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PSYC 207: Drugs, Brain, Society > Lecture 5: Neural Communication 2; Drug Properties > Flashcards

Lecture 5: Neural Communication 2; Drug Properties Flashcards

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1
Q

How does one neuron transmit its message to another?

A

• Released from one axon, bind to receptors of another neuron, often dendrites

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2
Q

End of the line

A
  • Axon ends in terminal boutons
  • Bouton has vesicles filled with neurotransmitters

• Action potential depolarizes bouton
o Vesicles fuse with membrane
o Neurotransmitters released into synapse

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3
Q

Welcome to the synapse

A

• Dendrite membrane has special receptors that fit, like lock and key, with the neurotransmitters
• Receptors are often just (closed) channels that open when they bind with neurotransmitter!
o i.e. ligand-gated ion channels

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4
Q

Receptor Types

A
  • Ionotropic: ligand-gated ion channels

* Metabotropic: signalling proteins — without allowing ions to cross, metabolize them

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5
Q

Ionotropic

A
  • AKA ligand-gated ion channels
  • Neurotransmitters = ligand
  • Channel is closed until the ion binds, then it opens
  • Allow ions to flow: Na+ flow inside, resting potential more negative on the inside
  • Little less specific, will let K+ flow out as well (force pushing on Na+ is much stronger than K+)
  • Excitatory [depolarize] — inside more positive, more towards 0 (EPSP)
  • Inhibitory [hyperpolarize] — (Chloride channel) more negative (IPSP)
  • Fast, transient effect: as soon as it bind to receptor, ions can cross the membrane, spread nearly instantaneously
  • Activity based on channel being opened, as soon as it floats away again — closed, no longer can flow, signal is gone
  • This method is very fast, but very transient— short lived
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6
Q

Metabotropic

A
  • AKA G-protein coupled receptors
  • Bind to the neurotransmitter
  • Don’t have a pore/hole — no way for ions to cross the membrane
  • The direct effects of the bind, are metabolic
  • Inside the cell, bound to G-proteins (signalling molecules): increase or decrease activity within the cell
  • Neurotransmitters binds, G-proteins break off from the receptor— become active to do their work (float through the cell causing signals)
  • Signals: increase the efficacy/length of time ions are open — indirectly causing EPSPs and IPSPs

• Most common, activate other signalling molecules — signalling other molecule, spreading out into these huge signal cascades
o Cause more channels/other types of proteins to be brought to the membrane
o Cause more receptors to be taken to/brought off the membrane/synapse
o Activate enzymes
o Can change the rate of transcription or translation down by the nucleus in the cell body — increase/decrease the amount of protein being made

  • Modulate cell: changing function
  • Modulate signals: how fast the ionotropic signals are received/the effects that they have on the neuron

• Slow, longer lasting effect
o Once you’ve activated a metabotropic receptor — can have long lasting effect, even up to days

• Cause signal cascades

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7
Q

Receptor Locations

A
  • Postsynaptic (dendrite)

* Presynaptic (axon)

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8
Q

Presynaptic receptors

A

Autoreceptors

Heteroceptors

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9
Q

Autoreceptors

A

 Bind to the same neurotransmitter that is being released from that neuron

 Dopamine; dopamine receptors — sending a chemical signal to itself

 Generally speaking, auto-receptors are inhibitory in nature & often, you find them out toward the edges of the synapse

 Little dopamine released; most will bind to postsynaptic receptor

 When you have lots of dopamine released; lots will flow to the edge of the synapse, will bind to the auto-receptors; inhibit the axon that released the dopamine

 Negative feedback mechanism: neuron to guide itself, you’ve released enough neurotransmitter, release less

 Ensures that the presynaptic axon isn’t releasing more neurotransmitter than necessary

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10
Q

Heteroceptors

A

 Bind to different neurotransmitters; not part of the synapse

 Usually found on the edges of the synapse — extra-synaptic

 There is another axon nearby, release a different neurotransmitter nearby

 Purpose: volume signal— turn up or turn down a signal, causing more or less neurotransmitter to be released

 Not the signal itself

 Norepinephrine binding on the presynaptic side; whenever the neuron release transmitter dopamine, will release more neurotransmitter than usual (heterosynaptic facilitation)

