutamate --> leads to activating NMDA receptors --> leads to too much calcium getting int o the cell --> leads to cell death!!!
• and as described earlier... a little bit of cell death leads to more cell death!!!

• 1. Mg2+: endogenous
• 2. ketamine: general anesthetic, dissociative anesthetic
• 3. phencyclidine, specifically phecyclidine piperdine (PCP): effects include euphoria, hallucinations, hostility, violent behavior.. chronic use leads to memory loss and cognitive impairment
• 4. methadone (top 200): has some affinity for NMDA receptor, but mainly an opoid antagonist which is used for opiate addiction (ex for heroine addiction) bec it binds to receptor but doesn't show effects of withdrawal
• 5. memantine (NAMENDA, top 200): used to slow progression of alzheimer's (memory loss)... can prevent extra neuronal death and improve memory loss

• 1. GABA_A receptors (ionotrophic) - chloride channel, fast response, stimulates IPSPs
• 2. GABA_B receptors (metabotrophic, GPCR) - increase K+ influx OR decrease Ca2+ influx, slower response than GABA_A, stimulates IPSPs

• glutamate decarboxylase converts glutamate to GABA
• glutamate decarboxylase only present in GABA-synthesizing neurons in CNS

• - increases chloride influx
• - increases inhibitory effects of GABA in the CNS
• - this is because they bind to diff site, they can bind when GABA binds and increase inhibitory effect
• - alcohol, bensodiazepines, barbituates and GABA all have different binding sites on receptor

• 1. benzodiazepines (ends in -AM)
• - increases RATE of channel opening
• - used for bipolar disorder (manic episodes), anxiety disorder, panic disorder, insomnia
• - anticonvulsant, antispasticity
• - examples: alprazolam, lorazepam, diazepam

• 2. barbituates
• - increases DURATION of channel opening
• - anticonvulsant, sedative/hypnotic
• - example: phenobarbital (top 200)

• anxiety is he pervasive feeling of apprehension
• basically helplessness, irritability, difficulty concentrating, insomnia
• GI disturbances, muscle tension, tachycarida

• common symptoms include excessive fear of doom, loss of control , nervousness, dread... depression may accompany
• examples: panic disorder, social anxiety disorder, generalized anxiety disorder, social phobia, specific phobias, OCD, posttraumatic stress syndrome

• Rx: anxiolytics
• 1. benzodiazepines... most commonly prescribed
• 2. antidperessants, beta-adrenergic blockers
• 3. buspirone... seratonin receptor agonist

• basically... promote sleep via GABA potentiation
• 1. benzodiazepines (top200): lorazepam and diazepam... inhibitory of other things, not just one pathway, so can make you sleepy
• 2. non-benzodiazepines (top200): zolpidem (AMBIEN) and eszopiclone (LUNESTA)... subtype specific, litte tolerance or dependence

• figure about shows how GABA alters activity of other NTs
• if GABA is also released, it causes a decrease in the amount of calcium that enters the cell
• GABA binds to the receptor to decrease the amount of calcium that goes in
• if we decrease calcium influx, we decrease the amt of NTs released, and therefore, decrease the effect on the postsynaptic cell
• we see that GABA is released from a separate neuron and acts on PREsynaptic cel
• GABA_B receptor alters calcium receptors
• (rembember... GABA_A is only for chloride, but B is for calcium and potassium)

• endogenous source in CNS
• has its own receptor and weakly binds to GABA_B receptor (responsible for sedation) - IPSP
• general sedative properties, addictive, and can cause wakefulness
• makes you sleepy BUT if you do wake up abruptly, hard to fall asleep

• unlike natural GABA, GHB can cross the blood brain barrier
• odorless, colorless liquid or powder, has a salty taste
• also a product of fermentation, found in some beers and wines in small amounts

• rave scene... basically called "liquid ecstacy" to reduce anxiety and create euphoria
• bar scene... called "date rape" to induce stupor and reduce memory
• gym scene... prolonged sleep causes increased growth hormone release
• sometimes homebrewed from commercial agents... lethality due to bad homebrews (bec drain cleaner is involved) and excess does of drug is too inhibitory to neurons

• ionotripic
• chloride channel
• inhibitory effect IPSP
• mostly affects spinal cord

if we inhibit glycine, we inhibit the inhibitor... cause opposite effect... loose inhibition

• 1. STRYCHNINE (from plant)
• - BLOCKS glycine receptor
• - rat poison
• - loss of negative control
• - causes convulsions and rigidity

• 2. TETANUS TOXIN (from bacteria)
• - INHIBITS glycine release
• - promotes spasticity and tetanus

• excitatory: glutamine and aspartate
• inhibitory: glycine and gaba

• ionotropic: NMDA, AMPA, kainate
• metabotropic glutamate receptor

excess glutamate which leads to increase of calcium into the cell and leads to excess neuron cell death

GABA, ethanol, barbituates and benzodiazepine

• gamma hydroxy butyrate
• weakly to GABA_B + GHB receptor (its own receptor)
• we have an endogenous source
• date rape, liquid exstacy... etc.

strychnine and tetanus toxin