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PMCOL 305 > Midterm I (Sep 3-Sep 24) > Flashcards

Midterm I (Sep 3-Sep 24) Flashcards

1
Q

drugs of abuse

A
  • act at specific target (NT receptors, transporters, related enzymes, pathways, etc)
  • > may have one or multiple targets but do not disrupt neuronal function in a universal or non-specific way
  • initially, users attracted to rewarding aspect but eventually take the drug just to feel normal
  • chronic use causes changes to neuronal circuitry, brain structure, connections
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2
Q

SUD (Substance Use Disorder)

A
  • substances separated into different drug disorders ( cocaine, alcohol, etc), each composed of 11 criteria from 4 categories (impaired control, social impairment, risky use and pharmacological indicators (tolerance, withdrawal)
  • severity depends on number or criteria (mild-2/3, moderate-4/5, severe-6+)
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3
Q

Addiction

A

long lasting, relapsing condition used to describe the most sever chronic stage of SUD; facilitated by changes in brain structure and neurochem, usually a result of escalating use, may involve pre-disposing qualities
-3Cs (Consequences, Control loss, Compulsive drug seeking and abuse)

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4
Q

What is the tipping point btw casual use and addiction?

A

usually some form of tolerance and dependence

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5
Q

stages of addiction

A
  • binge and intoxication
  • withdrawal and negative affect
  • craving, preoccupation and anticipation
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6
Q

binge and intoxication

A
  • involves basal ganglia, structure associated w reward pathway
  • DA release signals reward + euphoria, triggers pavlov. response and starts forming anticipatory associations to cues (ex. white powder, a room)
  • drug taking as an unusual form of learning and mem
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7
Q

withdrawal and negative affect

A
  • extended amygdala, also hippocampus
  • DA sensitivity decreases, tolerance increases, natural rewards release insufficient DA to stimulate the pathway; as a result, judgement of other stimuli is altered and the antireward effect sets in (when not taking the drug, the feeling of dysphoria and the stress response push you to take more to stop feeling so awful)
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8
Q

Craving, preoccupation and anticipation

A
  • PFC, which controls executive functions (self reg, decision making, assignment of value, error monitor, etc) should normally weigh options and filter out primitive urges
  • surges of DA can also flood the PFC though, impairing DA and Glu signaling and making it hard to filter and send out appropriate signals to avoid consequences
  • results in difficulty to resist strong urges or to follow through w decisions
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9
Q

tolerance

A

taking higher doses of the drug without feeling effects OR needing more drug to get the desired effects

  • users may become tolerant to desired side effects (high) but not undesired (side) effects due to differential changes in receptors or other drug targets (ex. chron. opiod users may dev. tolerance to vomiting but not constipation)
  • users can die bc the doses they take trigger dangerous side effects to which tolerance has not developed (ex. cardiovascular deaths in cocaine abuse)
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10
Q

dependence

A
  • physically/psychologically unwell when not taking drugs (ex. tired or sleepy in absence of stimulant)
  • state that occurs after using drug so frequently and consistently that it becomes difficult to function without it
  • typically occurs after tolerance starts, but both processes are linked
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11
Q

how are tolerance and dependence related?

A

Adaptation; as the brain tries to maintain homeostasis, it will change NT pathways and other physiol. responses

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12
Q

pharmacodynamic tolerance

A
  • sensitivity of neurons to the drug changes with chronic use, usually due to changes in NT receptors or transporters
  • may see a cross-tolerance btw drugs of the same class if they act at the same targets (ex. tol. to one opiod often results in tol to most)
  • responsible for most withdrawal effects when the drug is removed
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13
Q

effect of stimulants on neurochemistry

A
  • stimulant generally causes excess NT release and therefore excess neurotransmission
  • brain reduces number of receptors, moving activity back to an acceptable range of normal functioning (pharmacodynamic tolerance)
  • in absence of drug, levels of that NT in the brain are greatly reduced, leading to dysphoria (withdrawal)
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14
Q

effect of sedatives on neurochemistry

A

sedative usually cause insufficient NT release, which lowers neural activity

  • brain increases number of receptors to restore normal functioning (pharmacological tolerance)
  • in absence of the drug, the brain is overly sensitive to the NT (withdrawal)
  • this is especially dangerous as it can lead to seizure
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15
Q

drug disposition/metabolic tolerance

A

-chronic use of some drugs results in increased metabolism or excretion, typically due to increased activity or lvl of enzymes in liver (ex. ethanol tolerance due to up-regulation of liver enzymes and alternative metabolic pathways, allowing increased removal of ethanol from the blood)