 Some will have an inhibitory effect; cause less dopamine/neurotransmitter will be released —turn down the volume (heterosynaptic inhibition)

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11
Q

Neurotransmitter Clean-Up

A
  • diffusion
  • enzymatic degradation
  • reuptake
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12
Q

Diffusion

A

o Neurotransmitters float away

o Problems with diffusion:
 Finds another receptor, will activate those other things: want them to be targeted

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13
Q

Enzymatic degradation

A

o Long-thought to be the norm; bc it is what is found out in the muscles (acetylcholine is broken down by an enzyme into smaller components)

o COMT & MAO

o Enzymes breaking down the neurotransmitter into molecules that will no longer activate the receptors

o Might not be the most efficient; motor neurons releasing neurotransmitters over and over… (break down each time, would be energetically wasteful)

o Some degradation occurring inside the axon (presynaptic): neurons steadily create a new pool of neurotransmitter and are steadily breaking down some of the old pool — regularly, so that is doesn’t get mis-folded

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14
Q

• Reuptake

A

= most common for neurotransmitter clean-up

o Presynaptic

o Astrocytes

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15
Q

o Presynaptic reuptake

A

 Proteins on the membrane: PMAT (plasma membrane monoamine transporter , DAT (dopamine transporter)

 Bringing dopamine back into the neuron

 Similar to a pump; require energy; pushing against concentration gradient

 VMAT2 (vesicular monoamine transporter 2); transport monoamines to synaptic vesicles to be store for later use, require energy pushing against concentration gradient

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16
Q

o Astrocytes

A

 NET (norepinephrine transporter)

 Dopamine & norepinephrine very molecularly similar, transporter are near identical (serotonin)

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17
Q

Drug Types

A

Agonist

Antagonist

Other

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18
Q

Agonist

A

o Increases the function of a neurotransmitter system

o Binds to receptors on postsynaptic receptors themselves

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19
Q

Antagonist

A

o Decreases the function of a neurotransmitter system

o Binds to receptors on postsynaptic receptors themselves

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20
Q

Other

A

o Transporter blocker
 Prevent reuptake from occurring; more neurotransmitter floating in the synapse; more activity — agonist-like effect

o Reuptake inhibitor

o Enzyme inhibitor
 Prevent the degradation of the neurotransmitter; wouldn’t be broken down into its metabolites; floating around for a longer time; more time to activate — agonist-like effect

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21
Q

Drug Effects on Receptors

A
  • agonist
  • antagonist
  • partial agonists/antagonists
  • allosteric regulators
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22
Q

Drug Effects on Receptors

• Agonists

A

o Drugs that activate a neurotransmitter receptor; similar way to how the neurotransmitter would — cannabis molecule similarly shape to the molecules in our system, binds to the receptor causing artificial activation

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23
Q

• Antagonists: block neurotransmitter receptor

A

o Competitive antagonists
 Binds to the same location as the neurotransmitter receptor; instead of activating it just blocks it from being activated

o Noncompetitive antagonists
 Don’t block the binding site for neurotransmitters; can still bind to the receptor; but these drugs bind somewhere else on the receptor— causes the receptors to fail be activated
 Bind to the pore of the channel itself, in a ligand-gated ion channel: block any ions from going through

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24
Q

• Partial agonists/antagonists

A

o More common with agonism

o These drugs will have a lowered ability to activate the receptors

o Weaker effect on the receptor than a full receptor

o Dopamine drug; have weak effects on the serotonin system as well — depends on how it binds to the receptor

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25
Q

Allosteric regulators

A

o When they bind to the receptors, have no effect

o Ions do not flow/metabotropic processes do not occur

o Influence the effects of the neurotransmitter

o Positive modulators
 Increases the ability for the neurotransmitter to activate that receptor
 Effects to be stronger — increases the function

o Negative modulators
 Drug that binds; does not have any effects
 Decreases the ability for the neurotransmitter to activate the receptor

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26
Q

Small-Molecule Neurotransmitters

A
  • amino acids
  • monoamines
  • acetylcholine
  • unconventional neurotransmitters
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27
Q

