Physio Psych Part 2

Exocytosis

• Active transport process where cell expels large molecules, proteins, or waste by merging internal membrane bound sac with its outer plasma membrane

• Requires cellular energy since it moves large scale materials and quantities against concentration gradient

Vesicles

Bubble like structures wrapped in lipid bilayer membrane that are like cel’’s internal shipping containers

Role of Calcium (Ca) for exocytosis

• Ca acts as ultimate execution signal and on witch for regulated exocytosis

• When cell is stimulated by electrical impulse hitting nerve cell, channels on cell membrane open which causes Ca ions to rush in which Ca then binds to protein called synaptotagmin on vesicle’s membrane

• Once Ca binds to it, the protein changes shape which forces vesicle to lock together lightly with outer cell membrane triggering instant fusion and release of vesicle’s contents

• Without Ca, vesicles would remain trapped at edge of cell membrane fully loaded but unable to open

Standard chemical synapse

• Electrical action potential reaches axon terminal and triggers Ca channels to open, this causes vesicles to release chemical neurotransmitters into synaptic cleft where molecules bind to postsynaptic receptors to open ion channels

• Chemical because electrical signal is converted into chemical message that diffuses across space

• One direction from presynaptic to postsynaptic and slower

• Benefit are highly flexible and capable of signal modulation, amplification, and plasticity

Gap junction (electrical) synapse

• Two adjacent neurons physically connected by specialized proten channels forming gap junction

• Ions flow directly through these continuous tunnels

• Electrical because no chemical messengers are needed as ionic current itself passes straight through bridge without conversion

• Ions can flow in either direction depending on membrane potential

• Instantaneous and speedy, extremely reliable

• Benefits are ideal for rapid highly synchronized firing across groups of cells

EPSP

• Depolarization (inside of cell becomes more positive and closer to threshold to fire action potential)

• Postively charged Na+ or Ca ions rush into cell

• Graded, because their size or amplitude is directly proportional to strength of stimulus which differs from all or none action potential

IPSP

• Hyperpolarization (inside of cell becomes more negative and farther away from action potential threshold)

• Negatively charged Cl ions rush into cell

• ALso can be caused by positively charged K ions leaving cell

Why EPSP and IPSP are local potentials

• They stay in small area of cell membrane with short distance signals and fade out quickly as they travel

• Axon hillock acts as neuron’s decision center by combining all incoming signals, if combined voltage reaches threshold of -55mV then action potential starts

• Sensory receptors or synapses generate graded local potentials, when sum of these charges makes axon hillock positive enough then voltage gated channels open to fire action potential

• Stronger or longer lasting receptor activity produces more depolarization at axon hillock

Ionotropic receptors

• Directly coupled ligand gated ion channel that produces fast and short lived electrical changes that stays close to local membrane area

• When neurotransmitter binds, channel opens immedietly to let ions cross membrane

• Glutamate receptor: allow influx of Na or Ca rapidly depolaraize postsynaptic membrane for fast excitation

• GABA receptor: acts as Cl channel, when activated Cl rushes into cell hyperpolarizing membrane to instantly inhibit neuron

Metabotropic receptors

• Receptors that trigger slow and long lasting signaling cascades, separate proteins linked indirectly to ion channels through second protein messengers

• Takes longer to develop because of neurotransmitter binding activtates second messenger system and effect can last for long time

• Glutamate receptor: divided into groups that modulate neural exictability or inhibit further glutamate release by slow secondary messenger pathways

• GABA receptors: are coupled to proteins that slowly open K channels or suppress Cl channels producing prolonged inhibitory postsynaptic potential

Second messenger systems

1. Neurotransmitter binds to receptor

2. Change in configuration of receptor protein

3. Release G protein

4. Activate adenylyl cyclase

5. Produces 2nd messenger

6. 2nd messenger activates other proteins that open/close ion channels, alter production of proteins, activate genes

Receptors

• Delay between action potential and neurotransmitter binding (chemical synapse) which takes up more time vs gap junction which is 10 microseconds

• Each neurotransmitter has several receptors it can bind to where each type of receptor can trigger a different response

• Receptor sub types each neurotransmitter has: Acetylcholine has 2 receptors, Dopamine have 5, Serotonin have 5-HT types

• There’s incredible variety with the few neurotransmitters as each one works through many different receptors leading to different effects based on the receptor it lands on, development of new receptors may be part of evolutionary process

