exam 2

axo-dendretic

• majority of synapses in the brain

• axon terminals synapse with dendrites or on dendretic spines

axo-axonic

• synapses that allow for regulation of neurotransmitter release from the targeted axon terminal

input location & strength

• distance between the synapse & axon hillock is inversely proportional to the ability

what influences the synapse more

• axo-somatic synapses tend to influence the post synaptic neuron more than axo-dendretic synapses

neurotransmitter

• a chemical, gas, or hormone that is synthesized in & released from a neuron

• never go into the cell

large neurotransmitters

• peptides and hormones

• synthesized in the soma & then transported down to the axon terminal (microtubules)

small neurotransmitters

• amino acids, monoamines, acetoycholine, & gases

• synthesized in the terminals

vessicles

where neurotransmitters are stored in the membrane

steps to neurotransmission

• action potential is porpogates over presynaptic membrane

• depolarization of the terminal leads to Ca2+ influx

• Ca2+ promotes exocytosis, the fusion of vesicles w/ membrane which releases neurotransmitter into cleft

• bining of neurotransmitter to receptors open channels permitting ion flow

• excitatory or inhibitory postsynaptic potentials spread over dendrites and the cell body to the axon hillock

what ends neurotransmission

• transmitter degredation (enzymes)

• transmitter removal through reuptake tansporters

• autoreceptor activation (regulate calcium channels & machinery involved in exocytosis)

• diffusion (neurotransmitters simply move out of the synaptic cleft

two mechanisms of neurotransmitter deactivation

• reuptake: usually occurs with small neurotransmitters

• enzyme degredation: breakdown thriugh enzymes usually accurs with large neurotransmitters

preventing neurotransmitter rerelease

autoreceptors

autoreceptors

• receptors that are located on the edges of the active zone on the presynaptic terminal, regulate calcium channels and the machinery involved in exocytosis

• released neurotransmitters are deactivated by either reuptake or enzymatic degredation

transmitter receptors

• ionotropic receptors = ligand gated receptors

• metabotropic receptors

• metabotropic receptors II

ionotropic receptors

• ligand-gated ion channel

• fast transmission

• neurotransmitter binds directly to the receptor

• channel opens immediately

• ions flow across the membrane for a brief time

metabotropic receptors

• indirectly linked with ion channels through signal transduction mechanisms

• G protein-coupled receptors (GPCR’s)

• slower transmission

• neurotransmitter binds to a GCPR

• G protein activates

• G protein binds to an adjacent ion channel

metabotropic receptors II

• G protein-coupled receptors (GPCR’s)

• slower transmission

• neurotransmitter binds to a GCPR

• G protein activates

• G protein activates a second messenger

• second messengers act on ion channels & other cellular targets

neurotransmission gap junctions

• specialized type of synapse between 2 excitable cells (cardiac muscle cells, smooth muscle cells, & some neurons

• ions flow directly from one neuron to another

• 0 time delay

• no neurotransmitter required

• good for synchronus activation of muscle fibers

signal versatility

• any given neuron can release only a few types of neurotransmitters but can recieve & respond to multiple

receptor subtypes

• the same neurotransmitter may bind to a variety of subtypes which trigger different responses (some excitatory, some inhibitory)

inhibitory effects of neurotransmitters

• reduce the # of action potentials in the postsynaptic cell (usually through Cl- ligand gated channels)

excitatory effects of neurotransmitters

• increase # of action potentials (usually not through Na+ channels)

ligand-receptor interactions

• receptors only recognize certain ligands and this interaction is based mostly on the chemical/physical structure of the ligand

• since neurotransmitters have different chemical structures, the interaction between a receptor and its transmitter is specific (only glutamate can activate glutamate receptors)

• multiple receptors for each transmitter so one can activate different receptors

major families of neurotransmitters

• amino acids; made in axon terminal

• amines: made in axon terminal

• peptides: made in soma

• gases: made in axon terminal

amino acids

• glutamate: small, ionotropic (excitatory), metabotropic (inhib, & exc), STOP

• GABA: small, GABA-A (ionotropic, inhibitory), GABA-B (metabotropic, inhibitory), go

amines

• dopamine: small, only metabotropic (inhib, & exc)

• serotonin: small, 1 ionotropic (excitatory), metabotropic (in, & exc)

• acetylcholine: small, nicotinic (ionotopic, excitatory), muscarinic (metabotropic, both)

• norepinepherine: small, only metabotropic (inhibitory, & excitatory)

peptides

• many (100’s): large, all kinds ionotropic (both), metabotropic (both)

gases

• nitric: small, no receptors

roles of amino acids

• small molecule neurotransmitters

• building blocks of proteins

• glutamate, glycine, aspartate (from food, have excitatory effects)

• mediate majority of fast, directed synapses

• signal is terminated through reuptake mechanisms

roles of amines

• more diffuse effects than amino acid neurotransmitters

• monoamines: dopamine, epinepherine, & norepinepherine are made from tyrosine

• indolamines: serotonin made from trytophan (in milk & turkey)