Amino acids

A
  • glutamate

- GABA

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28
Q

Monoamines

A
  • catecholamines

- indolamines

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29
Q

Catecholamines

A
  • dopamine
  • norepinephrine
  • epinephrine
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30
Q

Indolamines

A

Serotonin

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31
Q

Acetylcholine

A

Acetylcholine

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32
Q

Large neurotransmitter

A

Neuropeptides

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33
Q

Neuropeptides

A

Opioids

  • Co-occurrence; some neurons release multiple neurotransmitter types — usually one small and one large
  • We know lots about small; far less about large (string of amino acids)

• Large molecules
o We know very little about what they do
o Opioids; endogenous version of heroine and morphine (endogenous opioids)
o Somatosensation; pain

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34
Q

Glutamate

A
  • Primary excitatory neurotransmitter : most often, to cause EPSPs
  • Used throughout the brain
  • Ionotropic
  • Metabotropic
  • Neurotransmitters doesn’t determine the action — all that matters is the receptor type, same neurotransmitter could have excitatory or inhibitory effects depending on the receptor that it is binding to ***
  • Often not a great target for drugs — why?
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35
Q

• Ionotropic (glutamate)

A

o AMPAR
 Name receptors after drugs that they bind to
 Binds to AMPA = AMPA receptor
 Glutamate binds; sodium flows into the cells; causes AP/EPSPs

o NMDAR
 Binds to NMDA = NMDA receptor
 Related to learning/memory: special properties, allow Calcium and Na+ into the cells
 About 10,000 times more Calcium on the outside of the cell; great force — carefully guarded/regulated

o Kainate receptor
 Binds to Kainate = Kainate receptor

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36
Q

• Metabotropic (glutamate)

A

o mGlur

 mGlur5: inhibitory effect, auto-feedback

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37
Q

• Often not a great target for drugs — why? (Glutamate)

A

o Throughout entire brain

o Any glutamate agonist or antagonist is going to effect the activity across the entire brain

o If you were trying to target a specific system— not going to happen

o Glutamate drugs will overall increase or decrease activity in the brain

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38
Q

Drugs: Glutamate (all antagonist)

A

• Barbiturates
o Sodium pentobarbital: use in anesthetic, part of lethal injection in some countries

• Nitrous oxide
o laughing gas used in the dentist

• Ketamine
o Horse tranquilizer
o Also used to tranquilize other animals
o Sedation

• Ethanol
o Alcohol

• Pattern?
o Sedating; tranquilizing; diminishing activities
o Glutamate antagonist— decreasing that excitation throughout the whole brain, unified effect/pattern
o Danger of the drugs: if you suppress glutamates functions too much, prevent excitation too much — lead to you have very little activity, lead to heart failure, stop breathing

• Agonist?
o AMPA/NMDA
o The opposite of sedation is not stimulation; but rather crippling anxiety and seizure
o Glutamate already pretty active, if you go higher, doesn’t tend to cause stimulation
o Too much; over firing = seizures

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39
Q

GABA

A
  • AKA gamma-aminobutyric acid
  • Primary inhibitory neurotransmitter
  • Used throughout the brain

• Ionotropic and metabotropic
o Ionotropic: GABAa — chloride channels, lets them come in causes IPSPs
o Metabotropic: GABAb — cAMP, suppression of activity in the neuron, lead to hyperpolarization — less likelihood of firing AP

• Again, often not great target for drugs
o Find GABA almost everywhere in the brain
o Less ubiquitous then glutamate

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40
Q

Drugs: GABA (all agonists: increases inhibition in the brain)

A

GABA antagonist would decrease inhibition in the brain

• Benzodiazepines
o Xanax, Ativan: anti-anxiety medication, around forever
o Know their harms, instead of changing the laws, they change the name
o Rolling Stones “mothers little helper” — name in the 60s, housewife’s would take them to relieve their anxiety

• Ethanol
o Decrease excitation; increasing inhibition
o Very strong suppressing effect on activity in the brain

• Chloroform
o Knocked-out for kidnapping

• Ether
o Surgical purpose; sometimes off-labelled by doctors to get high

• Pattern?
o Causing sedation/inhibition across the brain
o Look like glutamate antagonists