Neurotransmitters in terms of exocytosis process

• Neurotransmitters stored in vesicle that will bind with postsynaptic neuron

• 3 major ways of removing NT at synaptic cleft to clear out synaptic space so that next action potential can be efficient: active reuptake (recycling), enzymatic breakdown (builders or destroyers of neurotransmitters are enzymes), diffusion (neurotransmitter floats away)

Reuptake

• Neuron recycles neurotransmitter

• Repackaged into vesicles (endocytosis), reuptake transporter

• Common with 5-HT and catechlomines such as dopamine, norepinephrine, and epinephrine

Enzymatic breakdown

• Inactivation of NTs

• Enzymes speed up chemical reactions by either building molecules or breaking them apart

• For enzymatic breakdown, enzymes break down neurotransmitters

• MAO enzyme (monoamine oxidase): breaks down NT monoamines which includes serotonin and the catecholamines

• MAO inhibitors: antidepressant drugs that block MAO, if enzyme can’t break down those NTs more of them stay around which boosts mood related signaling

• AChE (acetylcholinersterase): enzyme that breaks down ACh

Nerve agents

• Includes Acetylcholinesterase inhibiters which are nerve agents working by blocking AChE

• This creates more ACh remaining in the synapse causing overstimulation and symptoms across neuromuscular like twitching and paralysis, autonomic effects like nausea and sweating, and brain like headache and confusion

Chemical part of neurotransmitters

• At most synapses signal is carried across gap by chemical rather than electricity

• 4 kinds of chemical messengers: neurotransmitter (classic messenger released by one neuron crossing synapse and quickly triggering response in next cell), neuromodulators (adjust how strongly neurons respond to other signals), peptides (act as NT or neuromodulators), hormones (chemicals released into bloodstream traveling to distant targets more slowly and broadly)

Major categories of neurotransmitters

• Biogenic amines: family of NTs made from amino acids having amine group

  • Acetylcholine: muscle movement, attention, memory)

  • Monoamines: serotonin 5-HT (mood, sleep, appetite) and catecholamines (Dopamine- reward, motivation, movement, Norepinephrine- alertness, arousal, fight or flight, Epinephrine- also fight or flight, stress and energy boose)

• Amino acids: GABA inhibitory calming neural activity down, Glutamate excitatory ramping neural activity up

• Peptides: modulators

• Purines

• Gases

Neurotransmitter creation

• Neuron that sends presynaptic neuron signal makes NT

• Materials generally come from diet and enzymes convert those ingredients into finished neurotransmitter

• Not every enzyme in every neuron where each neuron has specific enzymes needed to make its own type of NT

• Ex. Acetylcholine synthesis: Acetyl co enzyme A produced in mitochondria + choline from diet with the help of enzyme CAT creates ACh

Choline

• Dietary supplementation

• Promotes earlier learning

• May attenuate effects of fetal alcohol exposure

• May be preventive for Alzheimer’s disease

Synthesis and relation between catecholamines (DA, NE, E)

• DA, NE, E built in one chain where each product becomes starting material for next step and each step needing own enzyme

• Pheynylalanine from diet has PKU enzyme which will break down to Tyrosine also from diet and has Dopa enzyme which will break down to dopamine which will break down to norepineprhine and then to epinephrine

Transport

• Neurotransmitters manufactured in cell body but needs to be transported to axon terminal

• NTs get packaged into vesicles to transport to axon terminal until neuron fires where vesicle will release their contents

• Transport of neurotransmitters and other compounds occur by microtubules like subway system in neuron

Psychopharmacology

• How various drugs impact system

• With respect to drugs and behavior it’s major motivation system in brain

• General focus on drug impacts changing activity of NT production, NT availability, or on other receptors directly

Endogenous

• Chemicals naturally found and produced in body by genetic basis

• Includes neurotransmitters, neuromodulators, enzymes, hormones

Exogenous

Chemicals, toxins, drugs, medications introduced from the outside

Possible drug effects on neurotransmitters

• Change synthesis of NT

• Prevent packaging in vesicles

• Increase or decrease in NT release

• Affect inactivation of NT, could prevent enzyme activity or increase it

• Directly affect NT receptors, activate or inhibit

Agonist drugs

• Increase receptor activation

• Direct agonist: attaches to same receptor as NT and has same action as NT

• Indirect agonist: increases NT activity by other means such as increase synthesis, increase release, and decrease breakdown/reuptake of NT

Antagonist drugs

• Decrease receptor activation

• Direct antagonist: attaches to and blocks NT receptor so no receptor activity

• Indirect antagonist: decreases NT effects in another way such as decrease synthesis, prevent release, increase rate of breakdown/reuptake

