Addiction & Neurodegenerative Disorders

substance abuse disorders & causes

genetic predispositions from gene variants cause addiction to specific drug & can increase risk to developing addiction

• ex: genetic factors account for 50% of alcoholism

what explains the addiction risk of different drugs in reinforcement learning? (not related to genetic factors, think abt neural circuitry)

the relative speed by which dopamine is released/dopamine levels rise

• immediate reinforcement much more effective than delayed reinforcement

  • doesn’t explain alchohol bc alchohol addiction builds up over years

relationship between tolerance & withdrawal and addiciton

tolerance & withdrawal can be indicative of drug use but they aren’t required within addiction

• cocaine addiction doesn’t exhibit tolerance or withdrawal on addicts

tolerance & withdrawal

physical dependence on drug

tolerance: body becomes used to & needs bigger doses to feel effects of drug

withdrawal: you exhibit opposite side effects as drug’s initial symptoms, only occurs after tolerance builds

how does negative reinforcement relate to drug addiciton?

initially thought to fully explain why addicts keep using— they want to have the removal of aversive stimuli (withdrawal symptoms)

• doesn’t fully explain bc often addiction outlasts the withdrawal stage

comorbidity aspect of addiction & what explains it

ppl with schizophrenia & ADHD more likely to have addiction

• explanation: circuit dysregulations in PFC, basal ganglia, & dopamine signaling may be common factors in all these disorders

what is PFC used for in context of addiction

helps process context for priorities, addicts show deficits in tasks involving PFC

how neural circuitry works to promote drug use (basal ganglia & PFC)

basal ganglia strengthens habitual responses to drug use by deeming drugs the best option— reducing need for PFC (using higher-order thinking to halt decisions based on realistic priorities)

drugs & context-specificity

people who have never smoked on an airplane won’t feel cravings on airplane bc of context specificity for drug use

3 diff types of treatment for drug use

• blocking receptors (antagonists)

• maintenance approach

• brain stimulation approach

antagonists used for substance abuse treatment

narcan/naloxone: extremely rapid & short-lived opioid receptor antagonist that reverses effects of opiate overdose

naltrexone: high affinity (strong binding to receptor), slow onset, long-acting opioid receptor antagonist that helps reduce cravings for alcoholics/opiate addicts for daily use

• doesn’t actually work in practice, cravings for food, alcohol, other drugs also reduced

maintenance approach drugs

methadone: potent opiate agonist w/ slower onset & offset than heroine doses, substitute for heroin that allows ppl to live more functional lives

• works well when taken in approprite contexts (methadone clinics)

buprenorphine: high affinity, partial opioid reeptor agonist to treat opiate addiction, only half activates receptor so ppl never get too high

• partial— allows patients to take pills home, mixed w/ naloxone to eliminate euphoric rush

varenicline: partial agonist at nicotine receptors thats prescribed to treat nicotine addiction, elicits same dopamine release that nicotine gives

brain stimulation approach treatment for addiciton

TMS & deep brain stimulation

neurodegenerative disorder in order of commonality

alzheimer’s, parkinson’s, MS, huntington

MS: what kind of disorder & causes & effects (within neural circuitry— not general yet)

autoimmune disorder

caused by:

• immune cells enter brain & attack oligodendrocytes, thinking they’re problematic

  • causes demyelination & leaves behind hard patches (scars) called sclerotic plaques

  • neurons aren’t attacked but APs can’t successfully propagate down demyelinated axons

symptoms of MS, when do they start?

late 20’s

• blurred vision, tingling, numbness, pain, dizziness, muscle weaknesses/spasms

usual circuit/process of symptoms for MS

remitting-relapsing MS: symptoms tend to flare up & then recede for varying amounts of time

progressive MS: follows ^^ stage, progressive increase of symptoms

general causes of MS

genetic susceptibility & viral infections

• genetic predisposition causes abnormal immune response to viral infection

• some correlation with Epstein-Barr infection (all patients w/ infection also had MS later)

drug treatment for MS

• monoclonal antibodies inject into immune system to attack immune cells that are destroying myelin

• other cells limit movement of immune cells into CNS or make immune cells prioritize other issues

explain how neurodegenerative diseases come to be

come from buildup of one or more misfolded proteins

if rate that proteosome recycles misfolded proteins gets exceeded by rate new misfolded proteins are being formed— issue starts