• Antagonist?
o Cause seizures, decrease inhibition

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41
Q

The Amines

A 
related to neuro-modulators 
•	Dopamine (skipping for now)
•	Epinephrine (adrenaline)
•	Norepinephrine (noradrenaline)
•	Histamine
•	Serotonin
•	All metabotropic— play a modulatory role
42
Q

• All metabotropic— play a modulatory role

A

o Related to neuro-modulation

o Modulating glutamate/GABA receptors

o Heteroceptors: increase the size of the signal or decrease the size of the signal

o Often not a very direct/targeted thing: axon will have many terminals down it — strings of beads/pearls design, all releasing the same neurotransmitter at the same time across a very broad area

o Rather than thinking of it like a wire; more like watering a lawn

o Across huge brain area; affects many different cells all at once

o Act on metabotropic receptors — slower, signal cascades, leads to a hint that they are playing modulatory role

43
Q

Norepinephrine (aka noradrenaline)

A
  • Originates in brain stem region called the locus coeruleus “blue location” —released all across the brain
  • Turning on/up the signals across the whole brain
  • When we are startled (ex. Loud sounds), feel more awake, alert
  • Causes heterosynaptic facilitation (via heteroceptors): norepinephrine is released, binds to heteroceptors on synapses, increases any subsequence release — make EPSPs stronger, not a signal (telling those synapses to have a strong signal)
  • Enhancement of memory by stress/emotion: sometimes pathological (PTSD) - essentially have vivid memories of these averse events
  • Evolutionarily useful
44
Q

Propranolol

A

(norepinephrine receptor antagonist) beta-blockers

• Propranolol (norepinephrine receptor antagonist, aka noradrenergic receptor antagonist)
o Use this so that the drugs will bind to receptors on our hearts
o Used off label: stressful talk, conference presentation — reduce overall stress/arousal label
o Lots of norepinephrine receptors in brain, as well as our hearts
o May trigger PTSD
o Very high autonomic: heart pounding, guts twisting, sweating profusely, feel anxious

• Potential PTSD treatment via reconsolidation
o Consolidation means: taking things from working memory to be stored in long-term (semantic) memory
o Putting in back into long-term memory, in a fragile state: can be manipulated/distorted or changed
o Car crash — car is on fire — saving another person: inclined to enrich these stories that may include details that aren’t so accurate
o Propranolol interferes with that reconsolidation: bring someone in, under calm condition, give the norepinephrine receptor antagonist, ask them about the traumatic event and what happened — stress levels low, not reacting to the emotional event the way they would
o Relay this memory through reconsolidation— no longer elicits twisting of the guts, heart pounding … decreasing the emotional arousal (details don’t go away, content doesn’t change)
o Therapy very high risk — potential for problems
o Studying done in the army, might be used with heartbreak

• Eternal Sunshine of the Spotless Mind?
o Not quite, but not entirely unalike

45
Q

Serotonin

A
  • Primarily from the raphe nuclei (brainstem) - reticular activation system
  • Precursor: tryptophan (amino acid: high protein content)
  • To get across the brain; need carbohydrates at the same times

• Serotonin depletion studies
o Bring participants into the live; live-in for a few days
o Control group: regular diet
o Experimental group: tryptophan removed from the diet
o Results: over the course of eating the tryptophan depleted diet, serotonin levels deplete as well
 Increased amount of aggression
 Tend to have increased impulsivity
 Cognitive flexibility declines: perform worse on tests like the stroop tests
 Do not seem to decrease mood
 Relationship with mood is subtle
 Family members with history depression (will see decrease in mood) vs Family member do not have history of depression (no decrease in mood)

46
Q

Selective Serotonin Reuptake Inhibitors

A

• Aka SSRIs, e.g. Prozac (fluoxetine)
o Block those reuptake transporters (along the axon/glia/astrocytes); slow down reuptake back into the axon; create higher amount of serotonin in synapse — keep binding to receptors, working like serotonin agonists [indirect effect]

• For depression
o Theory that depression is a chemical imbalance
o Other mitigating factors: chronic stress