Agonists used for treatment

• GABA: anti anxiety drugs

• Serotonin: anti depressant drugs

• Acetylcholine: movement disorders

Antagonist used for treatment

Dopamine: anti psychotic drugs

Receptors aren’t fixed

• Receptor proteins have particular life span and number of them can change

• Up regulation: number of receptors increases

• Down regulation: number of receptors reduced

• These changes can occur in response to changes in nervous system such as chronic activation or inhibition and drugs can cause activation or inhibition so it isn’t random

• Particularly useful in explaining tolerance because brain down regulates receptors to cope with drug repeatedly flooding brain with signal so person needs more of drug to get the same effect due to building tolerance

• Upregulation often occurs within minimal activation of receptors, can result in increased sensitivity

• Becomes relevant when there’s sudden change in behavior or environment

Receptor subtypes

• Very important in clinical pharmacology research

• Receptor subtype is receptors for same chemical coming in slightly different forms where each does a different job

• Drug can cause side effects, because it could bind to more than one subtype where one might produce effect wanted while the other subtype produces effect not wanted since drug can’t tell the difference

• Big goal of neuropharmacology is to design drugs that bind with greater attraction to one receptor subtype, initiate selective effect, limit side effect by not activating other subtypes

Substance use disorder

• Patterns of symptoms resulting from use of substance you continue to take despite experiencing negative outcome

• Key point in determining addiction is continuing to perform action in spite of negative consequences

• What ultimately drives these behaviors is similar across different addictions

Modeling addiction

• Drug self administration method allows to determine addictiveness of drug

• If animal given opportunity to self administer and give high dose, we can assume drug is rewarding and has reinforcing properties having abuse potential

• Antidepressants are one example off drug that animals don’t self administer

First discovery of reward

• Olds & Milner contributed to public understanding that using drug will lead to addiction

• Reinforcement from electrical stimulation by putting electrodes into brain

• Looks at where animals self stimulate to generate activity in brain, the area was nucleus accumbens

• Inspired Alexander’s rat park experiment which demonstrated more nuance where rats consumed water with morphine, some rats were started in an enclosure with options for activities instead of a small enclosure that Milner used and found that there was far less consumption of morphine water than the rats who in the small enclosure, rats who started in enclosed cage that consumed morphine who were moved into the activities cage then chose plain water over morphine due to lack of competing options for motivation

Mesolimbic pathway

• From Ventral Tegmental Area (VTA) in midbrain to Nucleus Accumbens (NAcc) is critical pathway with respect to drugs and addiction

• If something drives VTA it will drive the Nucleus Accumbens and then drive activity

• Dopaminergic pathway, activation of dopamine receptors in NAcc important

• NAcc is part of Basal Ganglia as we can physically respond to the reward

• There’s also mesocortical pathway which is from VTA to vmPFC

Motivation pathway

• Reward pathway

• DA (dopamine) cell bodies in ventral tegmental area

• Medial forebrain bundle, axons from VTA to NAcc

• Release dopamine in NAcc, dopamine delivered here creates activity, NAcc decreases activity which equals to motivation and reward

• Research shown separation between motivation/reward and liking

• Mesolimbic pathway is like reward

Addictive behaviors

• Drugs aren’t alone in driving addiction

• All things driving addiction release dopamine in nucleus accumbens

• Existence of this system can be seen in evolutionary context such as eating

• Addictive potential relates relative activiation of NAcc in comparison to baseline level of activity, baseline determined by typical environment of how much activity there is in NAcc in your day to day, huge implications for addiction treatment

Evidence in support

• Set up Skinner box where plain food is freely available but have to press bar for sugar pellets

• Rats given dopamine antagonist that blocks dopamine exhibit very different behavior from controls by consuming a lot of the freely available food as they’re not motivated because there’s opiod receptors that influence activity in VTA

Stimulant drugs

• Increase activity, arousal, alertness, elevate mood, decrease fatigue

• Amphetamines

• Cocaine

Amphetamines

• Parent compound of family of synthetic psychostimulants, structurally related to dopamine

• Amphetamine and methamphetamine are indirect agonists of catecholaminergic systems including dopamine and NE

• Mechanism of action: molecules enter dopamine nerve terminals through the dompanine transporters (DAT) and cause vesicles with DA to open inside presynaptic cell, then released DA is transported outside cell be reversal of DAT and skips exocytosis and results in high concentrations of DA outside cell