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16
Q

physical dependence

A
  • the longer and more intense the drug use, the greater the probability that the brain will change to compensate (ex. opiod use causes constipation, the body upregulates other mechanisms to pass food through the GI, withdrawal can lead to diarrhea)
  • once adaptive changes occur in the body, the user needs to keep using the drug to prevent withdrawal symptoms resulting from uncompensated adaptive change
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17
Q

psychological dependence

A
  • drugs that are reinforcing (stimulate reward pathway when taken) tend to produce psych. dependence, which manifests s compulsion or perceived need for use
  • also linked to changes in brain in response to drug use
  • long lasting changes in specific brain regions result in craving and relapse after quitting
  • powerful driving force behind repeated drug use
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18
Q

genetic factors of addiction

A
  • genetic factors (specific differences in genes) account for ~50% of the risk for addiction
  • twin studies: monozyg. twins have more sim. r8s of addiction than dizyg. twins
  • adoption studies: kids more likely to have habits of birth than adopted family
  • env. (culture, stress, peers, family, attitudes) also plays a role in risk
  • epigenetics (changes in gene expression) thought to play larger role, esp. in long-lasting neuroplasticity associated w addition (in animal studies, epigen. changes can be pass to offspring and affect their responses to drugs)
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19
Q

“candidate” gene approach

A
  • initially thought we could find a link btw variations in genes considered important for abuse (based on pre-exisiting knowledge) and drug abuse/dependence
    ex. genes for DAT (DA transporter protein), DRD2 (DA receptor D2), OPRM1 (mu opiod receptor)
  • results are confusing and often contradictory, suggesting that no one change in a gene makes you susceptible to a drug
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20
Q

genome-wide association studies (GWAS)

A

compare as many genes as possible btw dependent vs non-dependent subjects; no prior suspicions necessary as results will show differences at any genetic location present and reduced bias

  • shows addiction is highly polygenic
  • unexpectedly, few genes thought important a priori were identified; rather, many were from genes involved in neuronal adhesion (important in neuroplasticity), suggesting drug dependence may be a learning problem
  • certain genes show up in several diff. studies suggesting overlap btw those responsible for susceptibility to diff drugs of abuse
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21
Q

major routes of administration

A
  • mouth
  • injection
  • inhalation
  • insufflation (snorting)
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22
Q

bioavailability

A

the fraction of administered drug that ends up in the circulation: by definition, 100% for IV, but can be significantly less for other routes

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23
Q

oral administration

A
  • simple, easy, no training required
  • drugs taken orally must be able to pass through cells lining gut (usually only lipid soluble, neutral drugs can be absorbed)
  • drugs poorly absorbed fr GI have low bioavailability
  • in order to take effect, the drug must make it through the intestines, liver, R heart, lungs, and L heart before the brain
  • slowest; time lag means drugs swallowed can be slightly less addictive
  • some may be completely metabolized by enzymes in liver (ctyochrome P450 “CYP” enzymes/gut before
  • drug continues circulating to the liver and will eventually be cleared from the body
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24
Q

intravenous (IV) injection

A
  • drug is delivered directly into the bloodstream, less diffusion
  • rapid onset with 100% of the dose available in the plasma
  • rate of injection affects peak height (conc of drug in brain)
  • control and deliver high concentrations
  • blood vessels rel. insensitive to irritants so can inject drugs that contain contaminants (ex. crushed pills that would eventually cause necrosis via IM/subQ injection), but veins will eventually collapse
  • collateral health risks (HIV, hep, bacteria)
  • when done correctly, drug will bypass liver, go directly to R heart then L heart then brain
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25
Q

Instramuscular (IM) and subcutaneous (SubQ) injection

A
  • drug absorption depends on diffusion through tissue and removal by local blood flow
  • IM absorption more rapid because of better blood supply, but both typically faster than oral
  • > most rapid IM in deltoid, intermediate in thigh, lowest in glutes (due to differences in blood supply)
  • advantages of IM over subQ are larger volumes (less bubbling) and less chance of irritation (necrosis)
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26
Q

inhalation

A
  • drug gets to brain a couple seconds faster than IV because it bypasses the R heart, going from the lungs to thee L heart to the brain
  • lungs have huge surface area for absorption and the blood vessels there take u p the drug very quickly
  • bypasses first pass metabolism
  • dosage is harder to control, but experienced users learn to titrate drug delivery (ex. smokers tend to take fewer puffs of cigarettes with high nic levels)
  • includes smoking and huffing
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27
Q

alternative routes of administration

A
  • transdermal, rectal, vaginal (ex. alcohol-soaked tampon); can bypass liver if done right
  • eyeball shots (holding liquor to the eye; just corrodes the outer layer)
  • snorting cocaine (dissolves in and absorbed by mucous membranes in nose), chewing tobaccos (nic absorbed by oral cavity mucosa); both avoid first pass liver metabolism
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28
Q