• Block serotonin from being removed from synapse

• Effects of SSRIs quick, improvements slow
o Within 45 minutes, working
o Ever been prescribed: (before said 2-3 weeks) now, might take a month before feeling the benefits of relieving depression

47
Q

SSRI efficacy

A
  • Meta-analyses: SSRIs no better than placebo for mild to moderate depression
  • May help with major depression (BUT…)
  • Connection between serotonin and mood? Yes, but story is more complicated — No, serotonin is not the mood molecule
  • Many drugs that effect serotonin system, LSD/acid/magic mushrooms, causes hallucinations — changes in perception of reality
  • Drug-placebo differences in anti-depressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication
48
Q

• Meta-analyses: SSRIs no better than placebo for mild to moderate depression

A

o Withheld 75% of the data before releasing the drug: convincing/only presenting the result that are meaningful to them

o Not a great picture of efficacy when the drug first came out

o Once available, scientists could study, ask do they help with depression/really work?

o Meta-analysis: grab all these different studies covering the same topic, put them together into a very large sample size, analysis of all the previous analyses

o Data goes in the same direction: is some variety

o Hamilton Rating Scale for Depression:

49
Q

Hamilton rating scale for depression

A

 25+ (anything above, considering to end your life — severe depression)

 25 below (mild depression)

 White dots: placebo (sugar pill, no medication)

 Black dots: medication condition (SSRIs)

 For mild to moderate depression… no better effect that a placebo

 But, for severe depression (25+) is some sort of relationship, SSRIs might help these individuals

50
Q

• May help with major depression (BUT…)

A

o Suffering from major depression: regression to the mean, can spontaneously resolve

o We cannot be 100% certain that the SRRIs are making a different

o Effect size is really small, not very much

o Consider against the side-effect profile:
 Insomnia
 Weight gain
 Sexual dysfunction

51
Q

Acetylcholine

A
  • First neurotransmitter discovered
  • The neuromuscular junction
  • Causes your muscle cells to contract
  • Synapse
  • Also basal forebrain
  • Nicotine
  • Nicotinic receptors also in the brain
52
Q

The neuromuscular junction

A
  • Motor neurons release acetylcholine onto the muscles

- Relatively easy to store

53
Q

Synapse (A)

A

o Between a neuron and a muscle cell

o Neuromuscular Junction

o Any drug that acts on acetylcholine, is going to react on the muscle on the receptor cells, causes muscle to contract

54
Q

Basal forebrains

A

o Wakefulness, attention, etc.

o (Close to basal ganglia)

o Releases a lot of acetylcholine and activates/increases the function of a variety of cells (not too different from norepinephrine)

55
Q

Nicotine

A

o Receptors on the muscle cell label nicotinic receptors: bind to acetylcholine

o Ligand-gated ion channels: fast, transient (ionotropic)

o Affecting acetylcholine receptors — Why it can have mild psychostimulus effects

o Unpleasant effect on the muscle cells: nausea, unpleasant feelings in the stomach (use too much, for the first time)

56
Q

Nicotinic receptors also in the brain

A

o Metabotropic acetylcholine receptors

o Critical role in wakefulness, attention arousal

57
Q

Endocannabinoids

A
  • Name the receptors after the drugs…
  • Affects the brain; has psychoactive affects — didn’t know what system it ran off, looking for the system based on the molecules in cannabis… very similarly shaped molecules to the psychoactive ingredients in cannabis
  • “The cannabis inside you” — endocannabinoids
  • Travel from dendrite to axon, i.e. retrograde transmission
  • Weaken connection between two cells at a synapse
  • Cannabis: the psychoactive ingredients (THC), float over the membrane very easily, binds to this cannabinoid receptors in your brain — causes a weakening at these synapses
58
Q

• Travel from dendrite to axon, i.e. retrograde transmission

A

o Rather than being produced and released from the axon; endocannabinoids are released by the dendrites

o Completely opposite side

o Can cross through membranes really well — drug affect brain well, pass the blood brain barrier

o Mean they also cannot be stored in vesicles

o When you need them, dendrites will make them on the spot; float away; find their receptors on the presynaptic side (on the axon)

o Retrograde transmission: from dendrites to the axon

o We don’t understand all the parameters of what the endocannabinoids system plays… we do know some of the effects