• NE releasing effects of amphetamines occur in brain and in sympathic nervous system

• Consequently these compounds have potent sympathomimetic (mimicing sympatheic activity) actions

How amphetamine affect mesolimbic pathway

• Animal and human studies show increases in DA levels in nucleus accumbens by reverse transport of DA

Chronic effects and connections

• Insomnia makes sense as sympathomimetic

• Mental states resembling schizoprenia (excess DA activity) amphetamine psychosis, may include paranoia

• Aggressiveness

• Dependence- if there’s fewer DA downregulation then amount of DA naturally releases has less impact so it won’t be as motivating, withdrawal symptoms are irritability and confusion

• Engage in repetive behavior and become fixated on trivial actions- may involve increased activity of salience network (includes insular cortex and anterior cingulate cortex), there are connections between mesolimbic pathway and salience network

Long term brain effects of methamphetamines

• Brain image shows reduction in striatl DAT binding with chronic methamphetamine use

Stimulant

• MDMA (ecstasy): stimulates DA release and reverses DA transporter like amphetamines, also stimulates 5 HT release and reverses 5 HT transporter which differs from amphetamines, hallucinogenic effects may be due to increased 5 HT release, at high doses it may destroy serotonin producing cells which may put people at greater risk for depression later, also releases hormone oxytocine, can lead to death from cardiovascular distress or hypothermia

• Cocaine: different from amphetamines, blocks reuptake transporter, indirect agonist blocks reuptake of DA, NE, E, longer action of NTs in synapse, effect on mesolimbic pathway it increases in DA levels in nucleus via DA reuptake inhibition appear to mediate reinforcing effects of cocaine

• Methylphenidate: reuptake inhibitor, taken orally with no rapid high, gradual onset and more sustained action than cocaine, increased alertness and attention

Cocaine vs methamphetamine

• It takes about 1 hour to get out cocaine while many for methamphetamine

ADHD Treatment

• Psychostimulants in low doses produce calming effect in more than half children with ADHD

• Brain imaging studies found differences in right prefrontal cortex in ADHD patients compared to controls

• Output neurons of prefrontal cortex are innervated by noradrenergic and dopaminergic systems with key receptors a2A for NE and D for DA

• NE activiation of a2A receptors enhance strength of relevant sensory input, increases ability to pay attention to what you want to pay attention to

• DA activiation of D receptors weakens irrelevant sensory input, increases ability to ignore what you don’t want to pay attention to

How stimulants help ADHD

• Arnsten argue that prefrontal cortex function is an inverted U shaped function of activity of both catecholaminergic systems, the action of stimulants is to enhance catecholaminergic activity in prefrontal cortex

• DA activity in prefrontal cortex may be reduced with ADHD

• Medications have a differing range of how much it raises DA and/or NE

Sedatives

• Barbiturates and Benzodiazepines

• Primary mechanism of action involves enhancing GABA transmission

• GABA is major inhibitory neurotransmitter, GABAa receptor is Cl channel

• GABA and GABA agonsts allow Cl to move into cell and result in hyperpolarization

Barbiturates

• Increase affinity of GABAa receptor for GABA, but differ from Benzodiazepine in what they do when GABA binds

• Barbiturates can increase duration of opening channel

• They can open Cl channel without GABA making them potentially lethal while benzodiazepines aren’t

Benzodiazepines

• Enhance effect of GABA by increasing affinity of channel for GABA and increase rate of opening of channel when GABA binds

• Modulatory because in absence of GABA they hav no effect on channel opening

• Because it only modulates GABA needed for effect it’s much safer than barbiturates

• Recreational use of BDZs often combined with alcohol, opiods, or other CNS depressent and these combinations can be highly toxic

• BDZ direct antagonists exist and used to reverse effects of DBZ, drug cleared gradually from body and metabolized during time

Opiate drugs

• Narcotic analgesics derived from opium poppy

• Morphine, heroin, codeine, oxycodone, hydrocodone made in labs

• Act on opiate receptors, endogenous chemical is endorphins which is endogenous morphine that’s naturally released with effects of pain relief

Identifying receptors

• Opioid receptors identified with radioligand binding methods

• As amount of radioactively labeled ligand increases, binding increases then tapers off until receptors fully occupied

• Able to show naloxone didn’t bind to other receptors

Dopamine cell bodies in VTA

• Opiod receptor activiation in general is inhibitory and interacts with GABA systems

• If GABA activates receptors the DA is less to fire so shutting down GABA creates double negative and creates excitation