Administration routes and abuse potential

A

the faster a drug reaches the brain and the higher the concentration delivered, the greater the abuse potential

ex. heroin, a derivative is a modified version of morphine designed to reach the brain faster, and has a greater abuse potential
- oral amphetamines have mod potential, smokeable methamphetamine has a very high potential
- crack, a cheap smokeable version of cocaine, has a very high potential
- hallucinogens have v low abuse potential and cause little physiological damage

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29
Q

pharmacokinetics-ADME

A

-absorption
-distribution
-metabolism
-excretion
most drugs either removed from system by metabolism in the liver, excretion (via intestines, kidney, lungs, sweat glands) or a combination
-some drugs are bound to proteins in the blood that render them inert, some are not metabolized extensively and excreted unchanged

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30
Q

dose-response curves

A
  • sigmoidal
  • describe relationship btw amt of drug in system and response if produces, or the percentage of the population it affects
  • note there is a max response for any given effect at a certain dose, beyond which no more effects can be measured
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31
Q

TD50

A

toxic dose, or conc of the drug that’s toxic to 50% of users

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32
Q

ED50

A

effective dose, or conc that produces the desired effect in 50% of users

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33
Q

TI

A

therapeutic index, TD50/ED50

  • the bigger the difference, the farther apart those two curves lie
  • gives rel. info regarding safety (ex. if TI dose is 2, the deadly/toxic dose is only 2x the effective dose (dangerous))
  • note that TI values can drop dramatically if other drugs are present*
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34
Q

reinforcement

A

a behavioural event followed by a consequent event such that the drug behaviour is then more likely to be repeated

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35
Q

drugs as reinforcers

A
  • strength of reinforcing property correlates strongly with addiction potential of drugs
  • drugs can hijack the reward pathway to promote drug taking behaviours
  • in animal models, the more reinforcing the drug, the harder the animal will work to get it
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36
Q

extinction

A

reducing the drug-seeking behaviours to zero by removing the reward (drug)

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37
Q

models for reinstatement

A
  • measure vulnerability to relapse into drug abuse
  • animals trained to self administer, behaviour then extinguished by discontinuing drug delivery, seeking behaviour eventually dissipates
  • test which stim cause animal to reinstate drugg-seeking or administering behav even tho no drug available
  • > found the same things cause reinstatement in humans (stress, small dose, cues)
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38
Q

conditioned place-preference

A

can tell us whether a drug had a reinforcing, euphoric effect or an aversive one
-animal is trained to associate one chamber w the drug; they are then placed in a anteroom btw a neutral chamber and the drug associated chamber and studying where it spends most time can tell us the effect of the drug

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39
Q

in-vivo microdialysis

A
  • sterotaxic surgery is used to precisely implant a probe at a specific region or structure within an animal brain
  • brain fluid is sucked out to capture NT release, artificial CSF pumped back in
  • can monitor release of DA and other NTs, by analyzing content of CSF under diff conditions (ex. learn that while exercise stims animal reward pathway, the strongest nat stim in mice is mating)
  • measurement of chems given as % of the baseline signal
  • poor time res (sampling captures release over mins rather than secs); might miss some info
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40
Q

Fast-scan cyclic voltammetry

A
  • measures a change in NT conc (as oppposed to % of baseline)
  • fine time res (seconds rather than minutes)
  • probe inserted with sterotaxic surgery
  • apply voltage down the probe; it strips electrons off DA (oxidizing it) and we can then measure the number of electrons to indirectly assess DA release
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41
Q

electrophsiology

A
  • technique that measures activity of neurons we believe are releasing DA (the more rapidly it fires (spikes/sec), the more DA release events are occurring)
  • activity is wirelessly recorded in real time
  • can measure fields of neurons or indv ones
42
Q

mesocorticolimbic pathway

A
  • inf, the reward pathway (a combo of mesolim and mesocort paths)
  • DA as the maj NT
  • most drugs of abuse act either directly or indirect on components of one or both paths
  • blocking these DA receptors produces anhedonia (loss of ability to feel pleasure), motivation loss
  • disrupting messolim (/blocking its DA receptors) prevents self-administration
43
Q

where does the DA in the mesocorticolimbic pathway come from?