59
Q

• Weaken connection between two cells at a synapse

A

o Decreases subsequent release from this axon

o Internal intracellular effects

o Main role is wreaking the connection between the synapse: between these two neurons

o Sometimes due to an auto-receptor type function: negative feedback mechanism

o In a lot of circumstances, seem to be deliberately released to weaken this connection between synapses

o Why would the brain want to do this? Molecular mechanism for forgetting — if all memory is is a change in structure and function of the synapses… weakening the synapses in effect is like weakening a memory

60
Q

Why would the brain want to do this? Molecular mechanism for forgetting — if all memory is is a change in structure and function of the synapses… weakening the synapses in effect is like weakening a memory

A

 Brain want to do this: there is information that is important to remember, we want to access that information quickly under situations of duress or challenge

 Connections for what are meaningless: across childhood/development, the pruning away of synapses — connection between neurons that shouldn’t be connected (apart of getting older, wiser, smarter) — might not be

61
Q

• Cannabis: the psychoactive ingredients (THC), float over the membrane very easily, binds to this cannabinoid receptors in your brain — causes a weakening at these synapses

A

o Smoking too much weed leads to… uhhh I forget

o Relationship between excessive cannabis use and problems in retaining longer term memories

62
Q

Adenosine

A
  • Not exactly like a regular neurotransmitter
  • Remember: ATP (adenosine triphosphate) is cellular energy
  • Adenosine is ATP byproduct
  • Adenosine receptors
  • Caffeine/theophylline
63
Q

Remember: ATP (adenosine triphosphate) is cellular energy

A

o When we use that cellular energy, say to fuel/power the Na+/K+ pump— break off one of the phosphate groups, leave you with adenosine diphosphate ADP

o Then you can use ADP to perform more stuff in the cell — break off another phosphate group, leave you with adenosine monophosphate AMP

o In some cases, you can break off the last phosphate group, leave you with adenosine

o No super common: slowly across the day, your adenosine levels are building up, especially across the waking day — adenosine is just building up because of activity in your cells

o Daytime accumulation of sleepiness — not the method of sleeping/waking

o Explains why you progressively get more tired across the day

64
Q

Adenosine receptors

A

o All across brain; also across the body

o Metabotropic receptors

o When they bind, do have this inhibitory effect

65
Q

• Caffeine/theophylline

A

o Caffeine activating/bind on these adenosine receptors

o Adenosine receptor antagonist: blocks

o Adenosine can no longer activate these receptors; no longer cause sleepiness; feel more awake

o Problem: brain cells require adenosine signals, when your brain is no longer receiving adenosine signals, knows something is wrongs — adapts accordingly
 Drinking coffee everyday, brain cells are going to add more adenosine receptors to the plasma membrane
 Had 5; drink coffee everyday; cell will add 5 more receptors
 Over time, you get none of the waking up benefits of caffeine… want to get the benefits, need that second cup — cells will recognize this and add more adenosine receptors
 Stop drinking coffee — loads of adenosine receptors on the membrane, no caffeine to block them… adenosine binds, feel super tired and lethargic
 Might be good in the short term… body adapts

66
Q

Endogenous Opioids

A
  • Large category of neurotransmitters
  • Aka endorphins “endogenous morphine”
  • Giant peptide neurotransmitters
  • The neurotransmitter system that exogenous opioids (e.g. heroin, morphine, codeine, OxyContin, Percocet, Fentanyl) mimic
  • Why does your brain have these systems?
  • Fentanyl and naloxone
  • Receptors are all GPCRs (G-protein coupled receptors)
  • Receptors found in spinal cord, periacqueductal grey (PAG) [related to pain relief], nucleus accumbens [related to euphoria], more
67
Q

Aka endorphins “endogenous morphine”

A

o Receptors named after the drug that existed already

o Doesn’t exist for the purpose of drugs, just these drugs act on these systems

68
Q

• Giant peptide neurotransmitters

A

o Beta-endorphins
o Enkephalins
o Dynorphins

69
Q

• The neurotransmitter system that exogenous opioids (e.g. heroin, morphine, codeine, OxyContin, Percocet, Fentanyl) mimic

A

o Take these medications to relieve pain
o Recreational purposes: cause euphoria, pleasant high feeling
o Artificial activation of the endogenous opioid neurotransmitters
o Agonists, cause the same effect as the neurotransmitter, but at very very strong levels

70
Q

• Why does your brain have these systems?