• signal terminated through reuptake & are broken down by enzymes

roles of pepties

• slower signaling than small neurotransmitters

• signal is terminated by degredative enzymes in synaptic cleft

• released by cell body & dendrites

roles of soluble gases

• nitric oxide & carbon monoxide

• made in cell body & diffuse across membrane

• believed to play a role in retrograde transmission (signaling from post neuron to presynaptic neuron)

• NO & CO expand blood vessels to increase oxygen flow

• short lived

• broken down quickly by enzymes

psychoactive drugs

• drugs that affect our behavior

• must have a binding sit in the brain

• must cross the blood brain barrier

drug action

• molecular changes that can occur as a result of a drug or neurotransmitter binding to a receptor

drug effect

• widespread physiological or psychological changes as a result of these molecular changes

a ligand

a subatance that binds to a receptor and has one of three effects

• agonist

• antagonist

• inverse agonist

agonist

• imitates the normal effects of the transmitter by copying the neurotransmitter

• initiates the endogenous effects of the receptor

antagonist

• blocks the receptor from being activated by other ligands

inverse agonist

• initiates an effect that is the opposite of the normal function

indirect agonist

• enchances activation of the post synaptic receptors by increasing the levels of the neurotransmoitter in the synaptic cleft

co-agonist

• works to increase the ability of the neurotransmitter to bind tot he receptor - has a seperate binding site

competitive ligands

• agonists, antagonists, or inverse agonists

• because they bind to the same part of the receptor molecule as endogenous ligands

noncompetitve ligands

• co-agonists, non-competitve antagonists

• bind to secondary sites on the receptor seperate from the normal binding site of the receptor

binding affinity

• the degree of chemical attraction between a ligand & a receptor

• how strong a drug binds

efficacy

• the ability of a bound ligand to activate the receptor

• how likely a drug is to exert a biological response to the receptor

what are affinity and efficacy determined by

• the chemical or structural properties of a compound (size, shape, charge, etc.)

what happens if a drug has a low affinity for a receptor

• then the drug will quickly uncouple from the receptor to bind half the receptors at any given time a higher concentration of the drug is needed

what happens if a drug has a high affinity for a receptor

• the two weill stay together for a longer period of time, and a lower concentration of drug will be bound to more receptor at any time

drug potency

• a drug with a higher potency will evoke a larger response at a low concentration

• a drug with a lower potency will evoke a smalle rrsponse at a low concentration

done response curve

• a graph of the relationship between drug doses and the effects

• a tool to understand pharmacodynamics (the functional relationshio between drugs & their targets)

measures of efficacy

• agonists have high efficacy

• antagonists have low efficcy but have affinity

• partial agonists have a medium response regardless of dose

• full inverse agonists have high efficacy

• ED50

• the dose at which the drug shows half of its maximal effect “the effective dose”

• the dose at which the drug procuses a given effect in 50% of the population

relative potency

• the relative potencies of the drug by comparing their ED50 values

relative efficacy

• the ability of a drug to produce a response

TD50

• median toxic dose, dose required to get 50% of the population to report a specific toxic effect

LD50

• median lethal dose, dose required to reach 50% mortality

theraputic index

• the gap between the effective dosage of a drug and the toxic dosage

• Compares the ED50 to the TD50 or LD50

routes of administration

• ingestion/oral

• absorption

• inhalation

• injection

ingestion/oral

• ‘first pass' metabolism by liver & gut walls

absorption

• bypass the liver no ‘first pass’ metabolism

  • sublingual: under tongue → blood → brain

  • cutaneous: on skin → slow or fast release depending on fattiness

  • rectum: → blood → brain

inhalation

• bypass the liver

  • nose or lungs: → into blood → into brain

injection

• bypass the liver

  • intravenous: → into blood → into brain

  • subcutaneous: under skin → into fat → slow release

  • intramuscular: into muscle → slow release

drug circulation

• depends on the route of administration

• drug distribution: how soluble the drug molecule is in fat (ability to pass membrane, ability to bind to blood proteins)

• drug metabolism: enzymes convert drugs into metabolites, depending on the drug these can be harmful, therapeutic, or inactive

• drug elimination: through the kidneys or by enzymes in the liver

drug distribution

• how soluble the drug molecule is in fat

• ability to bind to blood proteins

drug metabolism

• enzymes convert drugs into metabolites

• depending on the drug these may be theraputic, harmful, or inactive

drug elimination

• depends on how its administered

• oral drugs are excreted into urine via the kidneys and/or by inactivation by enzymes in the liver

drug penetration of CNS

• blood brain barrier

mechanisms of drug actions

• diffusely

• specifically

tolerance & addiction

• with repeated use, the desired effect requires larger doses

• decrease in response elicited by the same dose

• increase in the amount needed to get the same effect

withdrawl symptoms

• discomfort or distress that follow discontinuing drug

• physical sign of dependence

tolerance and withdrawl

• manifestations of the same underlying physiological change

cross-tolerance

• tolerance to a whole class of chemically similar drugs

sensitization

• occurs when drug effects become stronger with repeated use

metabolic tolerance

• metabolic systems in the body (eg. liver) become more effective in eliminating the drug before it reaches the brain