A
  • DA releasing neurons in ventral tegmental area (VTA) are excited by drugs of abuse
  • this causes increased DA release onto:
  • nucleus accumbens (producing reward, euphoria)
  • amygdala and hippo (mem structures, likely involved in overlearning of drug-associated behaviours, cues)
  • PFC (higher cog function disruption)
44
Q

3 important NTs

A

DA (excite or inhib depending on the type of DA receptor it binds to)
GABA/gamma-aminobutyric acid (inhib, decreases prob of depolarization)
Glutamate (gen excite and increase prob of depol, but some presyn are inhib and act as -ive feedback syst. for glu release)

45
Q

phasic and tonic release

A
  • tonic is baseline (in a non-stimmed animal, midbrain DA neurons typ fire at low freq (1-5/s), producing ‘tone’ or basal stim of DA receptors)
  • high freq bursts (20+/s) of firing called phasic release (can be triggered by a drug, as well as introduction of a conditioned cue or stim associated w drug reward to an animal trained to self-admin)
46
Q

medium spiny neurons in the nucleus accumbens

A
  • in the ventral portion of the striatum
  • 95% of the neurons are MSNs
  • release GABA when depolarized
  • covered in cactus like spines with either D1 (excitatory) or D2 (inhibitory) receptors
  • activity modulated by DA, Glu and other NTs
47
Q

cues, memory structures, and drug-related behaviour

A
  • simple cues can trigger mem centres of brain in ppl who are drug-dependent, leading to reinstatement of drug-seeking behav
  • amyg and hippo activated in presence of drug-as’d cues, likely maj component of craving
  • extinguished drug-seeking behav can be restarted by direct stim of hippo
48
Q

Acute drug effects

A
  • predominantly DA related
  • during drug taking (and anticipation), lvl of DA in the nucleus accumbens increases
  • DA stims mem structures, creating strong emo mem of drug taking events (“overlearning”, possibly craving and relapse too)
49
Q

chronic drug effects

A
  • involve Glu and DA
  • repeated use changes strength of Glu signaling btw components of the pathways
  • changes in PFC modulation by DA; listt of behav control and decision making by abnormal Glu signaling
  • Glu-mediated signaling fr PFC, amg and hippo to nucleus accumbens altered
50
Q

D2 receptors and drug response

A
  • in alcoholic, obese, cocaine-dependent brains, fewer D2 receptors seen in reward areas
  • in gen, ppl diagnosed w any type of SAD have fewer D2 receptors and all types of addiction (whether to stims or depressants) correlate w low D2 lvl
  • D2R lvls can be changes w stim (ex. social stressors, exercise)
  • high levels of D2 may be protective
51
Q

Ritalin experiment

A
  • ritalin is a clinically safe drug that can be used to mimic cocaine
  • ppl w high lvls of D2 reported dysphoria after taking the drug, while ppl w low lvls experienced euphoria
  • suggests that low D2 levels could increase drug susceptibility
52
Q

an overview of DA receptors

A
  • physical structures to which NTs interact to pick up signals from another neuron
  • all have 7 protein domains
  • membrane proteins (span the lipid bilayer)
  • transducers (?)
  • coupled to G proteins, that dissociate fr the receptor, travel a distance w/in the neuron and mediate messages
53
Q

D1 receptors

A

Gs coupled (stim adenylyl cyclase (enzyme) to produce cAMP (common signaling molecule), activates kinases (which activate or inactivate various pathways by phosphorylating proteins))

  • gen. found on postsynaptic neurons
  • excitatory effect on neurotrans.
  • found on MSNs in areas most strongly as’d w reward
  • have low DA affinity (tonic DA background doesn’t have much effect, active only at high conc)
54
Q

D2 receptors

A
  • Gi/Go coupled (inhib adenylyl cyclase (enzyme, produces cAMP (common signaling molecule)),
  • postsyn receptor, but also presyn autoreceptor
  • found in pathways associated w aversion (as in addition to reward, DA can also shut down ability to feel aversion)
  • DA affinity 1000x higher than in D1 receptors (active at much lower conc, likely even the tonic basal DA)
55
Q

activity in dopaminergic synapses

A

when a D2 receptor is activated:

  1. K+ channel activity increases, voltage gated Ca channel activity decreases (membrane becomes hyperpolarized)
  2. increased amount and activity of DAT (membrane protein that sucks DA from the syn. cleft, reducing DA neurotransmission)
  3. PKA (protein kinase) activity decreases, decreasing phosphorylation of tyrosine hyroxylase (TH, enzyme important in DA synth)
56
Q

presynaptic D2 autoreceptor

A
  • act as a braking system; absence of these autoreceptors means no negative feedback to inhib DA release
  • D2 knockout mice are significantly more sensitive to cocaine
  • control the release of other NTs (ex. Glu)
57
Q

DA and expectation

A
  • response seems to be linked to magnitude of reward epected
  • train primates to recognize and associate symbols w certain doses of sucrose; measure electrophysiol. when symbol presented w/o expected reward/stim
  • as animal anticipates higher doses, firing r8 of the neuron being measured also increases
  • aversive effect if dose lower than expected is given, if larger does given effect is much more rewarding
  • the same dose can be rewarding if largest that the animal could reasonably expect, OR punishing if the smallest of expectable doses)
58
Q

Glu

A
  • linked to neuroplasticity, overlearning, relapse
  • changes in signaling may ‘lock-in’ certain drug-related behaviours
  • released fr presyn terminals (phasic/acute) and glial cells (tonic/baseline/long-lasting; produced by cystine-glu exchangers which suck up one cross-linked cystine and spit out one Glu)
  • presyn metabotropic glu receptors (mGluRs) activated by glial cell Glu release control their own neuron’s synaptic Glu release
59
Q

Glu and chronic drug use

A

chronic drug use can reduce tonic Glu release by:

  • inhibiting cys-glu exchanger (which is resonsible for ~60% of all glial Glu release); in turn, activation of presyn Glu autoreceptors drecreases
  • seems to cause more synaptic glu release during cue-, stress-, drug-induced reinstatement, esp in PFC
  • excess Glu induces neuroplasticity (structure/function of neurons change due to changes in gene expression), impairs communication btw PFC and nucleus accumbens
60
Q

ERK (extracellular signal-related kinase) pathway

A
  • activated only when DA and Glu are released simultaneously on a single neuron, acting on both D1 and NMDA receptors
    1. activation of D1 leads to increased cAMP production, as well as stim of Glu receptor function, which leads to increased influx of Ca
    2. a number of proteins in a pathway are affected, ultimately leading to phosphorylation of ERK
    3. ERK can then get into the nucleus and affect gene transcription and neuronal shape
  • can lead to changes in neuronal structure, proliferation
61
Q

Neuroplasticity

A
  • brain’s ability to reorganize and restructure itself
  • can include formation and death of neurons, formation or loss of and strengthening or weakening of neuronal/synaptic connections (pruning)
62
Q

commonalities of neuroplasticity in addiction

A

brain undergoes significant neuroplasticity, regardless of drug type, seen in chronic exposure and even single dose (though the more a drug is taken, the less reversible/transient the changes)

  • changes in neuronal structure, growth factors, and proteins that alter gene expression
  • drug induce decreased neurogenesis, which is linked to mem issues in animal models
63
Q

dendritic spines

A
  • small extensions that cover dendritic arms (in MSNs, VTA, hippo, etc)
  • shape and density change in response to various stim (stress, learning, drug)
  • those in the NAc make contact with other neurons
  • lots of Glu receptors on the bulb to respond to excitatory releases from PFC (also hippo, amyg)
64
Q

dendritic spine skeletons

A
  • dendrite arm made of actin
  • actin in the spine head is more branched to allow for fluidity (acting rearrangement necessary for shape/density change, which is triggered by Ca flowing thr the activated Glu receptors at the tip of the projections)
  • drugs seem to trigger modulations of the genes that code this cytoskeleton
65
Q

changes in neuronal structure due to stimulants

A
  • density and often size of dendritic spines increases

- the number of dendrites in the NAc also tends to increase

66
Q

changes in neuronal structure due to opiates

A
  • density and size of dendrites seems to decrease
  • the size of the VTA cell body is slightly decreased
  • unclear what effect it has on the dendritic spines
67
Q