A

o Euphoria: things that are pleasing should make you feel good
o Relieve pain (pain is useful, help us recuperate): in the heat of the moment, we don’t want to be feeling pain
 Mother in a car accident, has a broken leg, saves her child not knowing her leg is broken until she and her child are safe
 Allow her to take care of the situation without feeling pain

71
Q

• Fentanyl and naloxone

A

o We are living through an opioid epidemic right now
o Death toll are responsible for more loss of life than car crashes, COVID-19, suicides, and homicides all combined
o Fentanyl is a really strong opioid receptor agonist — so severely inhibiting, cause problems in the brainstem impacting respiration (breathing, and heart beating)
o A lot of individuals are carrying naloxone kits
 Opioid receptor antagonist
 Blocks the effects at opioid receptors — block the overdose
 In BC 12-15% of us know someone with a persistent problem with exogenous opioid drugs

72
Q

Receptors found in spinal cord, periacqueductal grey (PAG) [related to pain relief], nucleus accumbens [related to euphoria], more

A

o Metabotropic receptors
o Exogenous drugs bind to these receptors, agonists
o Dangerous situations, can use naloxone, an antagonist to block these systems

73
Q

Pharmacokinetics

A

• Drugs passage through the body (absorption → distribution → biotransformation → elimination)

Absorption

  • Drug administration
  • Drug absorbed into bloodstream

Distribution

  • Passage of drug from bloodstream into organs (esp. brain)
  • Must penetrate membranes

Biotransformation
- Drug broken down into metabolites by enzymes

Elimination

  • Drug or metabolites or both are eliminated from body
  • Urine; feces; lungs
74
Q

Absorption: Routes of Administration

A

• Absorption
o Usually in a pill or liquid
o Liberation: drugs molecule separate from the pill/liquid that it was delivered in

  • Intravenous
  • Intramuscular
  • Subcutaneous
  • Per os
  • Inhalation:
  • Insufflation:
  • Drug pKa & environmental pH
75
Q

Intravenous

A

injecting into the vein

o Highest concentration of the drug into your bloodstream

o Leads to it being broken down most quickly; duration the shortest

76
Q

• Intramuscular:

A

injecting into the muscle

o Pretty fast; not very pleasant, most drugs are acidic, injection painful

o The plasma concentration is pretty high; effects are a little bit longer than IV

77
Q

• Subcutaneous:

A

injecting just beneath the skin

o Doesn’t have immediate access to the blood

o Total concentration is lower over all, effect spread out over longer period of time

78
Q

• Per os:

A

orally

o Longest lasting effects

o Has to pass through intestines, stomach, often pass through liver, before it get to the blood

o Opportunities for the process to be interrupted along the way

o Potency is lower

79
Q

• Inhalation:

A

smoke smoking, burns, goes into your lungs, inhale (close to IV) — almost immediate access to blood

80
Q

• Insufflation:

A

snorting (cocaine), doesn’t get absorbed into lungs, but mucus membranes (closer to intramuscular)

81
Q

• Drug pKa & environmental pH

A

bind more easily with those alike themselves

82
Q

• Instrumentally

A

o Don’t want a needle, unless absolutely have to — would rather swallow a pill

o Want long lasting effects: pill for a headache, want it to last for the entire duration of the headache

o Per os, more favourable *

o Asthma inhalers: might want a fast effect, inhalation

83
Q

• Recreationally

A

o Typically looking for the strongest possible effects: higher concentration

o IV or inhalation

o Bad news: doesn’t last as long, but the high is longer

84
Q

Absorption: Drug pKa and Environmental pH

A
  • pKa & pH = measures of acidity
  • The lower, the more acidic
  • General rule, drugs will be best absorbed by tissues that match the acidity level
85
Q

Distribution

A
  • Bioavailability
  • Blood-brain barrier
  • Different drugs may have different potency, not necessarily based on the receptor, but it’s ability to cross the blood brain barrier (BBB) — effect bioavailability
  • Nonspecific binding
86
Q

• Bioavailability

A

o The drugs ability to reach the site of action

o Psychoactive drugs; site in the CNS, usually the brain!