functional tolerance

target issue/cells show less sensitivity to drug

receptor desensitization

after prolonged/chronic agonist activation, receptors can decrease in number

receptor sensitization

after prolonged/chronic abscence of agonist activation, receptors can increase in number

adaptations in postsynaptic receptors

• when there are abnormailites in NT levels

• when administering drug repeatedly

• hyperstimulation

• hypostimulation

hyperstimulation

• too much NT’s

• fewer receptors, reduced function

• reduce signal to postsynaptic neuron

hypostimulation

• too little NTs

• more receptors, enhanced function

• enhanced signal in postsynaptic neuron

contingent drug tolerance

• tolerance only develops to drug effects that are experienced

conditioned drug tolerance

• tolerance expressed only in the prescence of drug predictive stimuli

• if you’re always taking drugs after certain cues you develop a certain tolerance to the drugs effects in preparation for taking that drug

context-dependent studies

• tolerance in one environment but if you take it in another environment it might have more of an effect because you don’t have a tolerance there

• novel environments lead to drug overdose

incubation of drug cravings

• cues can trigger drug craving and relapse

• cues presented soon after drug withdrawal have less of an effect than cues presented later

liking (reward pathway)

• pleasure, euphoria

• conscious

• GABA, opiods, dopamine

• ventral palladium, paraventricular, nucleus accumbens

• taking drugs sometimes

• dips for the most part

wanting (reinforcement pathway)

• makes you seek out the drug

• craving, appetite, drive

• mostly unconscious (like being hungry)

• dopamine

• nucleus accumbens, ventral tegmental area, amygdala

• seeing or taking drugs

• keeps increasing

mesocorticolimbic pathway

• nearly all drugs of abuse work to increase dopamine in the nucleus accumbens

• natural reinforcers like food, sex, and exercise also do this

nucleus accumbens and addiction

• critical to reward and “wanting”

• self-administration of addictive drugs

• leads to conditioned place-preferences

• natural reinforcers

three stages of addiction development

• initial drug use

• habitual drug taking

  • positive incentive value - expectations

  • wanting vs. liking

  • incentive-sensitization

  • dopamine in the nucleus accumbens

• drug craving and addiction relapse

  • stress

  • drug priming (the effect you’re expecting to get)

  • conditioned environmental cues

severity of substance abuse disorder

• mild: 2-3 symptoms

• moderate: 4-5 symptoms

• severe: 6+ symptoms

  • habitual drug users who continue to use depite adverse effect and repeated attempts to stop

  • addiction =/= physical dependence

drug effects on conduction

• local anesthetics can block Na+ channels, preventing action potentials

drug effects on synaptic transmission

• disrupt storage of NT into vessicles

• disrupt release of NT - exocytosis

• alter NT reuptake - interference with transporters

• alter NT degredation - interfere with enzymes in the synapse

stimulants

• increase feelings of energy and well-being, produce sympathetic nervous system effects (fight or flight)

• cocaine, amphetamines

• nicotine, caffine, pseudopherine (allergy meds)

amphetamines & methamphetamines

• injected, inhaled

• reverses dopamine and norepinepherine transporters (indirect agonist) (instead of sucking up NTs they spit them out)

• powerfully addictive

• greater risk of developing parkinsons

• cardiographic abnormalities

coacine/crack

• from coca leaf

• commonly inhaled, absorbed across mucosal membranes, or injected

• blocks catecholamine (dopamine, norepinepherine, & serotonin) reuptake transporters (indirect agonist)

• euphoria (effects of dopaminergenic neurotransmission)

• crash of agitated depression within 15 to 30 minutes after neurotransmitters drop

• cocaine sprees

• large doses can cause psychosos with schizophrenic effects

nicotine

• from tobacco leaf

• usually inhaled

• agonist at nicotinic (ionotropic) acetylcholine receptors

• very fatty so it readily crosses the BBB

• heritability 55%

• causes compulsive drug cravings and withdrawl symptoms which contributes to relapse

• 70% change of becoming addicted

• reaches brain in 7 seconds

caffine

• orally consumed

• antagonist of select adenosine receptors found on GABA receptors

• inhibits GABA release

• antagonists of adenosine receptors on presynaptic glutamate neurons

autoreceptors

• bind to neurons and are sensitive to the neurotransmitters released only by the neuron they are attached to

• when they feel like that neurotransmitters levels are getting too high it tells the neuron to stop releasing that neurotransmitter causing a negative feedback loop

heteroreceptors

• bind to neurons and are sensitive to the neurotransmitters released by the adjacent different neuron they are attached to

• when they feel like that neurotransmitters levels are getting too high it tells the neuron to stop releasing that neurotransmitter causing a negative feedback loop