neuronal changes from a single exposure to cocaine

A
  • single dose of cocaine causes a much greater spike in AMPA activity (a Glu receptor), shown in increase of AMPA/NMDA ratio which can last 5-10 days (LTP, long-term potentiation)
  • suggests greater influx of Ca, which can increase density of spines and allow greater potential for excitatory input from other brain regions
  • only see increase in dendritic spines and AMPA/NMDA ratio of Type I DA neurons in the VTA of rats (no stat. sig. change in type II DA releasing neurons)
68
Q

drug taking cues and spine changes

A
  • rats trained to press a lever for cocaine, paired to a light flashing; dendritic spine head diameter increased while learning
  • behaviour extinguished, spine head diameter returns to normal
  • start pairing random level presses with the light again to trigger reinstatement
  • cue alone enough to trigger shape/size change (AMPA/NMDA ratio and diameter rapidly increase, w/in 15 min, meaning the new Glu receptors must be pre-made, ready to be inserted)
  • change seems to be mediated by Glu released on these dendrites (lesioning Glu projections fr PFC to NAc prevents effect)
69
Q

BDNF Pathway

A

-BDNF (brain-derived neurotrophic factor) production is stimulated by Ca influx, which increases its gene transcription
-BDNF stimulates ERK pathway, allowing it to get into the nucleus and stimulate genes (some of which code for cytoskeletal proteins involved in spine formation)
NOTE: stimulants increase BDNF levels (more spines, increase cell body size), which opiates reduce BDNF levels (fewer spines, less AMPA Glu receptors)

70
Q

correlates of neurogenesis

A

inhibition:

  • corticosteroids
  • anxiety
  • depression
  • addiction

stimulation:

  • enriched environment
  • physical exercise
  • antidepressants
  • electroconvulsive therapy
  • new growth seems linked to healthy brains
  • new neurons in hippo seem essentially for distinguishing whether cues signal pleasant or unpleasant experiences
71
Q

areas of neurogenesis

A

3 main areas in the adult brain:

  • subventricular zone (thin layer of striatal tissue that lines the lateral ventricle)
  • olfactory bulb
  • subgranular layer of cells in the hippocampal dentate gyrus (only region that shows altered neurogenesis in response to drugs)
72
Q

How do we measure neurogenesis?

A
  • introduce brdU (compound that mimics thymidine, will be heavily incorporated into new DNA)
  • brdU is similar enough to be incorporated into the DNA, but distinct enough to raise an antibody that will selectively target it
  • visualizing thin slices of hippo. tells us that new neurons are formed in the subgranular zone (SGZ), migrate to granular cell layer (GCL) where they mature and establish connections
73
Q

experiment: chronic cocaine use and neurogenesis

A
  • significant decrease in brdU incorporation due to decreased proliferation
  • similar results seen in single exposure to cocaine
74
Q

experiment: binge ecstasy and neurogenesis

A

(ecstasy=MDMA, usually consumed in short-term, heavy dosing)

-didn’t directly decrease neurogenesis, but is toxic enough to kill off vulnerable new neurons, decreasing survival rate

75
Q

other drugs and neurogenesis

A

methamphetamine: impairs new cell proliferation and survival
nicotine: impairs neurogenesis, certain types of mem
chronic morphine: also decreases neurogenesis (so it’s likely not an external side-effect stimulant users experience, such as the lack of sleep)

76
Q

experimentally inhibiting neurogenesis

A
  • the irradiated (no neurogen) animals were more likely to initially self-administer (higher freq of use), take higher doses and work harder for cocaine (suggesting the drug must be more rewarding for them than for he control animals, and that they were more vulnerable to addiction)
  • it’s also harder to extinguish behaviours in the irradiated mice, reinforcing the belief that addiction is a learning problem)
77
Q

role of HC neurogenesis in addiction/dependence

A
  • hippo crucial for learning and mem, esp contextual (associating places with events)
  • dysfunction may cause deficits in mem processing of drug-associated cues/context, enhance drug-reinforcement learning
  • lack of new HC neurons results in excess Glu release fr HC to PFC and NAc neurons in presence of drugs/cues
  • > excess Glu release at:-
  • PFC correlates w loss of neuronal mass, dysfunction, may lead to poor decision making
  • NAc may lead to excessive stim and gen dysfunction
78
Q

possible mechanisms for impaired neurogenesis

A
  • drugs that activate DA receptors present in hippo can inhibit neurogen
  • some drugs cause oxidative stress (produce damaging O-containing products) that damage mito in devel. neurons
  • some addictive drugs influence levels of growth factors (brain-derived neurotrophic factor, BDNF; vascular endothelial growth factor, VEGF)
79
Q

cannabidiol and THC

A
  • component of cannabis plants (not major active ingredient THC)
  • appears to increase adult neurogen by increasing cell survival and maturation; being explored as neuroprotective agent
  • dentate gyrus contains only cannabinoid type 1 (CB1) receptors, to which cannabidiol does not bind (?)
  • THC has no direct effect on neurogen, but may decrease learning by affecting other pathways
80
Q

relative concentrations of caffeine in drinks

A

highest: coffee
runner up: red bull (~1/2 of coffee)
medium: soda (~1/3), tea (~1/10)
lowest: chocolate milk (<1%)