87
Q

• Blood-brain barrier

A

o Quite effective of keeping most molecules out of the brain

o	Some have a better ability to cross
      1)	Small
      2)	Uncharged
      3)	Lipid-soluble: interact well with fats 
              	Ex. Cannabis
88
Q

• Nonspecific binding

A

o When you ingest a drug, by mouth

o Has to travel through, intestines, stomach, liver before reaching the bloodstream and brain

o Passing a lot of locations: molecules act by having a certain shape and charge

o Might encounter other things that they bind to, along the way to the site of action

o Not where were interested in the drug having effects

89
Q

Biotransformation & Bioavailability

A
  • First-pass metabolism
  • Active metabolites
  • Prodrugs
90
Q

• First-pass metabolism

A

o More of an issue with per os

o Drugs start to be broken down even before they reach their site of action

o Enzymes can break down molecules into metabolites: in body, esp. liver

o Lower bioavailability

91
Q

Active metabolites

A

o Enzyme breaks down the drug into metabolites

o Metabolites are also drugs, have psychoactive effects

o Still have psychoactive effect
 Stimulant-like effects — active metabolites also have stimulant effects
 Drugs for schizophrenia — active metabolites have anti-depression effects

o General rule: if a drug metabolism causes these active metabolites, then the total effect is going to be longer and more pronounced than if it didn’t have active metabolites

92
Q

• Prodrugs

A

o Drugs that don’t have any effect — on their own

o What happens, by virtue of these enzymes, these prodrugs can be turned into psychoactive drugs

o e.g. L-DOPA
 Increase the levels of dopamine the brain
 Pill won’t work; dopamine can’t cross the BBB
 Pill full of L-DOPA (precursor) to dopamine
 L-DOPA, can cross the BBB, enzymes will convert L-DOPA into dopamine

93
Q

Pharmacodynamics

A 
•	How the drug works
•	We’ve discussed this (agonism, antagonism, etc.)
•	Also: 
   o	Binding affinity
   o	Receptor efficacy
94
Q

o Binding affinity

A

 How strongly a drug binds to the receptor— strongly or weakly

 Stronger, the longer the effects lasts

 cf. Dissociation constant, Ka (inverse)

 For drugs that have a high binding affinity, the dissociation constant is low

 For drugs that have weak binding affinity, the dissociation constant is high

 Generally related to the strength of the drug

95
Q

o Receptor efficacy

A

 How effective a drug is at activation that receptor

 Some instances where drug can bind well, but not effective activate the receptor very well

96
Q

Adaptations to Chronic Drug Use

A
  • tolerance
  • sensitization
  • dependence
97
Q

Tolerance

A

o Very common in drug use

o Over long term use of a drug, adaptations occur within the brain/body, so that an individual needs a higher dose of the drug to achieve the same effect

98
Q

Sensitization

A

o Why sometimes tolerance, why sometimes sensitization?

o With prolonged use of the drug, adaptations that make one have an increased response to the drug

o Causes some effects, to become stronger/sensitized

o Contrary to how we usually think of drug use “become more immune”

o Under some condition — more intermittent, infrequent (weekend drinking)

o More common for stimulant drugs: increasing functioning (cocaine)

o Only usually for some effects: behavioural aspects — twitchiness, seeking out the drugs (motor effects)
 The pleasing subjective effects — often tolerates

o Need less of the drug to obtain the same effect

99
Q

• Dependence

A

o Not addiction (can be aspect of addiction)

o When you stop using the drug, you have withdrawal symptoms

o Body has developed an adaptation to taking the drug; without the drugs presence; the body is out of balance — feel unpleasant withdrawal effects

100
Q

Heroin Tolerance and Overdose

A
  • Tolerance isn’t as fixed as one might think
  • Highest likelihood of overdosing in an unfamiliar environment
  • Interaction between cues from the environment and tolerance levels/drug taking experience

PSYC 207: Drugs, Brain, Society (8 decks)

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