• clumps form when proteins misfold & now they are harder to break down

  • recycling process more difficult, new misfolded proteins still forming UH OH — problem grows quickly once clumps form

• large clumps break into smaller pieces → “seed clumps'“

  • can spread from cell to cell via active transport or cell death

ubiquitin protein

small molecular tag that gets attached to misfolded protein to alert cell to break it down

proteosome

breaks down misfolded proteins

Tau & Alpha-synuclein proteins

highly susceptible to misfolding, therefore → can misfold in many diff ways

alzheimer’s disorder

most common neurogenerative disorder, accounts for half of all cases of dementia

dementia

progressive impairments to memory, thinking, behavior due to neurological issue (neurodegenerative disease, repeated head injuries, strokes)

strongest genetic risk factor for Alzheimer’s

APOE 4 gene, harmful gene that slows clearance of B amplyoid (plaques) from brain & promotes aggregation into plaques

Parkinson’s disease symptoms

muscle rigidity, slowness of movement, tremors

at what age does parkinson’s usually occur

after 60

parkinson’s neural causes

death of dopamine neurons, where we usually find clumps of misfolded alpha-synuclein proteins (Lewy Bodies)

toxic gain of function vs loss of function in parkinson’s

toxic gain of function: dom gene mutation produces protein w/ toxic effects

• ex: for alpha-synuclein protein gene mutation, just one dom allele will lead to toxic gain of protein that increases likelihoods of misfolding & clumps & neurodegeneration

loss of function: two copies of recessive gene mutation results in loss of function

• ex: for parkin protein gene mutation, two recessive alleles will lead to loss of parkin proteins ubiquitating needed cells & leads to destruction of cells as they clump more & more without being destroyed

protective factors against parkinson’s

protective factors: caffeine, nicotine, excercise consumption

treatment for parkinson’s

for the 1st 10 years of disease: daily administration of L-dopa (precursor for dopamine) reduces motor symptoms by elevating dop levels in basal ganglia

• when pharmalogical treatments no longer work:

  • deep brain stimulation of subthalamic nucelus (in basal ganglia) to slow down overactivity

direct dopamine receptor agonists may be prescribed too— have side effects

huntington’s disease cause

caused by single dom gene mutation

harmful gene variant that contains more than 35 CAG repeats (below 26 is normal), protein longer & more likely to misfold & form clumps → aggregate in other brain neurons, cause dysregulated brain network → cell death

how do repetitions of CAG genes affect proteins in Huntington’s disease

more repeats of CAG → more likely for proteins to clump → toxic protein created that kills brain cells 

when do symptoms for Huntington usually appear and what are they

30- 50 years

• opposite of Parkinson’s: lack of coordination, flinging around

Antisense therapy

repeatedly injecting antisense DNA into spinal chord

• this antisense DNA binds to complementary mRNA sequence, preventing mRNA from being translated into proteins so toxic protein isn’t created and cant KILL BRAIN CELLS

what would you see if you cut into brain of alzheimer’s patient’s brain?

clumps of misfolded tau proteins & b-amyloid proteins, indicative of severe neurodegeneration

whats another name for misfolded tau proteins

neurofibrillary tangles

name for B-amyloid protein clumps

amyloid plaques

how do B-amyloid proteins result in becoming misfolded/clumped?

B amyloid plaques come from larger protein called APP

• secretase enzymes cut APP into 3 fragments, B amyloid being the middle

  • if cut fragment too long: protein more prone to clumping, plaques form as they clump

how are people w/ extra copy of chromsome 21 more prone to early-onset Alzheimer’s (ppl w/ down syndrome)

the gene for APP protein resides on chromosome 21, if you have extra copy your chance that B amyloid fragment is longer is higher & more vulnerable to amyloid plaques

describe gene mutation in presenlin that increases early-onset alzheimer’s

mutation for gene for presenlin protein

• this protein is responsible for forming secratese enzyme, if there’s mutation it makes it more likely that cut will go wrong & amyloid plaques form

risk factors for Alzheimer’s

age, TBI’s, APOE 4 allele

medications for Alzheimer’s

anti-amyloid monoclonal antibodies: encourage immune system to degrade B-amyloid & subsequently gets rid of clumps