81
Q

caffeine

A
  • a methylxanthine
  • world’s most consumed behaviourally active substance (maj sources include tea, coffee, choc, soda, E drinks, OTC drugs, etc)
  • similar but milder effects as classic pyschostims (cocaine, amphetamines): motor activation, arousal, increased conc and wakefulness
  • seems to potentiate DA system (in animal models, boosts DA release in mesocorticolim path)
82
Q

methylxanthines

A
  • include caffeine (coffee), theophylline (tea), theobromine (chocolate)
  • have similar structure to adenine, so can mimic effects of adenosine (a nat. occurring neural modulator)
83
Q

other important components of coffee

A

chlorogenic acids: fam of compound thought to boost liver’s abil. to metabolize/detoxify var. chemicals by inducing production of phase II enzymes (eg. glutathione S-transferase)

  • dihydrocaffeic acid: linked to anti-inflam. effects, improved vasc. health due to increased nitric oxide production (a short-lasting signal molecule important in blood vessel relaxation, which lowers BP)
  • kahweol, cafestol: diterpenes; induce prod. of phase II detoxifying enzymes, induce var. genes that increase resistance to oxidative stress (damage fr compounds w reactive O’s) BUT also as’d w cardiovasc. risk as they elevate cholsterol
84
Q

guaranine and meteine

A
  • “organic” alternatives to caffeine; chemically identical, but named differently because they come from different sources (yerba mate and guarana plants as opposed to coffee beans)
  • health canada has almost on the content of these in products, which companies exploit
85
Q

general physiological effects of caffeine

A
  • increased NT release, include noradrenaline (alertness), Glu (keeps brain active), DA (mood elevation)
  • BP: acts locally (dilates blood vessels) and centrally (constriction); high BP less likely in regular drinkers, but sometimes see acute BP and heart r8 increase in the coffee-naive
  • diuretic: in doses >=300 mg, can cause vasodilation in kidneys (the more blood flows to the kidney, the more stuff (including water) they can pull out), weakens bladder muscles, inhibits kidney resorption of water and sodium
86
Q

caffeine as a cognitive enhancer?

A
  • evidence leans to pos, effect on mem and learning (increases arousal and helps u focus more effectively)
  • hard to study behaviourally as mem and focus are so intertwined, so instead study neuronal lvl
  • acute caffeine exposure increases hippo. lvls of BDNF and its receptor TrkB by blocking adenosine from binding to its A1 receptor
  • in a study, participants were asked to memorize a number of objects and tested on them a day later; those given caffeine right after the memorization had better recall, but those given caffeine right before the test showed no change (suggests caffeine can improve mem consolidation but not retrieval)
87
Q

caffeine and the brain

A
  • antagonist at adenosine receptors (blocks adenosine from binding and acting)
  • > adenosine is a neromodulator for the release of NT via presyn receptors
  • while the major adenosine receptors are A1, A2A, A2B and A3, the caffeine effect seems most prominent with A1 and A2A
88
Q

A1 (adenosine) receptors

A
  • G protein coupled
  • pre and post syn
  • distributed thr/out brain, in reward pathway, many in hippo (where BDNF is important)
  • more common than A2A
  • activation inhibits adenylate cyclase (which produces cAMP when activated)
  • activation of A1R inhibits NT release

->in presence of caffeine, see a relative INCREASE in NT release (opp effect of activating A1R)

89
Q

A2A receptors

A
  • g protein coupled
  • pre and post syn
  • found mostly in DA rich brain regions and olfactory bulb, on GABA releasing neurons
  • stimulates adenylate cyclase to increase cAMP production
  • activation promotes NT release
  • activation

->in presence of caffeine see relative DECREASE in NT release (opp effect of activating A2AR)

90
Q

The complicated DA and adenosine receptor relationship

A
  • A receptors have been found to physically pair up with DA receptors to form complexes such that each partner in the pair has an opposite effect on cAMP (1 x A1 w 1 x D1; 2 x A2A w 2 x D2)
  • A1 and A2A have also been found to form 1:1 complexes
91
Q

caffeine and sleep

A

-for most non-addicted ppl, coffee inhib. abil. to sleep
mech:
-thought that adensonine mediates sleep/wakefulness; extracellular conc builds up during wake (possibly fr ATP metab in neurons) until a point is reached that triggers sleep
-this adenosine would normally bind to A2A receptors in the hypothal. to trigger GABA release, which inhibits arousal systems
->in presence of caffeine, adenosine is prevented fr binding A2A; the process is disrupted, GABA release is prevented and sleep is inhibited
-in animal models, the extracell. lvl of adenosine decreases markedly once the animal falls asleep

92
Q

overuse of caffeine (targets of high doses)

A
  • inhibits phosphdiesterase (PDE, enzyme which metabolizes cAMP); the high cAMP lvls result in relaxation of smooth muscle (vasodilation) and increased contraction of the heart muscle (dsyrhythmia, etc)
  • inhibits GABA-A receptors which can lead to seizure-like symptoms
  • increases Ca channel activation, which leads to influx of Ca thought to increase work capacity of muscle
  • dose response curves show that these effects only really occur at toxic doses though; tho normal consumption may see slight inhib. effects on PDE
  • at 1 cup of coffee, ~20% of receptors already feeling mild effects
93
Q

caffeine metabolism

A

-liver enzyme CYP1A2 demethylates caffeine, leading to 2 primary metabolic products which are also methylxanthines:
parxanthine (84%)-increases lipolysis (lipid metab) which leads to more glycerol + free fatty acids in blood plasma (may increase muscle strength and athletic performance)
theobromine (12%)-dilates blood vessels, increases urine volume
theophylline (4%)-inhibits PDE, increasing cAMP, which leads to relaxation of smooth muscle in airways (expands diameter, once prescribed for asthma!)

94
Q

metal analysis

A

used to examine link btw consuming coffee and risk of developing certain diseases
-artifically boosts end numbers by combining several smaller (and consistent) studies and analyzing them as one
1=general risk of getting the disease (usually in the coffee-abstinent pop)
>1 means taking the substance increases the risk while <1 suggests taking the substance may be protective
-‘sweet spot’ for coffee-related benefits is 3-4 cups/day

95
Q

caffeine and risk of heart attack

A

there are two variants of the CYP1A2 gene (the caffeine metabolizing enzyme)

  • studies suggest that individuals with 2 copies of the fast-metabolizing variant (*1A) can see protective effects when consuming up to 3 cups/day
  • having one of two copies of the slow-metabolizing gene (*1F) actually shows increased cardiovasc. risk with increased dosage
96
Q

other caffeine-related health issues

A

-osteoporosis (caffeine increases urinary excretion or Ca, inhibits absorption from diet, leading to -ive effects on bone density)
-increased risk of panic attacks due to stimulant effect (mostly in those with a pecific mutation in the A2AR)
-

97
Q

caffeine and Parkinson’s

A
  • several studies show strong, dose-dependent, inverse correlation btw caffeine intake and PD
  • in animal models, it’s believed that caffeine can lessen symptoms of onset PD by blocking the A2 receptor, inhibiting GABA release which allows for more DA release, thus reducing the /appearance/ of symptoms
98
Q

nootropics

A
  • derived from greek noos (mind) and tropein (towards)
  • drugs thought to be cog. enhancers, including ritalin (ADHD med), and drugs used to treat diseases that cause severely impaired neuronal functioning
  • contradictory results on if they even work, and LT heath effects unclear
99
Q

memantine

A
  • a nootropic
  • low-affinity revesible NMDAR antagonist (binds v weakly to the receptor preventing low lvl Glu signaling which is thought to cause background “noise” which may lead to distraction, but when present in high lvls Glu can displace it, allowing for receptors to be activated when Glu released from nerve endings)
  • side effects: confusion, dizziness, headache, constipation, body aches
100
Q

Rivastigmine

A
  • nootropic
  • acetylcholinesterase inhibitor (class of compounds that make up some of the most deadly nerve agents)
  • clinically used as a cog. enhancer in neurdegenerative diseases where there’s typ. a loss of Ach-releasing neurons
  • side effects: diarrhea +other GI issues, confusion, dizziness, hallucinations, seizures, irregular heartbeat, severe nausea

PMCOL 305 (3 decks)

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